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the primary trial recorded many more seizures than the secondary trial, despite having less than one tenth the number of patients in its total cohort.
|
Adverse Events 1:
Seizure 1/38 (2.63%)
Adverse Events 1:
Total: 92/490 (18.78%)
Anaemia * 1/490 (0.20%)
Anaemia of malignant disease * 0/490 (0.00%)
Febrile neutropenia * 0/490 (0.00%)
Neutropenia * 0/490 (0.00%)
Thrombocytopenia * 4/490 (0.82%)
Angina pectoris * 0/490 (0.00%)
Atrial fibrillation * 1/490 (0.20%)
Cardiomyopathy * 1/490 (0.20%)
Coronary artery disease * 0/490 (0.00%)
Pericardial effusion * 0/490 (0.00%)
Adverse Events 2:
Total: 99/488 (20.29%)
Anaemia * 1/488 (0.20%)
Anaemia of malignant disease * 1/488 (0.20%)
Febrile neutropenia * 2/488 (0.41%)
Neutropenia * 1/488 (0.20%)
Thrombocytopenia * 1/488 (0.20%)
Angina pectoris * 1/488 (0.20%)
Atrial fibrillation * 0/488 (0.00%)
Cardiomyopathy * 0/488 (0.00%)
Coronary artery disease * 1/488 (0.20%)
Pericardial effusion * 2/488 (0.41%)
|
Contradiction
|
In both the secondary trial and the primary trial the test cohorts produced better results than the control groups.
|
Outcome Measurement:
Progression-free Survival (PFS)
PFS was defined as the interval from study entry until disease progression or death resulting from any cause, which ever occurred first. Progression is defined as a 20% increase in the sum of longest diameter of target lesions (per RECIST criteria).
Time frame: Interval from randomization until disease progression or death, whichever occurs first, assessed up to 5 years
Results 1:
Arm/Group Title: Arm I (Lapatinib)
Arm/Group Description: Patients receive 1500 mg lapatinib ditosylate PO QD on days 1-28 and fulvestrant IM on days 1 (500 mg) and 15 (250 mg) of course 1 and on day 1 (250 mg)of each subsequent course.
Overall Number of Participants Analyzed: 146
Median (95% Confidence Interval)
Unit of Measure: months 4.7 (3.7 to 5.7)
Results 2:
Arm/Group Title: Arm II (Placebo)
Arm/Group Description: Patients receive placebo PO QD on days 1-28 and fulvestrant IM on days 1 (500 mg) and 15 (250 mg) of course 1 and on day 1 (250 mg) of each subsequent course.
Overall Number of Participants Analyzed: 145
Median (95% Confidence Interval)
Unit of Measure: months 3.8 (3.8 to 5.6)
Outcome Measurement:
Number of Participants With Overall Response (OR), Defined as Those Participants Achieving Complete Response (CR) or Partial Response (PR), Assessed Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0 and Cutaneous Lesions
RECIST-based response assessment was done at Weeks (Wks) 4 and 8 and every 8 weeks thereafter. Cutaneous disease assessment was done at Wk 4 and every 4 weeks thereafter. OR was evaluated when the skin and RECIST assessments coincided. Per RECIST, CR is the disappearance of all target and non-target lesions; PR is at least a 30 percent (%) decrease in the sum of the longest diameter (LD) of target lesions, taking as a reference the baseline sum LD. Cutaneous disease contained non-measurable and measurable skin disease, which was assessed by skin assessment tools.
Time frame: Baseline until disease progression/recurrence was documented, assessed for up to 66 weeks
Results 1:
Arm/Group Title: Cohort 1: Lapatinib 1500 mg + Pazopanib Placebo
Arm/Group Description: Participants received oral lapatinib 1500 milligrams (mg) (6 x 250 mg tablets) in combination with placebo (matching to pazopanib; 2 tablets) once daily (QD).
Overall Number of Participants Analyzed: 38
Measure Type: Number
Unit of Measure: participants 11
Results 2:
Arm/Group Title: Cohort 1: Lapatinib 1500 mg + Pazopanib 800 mg
Arm/Group Description: Participants received oral lapatinib 1500 mg (6 x 250 mg tablets) in combination with pazopanib 800 mg (2 x 400 mg tablets) QD.
Overall Number of Participants Analyzed: 38
Measure Type: Number
Unit of Measure: participants 17
|
Entailment
|
The most common adverse event in both cohorts of the primary trial was Anaphylaxis, which affected more than 10 patients in total.
|
Adverse Events 1:
Total: 9/2788 (0.32%)
Anaphylaxis 5/2788 (0.18%)
Infections and infestations - Other, specify 2/2788 (0.07%)
Nervous system disorders - Other, specify 0/2788 (0.00%)
Respiratory, thoracic and mediastinal disorders - Other, specify 1/2788 (0.04%)
Thromboembolic event 1/2788 (0.04%)
Adverse Events 2:
Total: 8/2800 (0.29%)
Anaphylaxis 5/2800 (0.18%)
Infections and infestations - Other, specify 0/2800 (0.00%)
Nervous system disorders - Other, specify 1/2800 (0.04%)
Respiratory, thoracic and mediastinal disorders - Other, specify 1/2800 (0.04%)
Thromboembolic event 2/2800 (0.07%)
|
Contradiction
|
the secondary trial and the primary trial both accept patients with HER-2/neu-overexpressing adenocarcinoma of the breast.
|
Inclusion Criteria:
Histologically confirmed hormone receptor positive (HR+) [(estrogen receptor (ER+) and/or progesterone receptors(PgR+)] breast cancer according to immunohistochemistry (IHC)
Inclusion Criteria:
Patients with histologically confirmed HER-2/neu-overexpressing adenocarcinoma of the breast; this is defined as HER-2+ by immunohistochemistry (IHC) 3+ staining or Fluorescence In-Situ Hybridization (FISH). Prior adjuvant Trastuzumab therapy is permitted. Patients must not be eligible for therapy of known curative potential for metastatic breast cancer if it is identified during the course of the study.
|
Entailment
|
Patients with T1N2M0, T2N1M0, T3N1M1 and TxN1M0 tumors are eliglbe for the primary trial.
|
Inclusion Criteria:
Pathologic confirmation of metastatic disease in at least one regional lymph node. Regional lymph nodes are defined as the ipsilateral axillary lymph nodes, ipsilateral supraclavicular lymph nodes, and ipsilateral internal mammary lymph nodes. Thus, any T stage is allowed as long as the N stage is 1 and M stage is 0.
|
Contradiction
|
One of the patients in cohort 2 of the primary trial experienced neutropenia persisting for more than 7 days.
|
Results 1:
Arm/Group Title: E7389 With Weekly Trastuzumab
Arm/Group Description: Eribulin mesylate (E7389) was administered intravenously on Day 1 and Day 8 of each 3 week cycle. Trastuzumab was administered intravenously weekly, with an initial dose of 4 mg/kg followed by 2 mg/kg for the remaining doses.
Overall Number of Participants Analyzed: 6
Measure Type: Number
Unit of Measure: Participants 0
Results 2:
Arm/Group Title: E7389 With Tri-weekly Trastuzumab
Arm/Group Description: Eribulin mesylate (E7389) was administered intravenously on Day 1 and Day 8 of each 3 week cycle. Trastuzumab was administered intravenously tri-weekly, with an initial dose of 8 mg/kg followed by 6 mg/kg for the remaining doses.
Overall Number of Participants Analyzed: 6
Measure Type: Number
Unit of Measure: Participants 0
|
Contradiction
|
the primary trial and the secondary trial do not record any of the same adverse events.
|
Adverse Events 1:
Total: 3/24 (12.50%)
Disseminated intravascular coagulation 0/24 (0.00%)
Death NOS 0/24 (0.00%)
Edema limbs 0/24 (0.00%)
Fatigue 0/24 (0.00%)
Hepatic failure 1/24 (4.17%)
Alanine aminotransferase increased 1/24 (4.17%)
Aspartate aminotransferase increased 1/24 (4.17%)
Blood bilirubin increased 0/24 (0.00%)
Ejection fraction decreased 1/24 (4.17%)
Adverse Events 2:
Total: 9/22 (40.91%)
Disseminated intravascular coagulation 1/22 (4.55%)
Death NOS 1/22 (4.55%)
Edema limbs 1/22 (4.55%)
Fatigue 1/22 (4.55%)
Hepatic failure 0/22 (0.00%)
Alanine aminotransferase increased 0/22 (0.00%)
Aspartate aminotransferase increased 1/22 (4.55%)
Blood bilirubin increased 1/22 (4.55%)
Ejection fraction decreased 1/22 (4.55%)
Adverse Events 1:
Total: 5/33 (15.15%)
Left Ventricular Thrombus * 1/33 (3.03%)
Nausea * 1/33 (3.03%)
Acute Cholecystitis * 1/33 (3.03%)
Renal Failure * 1/33 (3.03%)
Pneumonia * 1/33 (3.03%)
|
Entailment
|
patients with Multi-focal breast cancer cannot be accepted for the primary trial.
|
Inclusion Criteria:
Unifocal breast cancer recurrence
|
Entailment
|
the primary trial and the secondary trial have a different number of cohorts.
|
INTERVENTION 1:
Multicomponent Intervention
1.) A one-page paper-pencil agenda setting checklist completed immediately before a regularly scheduled medical oncology visit to elicit and align patient and companion perspectives regarding issues to discuss with the provider, and to stimulate discussion about the role of the companion in the visit, 2.) facilitated registration for the patient portal (for patient and family member, as desired by the patient), and 3.) education (as relevant) on access to doctor's electronic visit notes.
INTERVENTION 2:
Usual Care
Care as usual with the medical oncologist.
INTERVENTION 1:
Palbociclib+Letrozole India Cohort
Participants received Palbociclib orally once a day at 125 mg for 21 days followed by 7 days off treatment ofr each 28-day cycle. Participants received Letrozole orally at 2.5 mg once daily as continuous daily dosing schedule according to product labeling and in compliance with its local prescribing information
INTERVENTION 2:
Palbociclib+Letrozole Australia Cohort
Participants received Palbociclib orally once a day at 125 mg for 21 days followed by 7 days off treatment for each 28-day cycle. Participants received Letrozole orally at 2.5 mg once daily as continuous daily dosing schedule according to product labeling and in compliance with its local prescribing information
|
Contradiction
|
Patients with invasive breast cancer with a diameter of more than 70mm are included in the primary trial.
|
Ipsilateral biopsy-proven invasive breast cancer <5 cm in maximal dimension by Ultrasound or Mammography.
|
Contradiction
|
As the primary trial and the secondary trial use very similar outcome metrics, we can easily compare and contrast across their results.
|
Outcome Measurement:
Level of EGFR Expression
Estimated at the end of the trial Immunoreactivity will be evaluated qualitatively with regard to intensity as follows: Measured on a scale, ranging from 0-3+ 0=negative (no immunoreactivity)
1+ - 3+ = positive:
Outcome Measurement:
Systemic Tumor Response Rates (Complete Response+Partial Response)
The systemic tumor response refers to the response at the time of best overall response. The response criteria are specially adapted from Response Evaluation Criteria in Solid Tumor for Immunotherapies (Wolchok, et al., 2009).
Time frame: 9 weeks from the start of the treatment of RT
|
Contradiction
|
the primary trial reported more than 10 times the number of patients experiencing adverse events as the secondary trial .
|
Adverse Events 1:
Total: 28/36 (77.78%)
Lymphocytopenia 210/36 (27.78%)
Neutropenia 29/36 (25.00%)
Anemia 26/36 (16.67%)
Thrombocytopenia 24/36 (11.11%)
Hyperglycemia 27/36 (19.44%)
Nausea 213/36 (36.11%)
Diarrhea 211/36 (30.56%)
Fatigue 215/36 (41.67%)
Flu-like symptoms 26/36 (16.67%)
Hot Flashes 25/36 (13.89%)
AST/ALT elevation 211/36 (30.56%)
Arthralgia 24/36 (11.11%)
Adverse Events 1:
Total: 1/22 (4.55%)
Blood bilirubin increased 1/22 (4.55%)
Alkaline phosphatase increased 1/22 (4.55%)
|
Contradiction
|
Patients that are fully active and able to carry on all pre-disease performance without restriction are excluded from the primary trial.
|
Inclusion Criteria:
Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
|
Contradiction
|
the primary trial measured the Number of Participants With Disease Progression (PD) or Death, to evaluate the performance of its interventions.
|
Outcome Measurement:
Tumor Response
Best response recorded from the start of treatment until disease progression/recurrence using Response Evaluation Criteria In Solid Tumors (RECIST) criteria that defines when participants improve ("respond"), stay the same ("stable"), or worsen ("progression") during treatment.
Time frame: baseline to measured progressive disease
|
Contradiction
|
There were no cases of cardiac tamponade in the primary trial or the secondary trial.
|
Adverse Events 1:
Total: 0/3 (0.00%)
cardiac tamponade 0/3 (0.00%)
congestive heart failure 0/3 (0.00%)
pulmonary emobolism 0/3 (0.00%)
Adverse Events 2:
Total: 2/23 (8.70%)
cardiac tamponade 0/23 (0.00%)
congestive heart failure 1/23 (4.35%)
pulmonary emobolism 1/23 (4.35%)
Adverse Events 1:
Total: 12/32 (37.50%)
Anaemia 0/32 (0.00%)
Neutropenia 1/32 (3.13%)
Thrombocytopenia 4/32 (12.50%)
Atrial fibrillation 1/32 (3.13%)
Cardiac failure congestive 1/32 (3.13%)
Myocardial ischaemia 1/32 (3.13%)
Abdominal discomfort 0/32 (0.00%)
Ascites 1/32 (3.13%)
Constipation 0/32 (0.00%)
Rectal haemorrhage 1/32 (3.13%)
Vomiting 1/32 (3.13%)
Fatigue 1/32 (3.13%)
Adverse Events 2:
Total: 8/20 (40.00%)
Anaemia 1/20 (5.00%)
Neutropenia 0/20 (0.00%)
Thrombocytopenia 1/20 (5.00%)
Atrial fibrillation 0/20 (0.00%)
Cardiac failure congestive 0/20 (0.00%)
Myocardial ischaemia 0/20 (0.00%)
Abdominal discomfort 1/20 (5.00%)
Ascites 0/20 (0.00%)
Constipation 2/20 (10.00%)
Rectal haemorrhage 0/20 (0.00%)
Vomiting 0/20 (0.00%)
Fatigue 0/20 (0.00%)
|
Entailment
|
Unlike the secondary trial, the primary trial does not specify a specific dosage or frequency for its intervention.
|
INTERVENTION 1:
AB-101
Apply to both nipple/areola regions approximately 1 hour prior to sexual activity
AB-101: Apply approximately 1 hour prior to sexual activity
INTERVENTION 2:
Placebo
Apply to both nipple/areola regions approximately 1 hour prior to sexual activity
Placebo: Apply approximately 1 hour prior to sexual activity
INTERVENTION 1:
Letrozole + MRI
Protocol Therapy will consist of 6 months of letrozole, administered orally at a dose of 2.5 mg/day. Patients will have a bilateral MRI for disease evaluation at months 3 and 6.
|
Entailment
|
Across both cohorts of the primary trial a total of two patients had low levels of oxygen in their body tissues.
|
Adverse Events 1:
Total: 5/11 (45.45%)
Diabetes insipidus [1]1/11 (9.09%)
Nausea 0/11 (0.00%)
Ileus 1/11 (9.09%)
Dehydration 1/11 (9.09%)
Vomiting 0/11 (0.00%)
Pain NOS [2]2/11 (18.18%)
Pain - abdomen 0/11 (0.00%)
Fracture [3]0/11 (0.00%)
Progressive Disease 1/11 (9.09%)
CNS Ischemia 1/11 (9.09%)
Respiratory Failure 0/11 (0.00%)
Hypoxia 1/11 (9.09%)
Adverse Events 2:
Total: 8/21 (38.10%)
Diabetes insipidus [1]0/21 (0.00%)
Nausea 1/21 (4.76%)
Ileus 0/21 (0.00%)
Dehydration 1/21 (4.76%)
Vomiting 1/21 (4.76%)
Pain NOS [2]0/21 (0.00%)
Pain - abdomen 1/21 (4.76%)
Fracture [3]1/21 (4.76%)
Progressive Disease 1/21 (4.76%)
CNS Ischemia 1/21 (4.76%)
Respiratory Failure 1/21 (4.76%)
Hypoxia 1/21 (4.76%)
|
Entailment
|
less than 1% of either cohort of the primary trial was effect by either Pancytopenia or Coagulopathy.
|
Adverse Events 1:
Pancytopenia *2/425 (0.47%)
Coagulopathy *1/425 (0.24%)
Adverse Events 2:
Pancytopenia *0/406 (0.00%)
Coagulopathy *0/406 (0.00%)
|
Entailment
|
The the primary trial placebo group had a over 10% higher mean retention than the donepezil hydrochloride PO QD group.
|
Outcome Measurement:
Retention
Retention is the percentage of participants who stay in the study for 24 weeks.
Time frame: 24 Weeks
Results 1:
Arm/Group Title: Arm I
Arm/Group Description: Patients receive donepezil hydrochloride PO QD.
donepezil hydrochloride: Given PO
Overall Number of Participants Analyzed: 31
Mean (Standard Error)
Unit of Measure: percentage of participants 71.0 (8.3)
Results 2:
Arm/Group Title: Arm II
Arm/Group Description: Patients receive placebo PO QD.
Placebo: Given PO
Overall Number of Participants Analyzed: 31
Mean (Standard Error)
Unit of Measure: percentage of participants 80.7 (7.2)
|
Contradiction
|
the primary trial and the secondary trial both investigate Pharmacokinetics Itraconazole 500mg QD.
|
Outcome Measurement:
Pharmacokinetics (PK) of Oral Itraconazole
To determine the pharmacokinetics (PK) of oral itraconazole in patients with MBC by measuring mean trough plasma levels at steady state at weeks 2 and 4.
Time frame: pre-dose at Weeks 2 and 4
Results 1:
Arm/Group Title: Itraconazole
Arm/Group Description: oral itraconazole 200mg a day until disease progression or unacceptable toxicities.
Overall Number of Participants Analyzed: 12
Mean (Standard Deviation)
Unit of Measure: ng/mL Week 2 Intraconazole Concentration: 230.7 (216.8)
Week 4 Intraconazole Concentration: 305.8 (334.8)
Week 2 6-OH Itraconazole Concentration: 454.8 (429.3)
Week 4 6-OH Itraconazole Concentration: 501.6 (502.6)
Outcome Measurement:
Dose Escalation: To Evaluate the Safety and Tolerability of Escalating Doses of the MM-121 Plus Paclitaxel Combination Via Reporting of Dose-limiting Toxicity (DLT)
To establish the safety of escalating doses of MM-121 in combination with paclitaxel in order to determine the recommended phase 2 dose. Dose-escalation conducted using standard 3+3 model to determine maximum tolerated dose. Reports of Dose-Limiting Toxicities (DLTs) were assessed to determine the MTD.
Time frame: From date of first dose to 30 days after termination, the longest 163 weeks
|
Contradiction
|
Participants with HER2- primary breast tumors, confirmed by fluorescence in-situ hybridization are eligible for the secondary trial and the primary trial.
|
Inclusion Criteria:
Participant has histologically or cytologically confirmed adenocarcinoma of the breast that is now metastatic or locally-recurrent and inoperable with curative intent. Every effort should be made to make paraffin-embedded tissue or slides from the diagnostic biopsy or surgical specimen available for confirmation of diagnosis
Participants' primary and/or metastatic tumor is human epidermal growth factor receptor 2 (HER2)-negative by fluorescence in-situ hybridization (FISH) or chromogenic in-situ hybridization (CISH) or 0, 1+ overexpression by immunohistochemistry (IHC)
DISEASE CHARACTERISTICS:
Histologically or cytologically confirmed diagnosis of adenocarcinoma of the breast
Hormone receptor status:
Not specified
|
Entailment
|
At least one patient in the primary trial suffered from Gastroesophageal reflux disease.
|
Adverse Events 1:
Total: 8/24 (33.33%)
Restrictive Cardiomyopathy * 21/24 (4.17%)
Palpitations * 21/24 (4.17%)
GERD * 21/24 (4.17%)
Fever * 21/24 (4.17%)
Sepsis * 1/24 (4.17%)
Urinary Tract Infection * 21/24 (4.17%)
Influenza A * 21/24 (4.17%)
Dehydration * 21/24 (4.17%)
Hyponatremia * 21/24 (4.17%)
Worsening of Hypercalcemia * 21/24 (4.17%)
Bone Pain * 21/24 (4.17%)
|
Entailment
|
Sam has recently received a liver transplant, he is not eligible for the primary trial, but is eligible for the secondary trial.
|
Exclusion criteria:
Patients with organ transplants.
Inclusion Criteria:
Estrogen receptor or progesterone receptor positive breast cancer
Premenopausal with regular menstrual cycles
Exclusion Criteria:
Current oral contraceptives
|
Entailment
|
all subjects in the primary trial must undergo a minor surgery.
|
INTERVENTION 1:
AlloDerm RTU
Participants within this arm will have the acellular dermal matrix AlloDerm RTU implanted at the time of tissue expander placement.
AlloDerm RTU
INTERVENTION 2:
SurgiMend PRS
Participants within this arm will have the acellular dermal matrix SurgiMend PRS implanted at the time of tissue expander placement.
SurgiMend PRS
|
Entailment
|
cohorts 1 and 2 of the primary trial recorded a different number of patients that suffered from Congestive Heart Failure.
|
Outcome Measurement:
Congestive Heart Failure Rate
Clinical congestive heart failure includes patients with symptomatic decline in LVEF to at or below the lower limit of normal (LLN), or symptomatic diastolic dysfunction. 223 treated patients were included in the analysis.
Time frame: assessed on day 1 of cycles 5, 9, 17 and 25, and at end of treatment, then every 3 months for <2 years and every 6 months for 2-3 years from study entry
Results 1:
Arm/Group Title: Arm A (ddBAC > BT > B)
Arm/Group Description: Dose dense bevacizumab, cyclophosphamide and doxorubicin, followed by paclitaxel and bevacizumab, followed by bevacizumab
Overall Number of Participants Analyzed: 103
Measure Type: Number
Unit of Measure: percentage of participants 2.9 (0.6 to 8.3)
Results 2:
Arm/Group Title: Arm B (ddAC > BT > B)
Arm/Group Description: Dose dense doxorubicin and cyclophosphamide, followed by paclitaxel and bevacizumab, followed by bevacizumab
Overall Number of Participants Analyzed: 120
Measure Type: Number
Unit of Measure: percentage of participants 2.5 (0.5 to 7.1)
|
Contradiction
|
There were 0 observed cases of Tibia or Fibula fractures in the primary trial.
|
Adverse Events 1:
Total: 16/149 (10.74%)
Anaemia 0/149 (0.00%)
Febrile neutropenia 7/149 (4.70%)
Neutropenia 1/149 (0.67%)
Pancytopenia 1/149 (0.67%)
Atrial fibrillation 2/149 (1.34%)
Cardiac failure congestive 0/149 (0.00%)
Abdominal pain 0/149 (0.00%)
Diarrhoea 2/149 (1.34%)
Dyspepsia 0/149 (0.00%)
Gastritis haemorrhagic 0/149 (0.00%)
Nausea 2/149 (1.34%)
Adverse Events 2:
Total: 20/151 (13.25%)
Anaemia 1/151 (0.66%)
Febrile neutropenia 4/151 (2.65%)
Neutropenia 2/151 (1.32%)
Pancytopenia 0/151 (0.00%)
Atrial fibrillation 0/151 (0.00%)
Cardiac failure congestive 1/151 (0.66%)
Abdominal pain 1/151 (0.66%)
Diarrhoea 3/151 (1.99%)
Dyspepsia 1/151 (0.66%)
Gastritis haemorrhagic 1/151 (0.66%)
Nausea 1/151 (0.66%)
|
Entailment
|
Cohort 1 of the primary trial recorded the same number of instances of Neutropenic fever as Cohort 1 of the secondary trial.
|
Adverse Events 1:
Febrile neutropenia 3/364 (0.82%)
Adverse Events 1:
Febrile Neutropenia *0/25 (0.00%)
|
Contradiction
|
laboratory biomarker analysis is used in the secondary trial and the primary trial.
|
INTERVENTION 1:
Supportive Care (Dakin's Solution, Radiation Therapy)
Patients apply Dakin's solution topically daily over 10 minutes within 60 minutes of radiation therapy for up to 6 weeks.
Dakin's solution: Applied topically
radiation therapy: Undergo radiation therapy
questionnaire administration: Ancillary studies
laboratory biomarker analysis: Optional correlative studies
INTERVENTION 1:
Treatment (Neoadjuvant Therapy, Adjuvant Therapy)
See Detailed Description.
doxorubicin hydrochloride: Given IV
cyclophosphamide: Given PO
paclitaxel: Given IV
filgrastim: Given SC
capecitabine: Given PO
methotrexate: Given IV
vinorelbine tartrate: Given IV
needle biopsy: Correlative studies
therapeutic conventional surgery: Undergo definitive breast surgery
immunohistochemistry staining method: Correlative studies
trastuzumab: Given IV
tamoxifen citrate: Given PO
letrozole: Given PO
laboratory biomarker analysis: Correlative studies
|
Entailment
|
the primary trial investigates a novel chemotherapy treatment, whereas the secondary trial is testing a type of psychological therapy.
|
INTERVENTION 1:
Trastuzumab/Ixabepilone/Carboplatin
During the induction phase, patients were treated with Ixabepilone (BMS-247550) 15mg/m2 intravenously (IV) followed by carboplatin (AUC=2 IV) on days 1, 8 and 15 of a 28-day cycle for a maximum of 6 cycles. Trastuzumab was administered weekly (4mg/kg loading dose then 2mg/kg IV) starting on day 1. Routine premedication included H1 blocker (diphenhydramine 50 mg orally (PO) or IV), H2 blocker (ranitidine 150 mg PO or 50 mg IV or another equivalent H2 blocker), and at least a 5-HT3 antagonist and dexamethasone.
After completion of 24 weekly trastuzumab doses (induction therapy), trastuzumab were given at a dose of 6 mg/kg IV every 3 weeks (maintenance therapy) beginning one week after the 24th weekly dose. Trastuzumab were repeated every 21 days until disease progression or prohibitive toxicity.
INTERVENTION 1:
Stage 1 Clinical Management
The group will receive clinical management treatment only each session.
Clinical Management: Clinical management is a clear contrast method of psychological therapy, which is a half-structured interview and lasting for 20-25 minutes each session. Clinical management will be assigned to both experimental group and controlled group in the first stage of intervention.
Following are major elements:
Talk to the subjects to find their main problems; introduce knowledge and medication knowledge about cancer and depression; subjects reporting use of drugs for cancer and depression and a variety of signs and symptoms of the reaction. Encourage patients to adhere to drug treatment and to comply with this research program; The operation of CBT and clinical management should be conducted by the same person as far as possible.
|
Entailment
|
1 patient in cohort 1 of the primary trial was diagnosed with a Clear cell renal cell carcinoma.
|
Adverse Events 1:
Total: 2/60 (3.33%)
Bronchial infection 0/60 (0.00%)
Ankle fracture 1/60 (1.67%)
Clear cell kidney cancer 0/60 (0.00%)
Programmed peritoneal dialysis 1/60 (1.67%)
Endometrial atrophy 0/60 (0.00%)
Adverse Events 2:
Total: 3/58 (5.17%)
Bronchial infection 1/58 (1.72%)
Ankle fracture 0/58 (0.00%)
Clear cell kidney cancer 1/58 (1.72%)
Programmed peritoneal dialysis 0/58 (0.00%)
Endometrial atrophy 1/58 (1.72%)
|
Contradiction
|
One patient in the primary trial suffered from sepsis, due to the presence of an implanted device.
|
Adverse Events 1:
Device related sepsis 1/113 (0.88%)
|
Entailment
|
Both cohorts of the primary trial receive identical interventions; Pegylated Irinotecan Administered intravenously (IV) at 145 mg/m² as monotherapy once every 21 days , the differences between the cohorts is the type of cancers that patients are diagnosed with, cohort 1 is NSCLC, whereas cohort 2 is mBC and the number of cycles for each cohort, 1 for cohort 1 and 4 for cohort 2.
|
INTERVENTION 1:
Cohort A - Pegylated Irinotecan to Treat NSCLC
Patients with non-small cell lung carinoma (NSCLC) will receive pegylated irinotecan intravenously (IV) over 90 minutes every 21 days in the absence of disease progression or unacceptable toxicity.
Pegylated Irinotecan: Administered intravenously (IV) at 145 mg/m² as monotherapy once every 21 days (1 cycle)
INTERVENTION 2:
Cohort C - Pegylated Irinotecan to Treat mBC
Patients with metastatic breast cancer (MBC) to brain will receive pegylated irinotecan intravenously (IV) over 90 minutes every 21 days in the absence of disease progression or unacceptable toxicity.
Pegylated Irinotecan: Administered intravenously (IV) at 145 mg/m² as monotherapy once every 21 days (1 cycle)
|
Contradiction
|
Median (95% Confidence Interval) Progression-Free Survival (PFS) was over a year higher for patients in the Trastuzumab + Sunitinib group of the primary trial than for the Docetaxel group.
|
Outcome Measurement:
Progression-Free Survival (PFS)
PFS defined as time from date of randomization to date of the first documentation of objective tumor progression or death due to any cause, whichever occurred first. PFS calculated as (Months) = (first event date minus randomization date plus 1) divided by 30.4.
Time frame: Baseline up to Month 33
Results 1:
Arm/Group Title: Docetaxel + Sunitinib
Arm/Group Description: Sunitinib 37.5 milligrams (mg) daily by oral capsule for 2 weeks followed by a 1-week off-treatment period (Schedule 2/1) with docetaxel 75 milligrams per square meter (mg/m^2) every 3 weeks, or sunitinib 37.5 mg daily in continuous dosing (in absence of docetaxel), or docetaxel 100 mg/m^2 every 3 weeks (in absence of sunitinib).
Overall Number of Participants Analyzed: 296
Median (95% Confidence Interval)
Unit of Measure: months Independent radiology assessment: 8.6 (8.2 to 10.3)
Investigator's assessment: 8.2 (7.3 to 8.6)
Results 2:
Arm/Group Title: Docetaxel
Arm/Group Description: Docetaxel 100 mg/m^2 every 3 weeks
Overall Number of Participants Analyzed: 297
Median (95% Confidence Interval)
Unit of Measure: months Independent radiology assessment: 8.3 (7.7 to 9.6)
Investigator's assessment: 6.9 (6.5 to 7.3)
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Contradiction
|
Patients with left-sided breast cancer and an ECOG between 1-2 are excluded from the primary trial.
|
Inclusion Criteria:
All patients must have left-sided breast cancer.
Performance status should be 0-2 by ECOG criteria.
Exclusion Criteria:
Performance status > 2 by ECOG criteria
|
Contradiction
|
the primary trial recorded one patient with a catheter-related complication, whereas in the secondary trial none where observed.
|
Catheter site cellulitis 1/122 (0.82%)
Catheter site cellulitis 0/34 (0.00%)
Adverse Events 1:
Total: 17/65 (26.15%)
Febrile neutropenia 3/65 (4.62%)
Neutropenia 2/65 (3.08%)
Pancytopenia 1/65 (1.54%)
Thrombocytopenia 1/65 (1.54%)
Cardiac arrest 2/65 (3.08%)
Myocardial infarction 1/65 (1.54%)
Diarrhoea 5/65 (7.69%)
Stomatitis 1/65 (1.54%)
Vomiting 2/65 (3.08%)
Fatigue 1/65 (1.54%)
Jaundice 1/65 (1.54%)
Neutropenic infection 2/65 (3.08%)
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Entailment
|
Patients with HER2 positive tumors are excluded from the primary trial, but may be included in the secondary trial.
|
Inclusion Criteria:
HER-2/neu 1+ or 2+ by immunohistochemistry
Inclusion Criteria:
At least 18 years of age
Willing and able to provide informed consent
Reporting daily hot flashes
Able to read, write, and speak English
Postmenopausal to limit sample variability (> 12 months amenorrhea)
Greater then 1 month but < 5 years post-treatment (surgery, radiation, chemotherapy) for non-metastatic breast cancer.
These criteria allow inclusion of women successfully treated for recurrent breast cancer since there is no known reason to exclude them. Menopausal status is assessed using self-reports due to problems in reliably measuring follicle-stimulating hormone levels and estradiol in tamoxifen users.
Exclusion Criteria:
Exclusion criteria are current depression, history of migraines or hepatitis, abnormal chemistry profile (e.g., sodium, potassium, glucose), or a positive urine drug screen for illegal substances.
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Contradiction
|
Every participant in the secondary trial and the primary trial undergoes Laboratory Biomarker Analysis and completes a Questionnaire.
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INTERVENTION 1:
Arm I (Omega-3 Fatty Acid)
Patients receive omega-3 fatty acid PO daily for 7-14 days.
omega-3 fatty acid: Given PO
laboratory biomarker analysis: Correlative studies
INTERVENTION 2:
Arm II (Placebo)
Patients receive placebo PO daily for 7-14 days.
placebo: Given PO
laboratory biomarker analysis: Correlative studies
INTERVENTION 1:
Arm I (Curcumin-based Gel)
Patients apply curcumin-based gel topically TID approximately every 4-6 hours beginning on the first day of radiation therapy and continuing until 1 week after completion of radiation therapy.
Curcumin-based Gel: Applied topically
Laboratory Biomarker Analysis: Correlative studies
Questionnaire Administration: Ancillary studies
INTERVENTION 2:
Arm II (HPR Plus)
Patients apply HPR Plus™ topically TID approximately every 4-6 hours beginning on the first day of radiation therapy and continuing until 1 week after completion of radiation therapy.
Dermatologic Complications Management: Apply HPR Plus topically
Laboratory Biomarker Analysis: Correlative studies
Questionnaire Administration: Ancillary studies
|
Contradiction
|
the secondary trial and the primary trial both use irradiation techniques in their studies.
|
INTERVENTION 1:
4D Conformal Image-Guided Partial Breast RT
This is a single arm trial designed to look at the results in women treated with partial breast irradiation twice daily for 5 days.
4D Conformal Image-Guided Partial Breast RT: External beam partial breast radiation to target a portion of the breast twice a day for 5 days.
INTERVENTION 1:
Multicomponent Intervention
1.) A one-page paper-pencil agenda setting checklist completed immediately before a regularly scheduled medical oncology visit to elicit and align patient and companion perspectives regarding issues to discuss with the provider, and to stimulate discussion about the role of the companion in the visit, 2.) facilitated registration for the patient portal (for patient and family member, as desired by the patient), and 3.) education (as relevant) on access to doctor's electronic visit notes.
INTERVENTION 2:
Usual Care
Care as usual with the medical oncologist.
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Contradiction
|
Every patient in the primary trial is given tipifarnib PO, along with paclitaxel, doxorubicin hydrochloride and acyclophosphamide IV.
|
INTERVENTION 1:
Arm I
See Detailed Description
tipifarnib: Given orally
paclitaxel: Given IV
doxorubicin hydrochloride: Given IV
cyclophosphamide: Given IV
pegfilgrastim: Given SC
conventional surgery: surgical procedures performed on patients
axillary lymph node dissection: correlative study
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Entailment
|
There was just under 8 weeks difference in Progression-free Survival between the minimum and maximum PFS in the primary trial.
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Outcome Measurement:
Progression-free Survival (PFS)
Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Kaplan-Meier survival curves will be used. A 95% confidence interval for the median PFS will be calculated. A lower bound greater than 8 months would be strong evidence that Nab-Paclitaxel- bevacizumab induction therapy followed by bevacizumab-erlotinib hydrochloride maintenance therapy is superior to paclitaxel and bevacizumab. However, a median PFS of 13 months or greater (regardless of whether the 95% confidence interval for the median extends below 8 months) could also indicate promising results.
Time frame: Time from date of registration to date of first documentation of progression or symptomatic deterioration or death due to any cause, assessed up to 8 years
Results 1:
Arm/Group Title: Tx (Chemo, MoAb, and Enzyme Inhibitor)
Arm/Group Description: INDUCTION THERAPY: Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV on days 1, 8, and 15 and bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.
MAINTENANCE THERAPY: Patients achieving complete response, partial response, or stable disease after completion of induction therapy will receive bevacizumab IV over 30-90 minutes once every 14 or 21 days and erlotinib hydrochloride PO QD in the absence of disease progression or unacceptable toxicity.
paclitaxel albumin-stabilized nanoparticle formulation: Given IV
bevacizumab: Given IV
erlotinib hydrochloride: Given PO
Overall Number of Participants Analyzed: 55
Median (95% Confidence Interval)
Unit of Measure: Months 9.1 (7.2 to 11.1)
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Contradiction
|
Between both the primary trial and the secondary trial Bevacizumab is only administered to patients in cohort 2 of the secondary trial.
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INTERVENTION 1:
Arm 1: Yoga Intervention
Yoga Intervention
Yoga: Yoga sessions
INTERVENTION 2:
Arm 2: Educational Wellness Group
Educational Wellness Group
Education: Educational Wellness Group
INTERVENTION 1:
Arm A: Endocrine Therapy (ET)
Endocrine treatment consisting of either letrozole or fulvestrant. Patients will be randomized to receive bevacizumab 15mg/kg every 3 weeks plus endocrine treatment or endocrine treatment as a single agent. The patients will receive the assigned treatment until the progression of the disease, unacceptable toxicity or withdrawal of the consent.
Letrozole
Fulvestrant
INTERVENTION 2:
Arm B: ET With Bevacizumab (ET-B)
Endocrine treatment consisting of either letrozole or fulvestrant. Patients will be randomized to receive bevacizumab 15mg/kg i.v. on day 1 every 3 weeks plus endocrine treatment or endocrine treatment as a single agent. The patients will receive the assigned treatment until the progression of the disease, unacceptable toxicity or withdrawal of the consent.
Letrozole
Bevacizumab
Fulvestrant
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Entailment
|
60 patients in the primary trial were able to Complete at least 85% of the Planned Dose on Schedule.
|
Outcome Measurement:
Percentage of Subjects Able to Complete > 85% of the Planned Dose on Schedule
Feasibility will be determined by evaluating the percentage of subjects able to complete the neoadjuvant portion of the study on time with > 85% of the protocol-specified dose.
Time frame: From the start of treatment through the neoadjuvant treatment period (approximately 20 weeks)
Results 1:
Arm/Group Title: Neoadjuvant Therapy
Arm/Group Description: Neoadjuvant therapy will consist of epirubicin (100 mg/m^2) + cyclophosphamide (600 mg/m^2) every 2 weeks for 4 cycles; followed by a 3-week break; followed by docetaxel (75 mg/m^2) every 2 weeks for 4 cycles + trastuzumab (6 mg/kg [loading dose] once then 4 mg/kg [maintenance dose]) every 2 weeks for 4 treatments.
Overall Number of Participants Analyzed: 30
Measure Type: Number
Unit of Measure: percentage of participants 60
|
Contradiction
|
Patients with prior chemotherapy are eligible for the primary trial, but excluded from the secondary trial.
|
Inclusion Criteria:
Female subjects participating in FMSU004A protocol with known clinical status
Exclusion Criteria:
Subjects with unknown clinical status not participating in FMSU004A protocol.
Inclusion Criteria:
No prior chemotherapy for breast cancer
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Entailment
|
All the primary trial participants have the same number of calories in their diets throughout the duration of the study.
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INTERVENTION 1:
Behavioral Dietary Intervention
Beginning 2-4 weeks after completion of lumpectomy, patients receive food diaries to complete for 7-10 days. Dietary counselors then give patients guidelines for dietary modifications to reduce caloric intake by 25% of their normal diet. Patients follow caloric restricted diet for 10 weeks (2 weeks prior to radiation therapy, during 6 weeks of radiation therapy, and at least 2 weeks after radiation therapy). Patients undergo radiation therapy QD 5 days a week for 6 weeks.
Behavioral dietary intervention: Receive caloric restricted dietary intervention
Therapeutic conventional surgery: Undergo definitive lumpectomy
Radiation therapy: Undergo radiation therapy
Counseling intervention: Receive dietary counseling
Quality-of-life assessment: Ancillary studies
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Contradiction
|
Participants in the primary trial are assigned an intervention depending on their cancer diagnosis, whereas in the secondary trial the interventions are randomly assigned.
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INTERVENTION 1:
Healthy Volunteers
Healthy women will be screened for Magnetic Resonance Imaging (MRI) contraindications, and then undergo contrast injection, and SWIFT acquisition.
Magnetic resonance imaging: Patients and healthy volunteers will be first screened for MRI contraindications. The SWIFT MRI workflow will be performed as follows:
INTERVENTION 2:
Breast Cancer Patients
Breast cancer patients who have suspected breast lesion that will be biopsied will be screened for Magnetic Resonance Imaging (MRI) contraindications, and then undergo contrast injection and SWIFT acquisition.
Magnetic resonance imaging: Patients and healthy volunteers will be first screened for MRI contraindications. The SWIFT MRI workflow will be performed as follows:
INTERVENTION 1:
Hydrophor (Group A)
Group A (current standard of care): Patients will be instructed (by nurses and with printed study materials) to apply a thin layer of the Hydrophor daily, starting at the onset of radiation therapy (RT) and continuing until 2 weeks after the final RT session or until the RT site is healed (whichever is first). Hydrophor application should include the entire treatment area, including the axillae and shoulder/back area in patients treated with modified radical mastectomy. To avoid possible build-up effects, patients should not apply the Hydrophor within 4 hours of receiving RT. Patients should wash the application area daily with perfume-free soap and tap water. Patients will be asked to refrain from using other topical agents in the irradiated area.
INTERVENTION 2:
MediHoney (Group B)
Group B (study target): Patients will be instructed (by nurses and with printed study materials) to apply a thin layer of the Medihoney daily, starting at the onset of RT and continuing until 2 weeks after the final RT session or until the RT site is healed (whichever is first). Medihoney application should include the entire treatment area, including the axillae and shoulder/back area in patients treated with modified radical mastectomy. To avoid possible build-up effects, patients should not apply the Medihoney within 4 hours of receiving RT. Patients should wash the application area daily with perfume-free soap and tap water. Patients will be asked to refrain from using other topical agents in the irradiated area.
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Entailment
|
There were no patients with paranasal sinus reactions, or Left ventricular dysfunction in the primary trial.
|
Adverse Events 1:
Total: 21/107 (19.63%)
Febrile neutropenia * 10/107 (9.35%)
Neutropenia * 1/107 (0.93%)
Left ventricular dysfunction * 0/107 (0.00%)
Angina pectoris * 0/107 (0.00%)
Cardiac failure congestive * 0/107 (0.00%)
Diarrhoea * 2/107 (1.87%)
Abdominal strangulated hernia * 0/107 (0.00%)
Duodenal ulcer haemorrhage * 0/107 (0.00%)
Pyrexia * 1/107 (0.93%)
Adverse Events 2:
Total: 22/107 (20.56%)
Febrile neutropenia * 8/107 (7.48%)
Neutropenia * 6/107 (5.61%)
Left ventricular dysfunction * 3/107 (2.80%)
Angina pectoris * 1/107 (0.93%)
Cardiac failure congestive * 0/107 (0.00%)
Diarrhoea * 0/107 (0.00%)
Abdominal strangulated hernia * 1/107 (0.93%)
Duodenal ulcer haemorrhage * 0/107 (0.00%)
Pyrexia * 1/107 (0.93%)
|
Contradiction
|
A total of 32 patients in the primary trial had Diarrhoea.
|
Adverse Events 1:
Total: 19/213 (8.92%)
Pancytopenia 0/213 (0.00%)
Anaemia 1/213 (0.47%)
Atrial fibrillation 0/213 (0.00%)
Cardiac failure congestive 0/213 (0.00%)
Myocardial infarction 0/213 (0.00%)
Supraventricular tachycardia 0/213 (0.00%)
Diarrhoea 0/213 (0.00%)
Colitis 0/213 (0.00%)
Vomiting 1/213 (0.47%)
Nausea 1/213 (0.47%)
Enterocolitis 0/213 (0.00%)
Adverse Events 2:
Total: 133/416 (31.97%)
Pancytopenia 1/416 (0.24%)
Anaemia 0/416 (0.00%)
Atrial fibrillation 2/416 (0.48%)
Cardiac failure congestive 1/416 (0.24%)
Myocardial infarction 1/416 (0.24%)
Supraventricular tachycardia 1/416 (0.24%)
Diarrhoea 32/416 (7.69%)
Colitis 14/416 (3.37%)
Vomiting 4/416 (0.96%)
Nausea 3/416 (0.72%)
Enterocolitis 2/416 (0.48%)
|
Entailment
|
Cohort one of the primary trial reported 2/680 patients experiecing eye-related adverse events, whereas cohort two recorded none.
|
Adverse Events 1:
Total: 83/680 (12.21%)
Hemoglobin 11/680 (1.62%)
Transfusion: Platelets 0/680 (0.00%)
Transfusion: pRBCs 0/680 (0.00%)
Febrile neutropenia 49/680 (7.21%)
Edema 1/680 (0.15%)
Ischemia/infarction 0/680 (0.00%)
Palpitations 0/680 (0.00%)
Pericardial effusion 0/680 (0.00%)
Keratitis 1/680 (0.15%)
Double vision 1/680 (0.15%)
Colitis 1/680 (0.15%)
Adverse Events 2:
Total: 86/688 (12.50%)
Hemoglobin 15/688 (2.18%)
Transfusion: Platelets 1/688 (0.15%)
Transfusion: pRBCs 1/688 (0.15%)
Febrile neutropenia 41/688 (5.96%)
Edema 0/688 (0.00%)
Ischemia/infarction 0/688 (0.00%)
Palpitations 1/688 (0.15%)
Pericardial effusion 1/688 (0.15%)
Keratitis 0/688 (0.00%)
Double vision 0/688 (0.00%)
Colitis 0/688 (0.00%)
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Entailment
|
Neither the primary trial or the secondary trial are measuring Dose Limiting Toxicity of BYL719 in Combination With T-DM1.
|
Outcome Measurement:
Dose Limiting Toxicity (DLT) of Dose-escalating BYL719 in Combination With T-DM1
DLTs of BYL719 in combination with T-DM1 will be assessed using National Cancer Institute's Common Toxicity Criteria for adverse events version 4.0 (except for hyperglycemia). A DLT is described any grade 3 or higher, clinically significant toxicity (excluding alopecia) experienced during the first 21 days following first dose of BYL719 that is determined to be at least possibly related to study medication. Lower grades may also be considered DLTs if they lead to a dose interruption of more than 7 consecutive days of BYL719. In general adverse events (AEs) will be graded according to the following:
Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE
Time frame: The 1st 21 days (Cycle 1) of treatment
Outcome Measurement:
Endoxifen Concentrations in Participants Receiving Tamoxifen Citrate Dose of 20 mg or 40 mg Stratified by the Metabolizing CYP2D6 Genotypes
Measurements of plasma concentrations of the key active metabolite of tamoxifen, endoxifen, were measured at baseline and after 4 months of treatment; The most common CYP2D6 alleles have been grouped by functional activity classifications with descending activity: ultra-rapid (UM), extensive (EM), intermediate (IM) or poor (PM) metabolism. A given patient has two alleles, giving them 10 possible allelic combinations, or diplotypes (UM/UM, UM/EM, EM/EM, etc.). These diplotypes are collapsed into four phenotypes, UM, EM, IM or PM.
Time frame: 4 months
|
Contradiction
|
In both the secondary trial and the primary trial the test cohorts achieved better overall response than the control groups.
|
Outcome Measurement:
Progression-free Survival (PFS)
PFS was defined as the interval from study entry until disease progression or death resulting from any cause, which ever occurred first. Progression is defined as a 20% increase in the sum of longest diameter of target lesions (per RECIST criteria).
Time frame: Interval from randomization until disease progression or death, whichever occurs first, assessed up to 5 years
Results 1:
Arm/Group Title: Arm I (Lapatinib)
Arm/Group Description: Patients receive 1500 mg lapatinib ditosylate PO QD on days 1-28 and fulvestrant IM on days 1 (500 mg) and 15 (250 mg) of course 1 and on day 1 (250 mg)of each subsequent course.
Overall Number of Participants Analyzed: 146
Median (95% Confidence Interval)
Unit of Measure: months 4.7 (3.7 to 5.7)
Results 2:
Arm/Group Title: Arm II (Placebo)
Arm/Group Description: Patients receive placebo PO QD on days 1-28 and fulvestrant IM on days 1 (500 mg) and 15 (250 mg) of course 1 and on day 1 (250 mg) of each subsequent course.
Overall Number of Participants Analyzed: 145
Median (95% Confidence Interval)
Unit of Measure: months 3.8 (3.8 to 5.6)
Outcome Measurement:
Number of Participants With Overall Response (OR), Defined as Those Participants Achieving Complete Response (CR) or Partial Response (PR), Assessed Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0 and Cutaneous Lesions
RECIST-based response assessment was done at Weeks (Wks) 4 and 8 and every 8 weeks thereafter. Cutaneous disease assessment was done at Wk 4 and every 4 weeks thereafter. OR was evaluated when the skin and RECIST assessments coincided. Per RECIST, CR is the disappearance of all target and non-target lesions; PR is at least a 30 percent (%) decrease in the sum of the longest diameter (LD) of target lesions, taking as a reference the baseline sum LD. Cutaneous disease contained non-measurable and measurable skin disease, which was assessed by skin assessment tools.
Time frame: Baseline until disease progression/recurrence was documented, assessed for up to 66 weeks
Results 1:
Arm/Group Title: Cohort 1: Lapatinib 1500 mg + Pazopanib Placebo
Arm/Group Description: Participants received oral lapatinib 1500 milligrams (mg) (6 x 250 mg tablets) in combination with placebo (matching to pazopanib; 2 tablets) once daily (QD).
Overall Number of Participants Analyzed: 38
Measure Type: Number
Unit of Measure: participants 11
Results 2:
Arm/Group Title: Cohort 1: Lapatinib 1500 mg + Pazopanib 800 mg
Arm/Group Description: Participants received oral lapatinib 1500 mg (6 x 250 mg tablets) in combination with pazopanib 800 mg (2 x 400 mg tablets) QD.
Overall Number of Participants Analyzed: 38
Measure Type: Number
Unit of Measure: participants 17
|
Contradiction
|
Cohort 1 of the primary trial does not receive any Eribulin Mesylate With Prophylactic Filgrastim, whereas both cohorts in the secondary trial receive some.
|
INTERVENTION 1:
Vorinostat +Trastuzumab
Trastuzumab: 6 mg/kg once on Day 1, infused over 90 minutes, every 3 weeks;
Vorinostat 200 mg of SAHA orally twice a day, daily for 14 days out of a 21-day cycle
INTERVENTION 1:
Cohort 1: Eribulin Mesylate With Filgrastim as Needed
Participants initially received doxorubicin (60 mg/m^2) plus cyclophosphamide (600 mg/m^2) intravenously (IV) on Day 1, of every 14-day cycle for 4 cycles. Eribulin mesylate was administered following the doxorubicin plus cyclophosphamide regimen at a dose of 1.4 mg/m^2 IV over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle for 4 cycles (Cycles 5 to 8). In this Cohort growth factors, subcutaneous pegfilgrastim (6 mg) or filgrastim, could be used with eribulin therapy at the physician's discretion if neutropenia occurred that recovered to Grade 2.
|
Entailment
|
Patients with Platelet count over 100,000/mm³, ANC < 1,700/mm³ and Hemoglobin between 11 to 18 grams per deciliter are eligible for the primary trial.
|
PATIENT CHARACTERISTICS:
ANC 1,500/mm³
Platelet count 100,000/mm³
Hemoglobin 9.0 g/dL
|
Entailment
|
the secondary trial and the primary trial use non comparable evaluation metrics, and significantly different time frames.
|
Outcome Measurement:
Progression Free Survival (PFS) as Per RECIST v1.1 (by Local Investigator Assessment)
PFS Results presented for all MCS110 treated patients (with and without day 8 dose), in line with phase 2 study design.
Time frame: 4 years
Outcome Measurement:
Best Overall Response of Everolimus and Exemestane Treatment in Postmenopausal Women With Hormone Receptor Positive Locally Advanced or Metastatic Breast Cancer
The best Overall Response (OR) for each patient is determined from the sequence of investigator overall lesion responses according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1.). To be assigned a best OR of Complete Responese (CR) at least two determinations of CR at least 4 weeks apart before progression are required. To be assigned a best OR of Partial Response (PR) at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR) are required.The Overall Response Rate (ORR) was defined as the proportion of patients with a best OR of confirmed CR or PR by week 48.
Time frame: At 48 weeks
|
Entailment
|
Placebo treatment is used in cohort 2 of the secondary trial, but there is only a test group in the primary trial.
|
INTERVENTION 1:
Arm I (Omega-3-fatty Acid)
Patients receive oral omega-3-fatty acid twice daily (BID) or three times daily (TID) for 24 weeks in the absence of disease progression or unacceptable toxicity
INTERVENTION 2:
Arm II (Placebo)
Patients receive oral placebo BID or TID for 24 weeks in the absence of disease progression or unacceptable toxicity
INTERVENTION 1:
Accelerated Partial Breast Brachytherapy
Each patient will receive accelerated partial breast brachytherapy with multiple plane implant.
Patients will receive 3400 cGy delivered in 10 twice-daily fractions. Treatment is to be given over 5-7 days with a minimum of 6 hours separation between fractions.
|
Contradiction
|
Percentage of Participants With Clinical Objective Response (cOR) in the Breast, Evaluated by an Independent Radiological Evaluation Monitoring Committee was highest in cohort 2.
|
Outcome Measurement:
Percentage of Participants With Clinical Objective Response (cOR) in the Breast, Evaluated by an Independent Radiological Evaluation Monitoring Committee
cOR is defined as the documented evidence of complete response (CR) and partial response (PR) as assessed by ultrasound examination using Response Evaluation Criteria In Solid Tumors (RECIST). CR is defined as the disappearance of all target lesions (TLs) and non-TLs and the appearance of no new lesions (NLs). PR for TLs is defined as a >=30% decrease in the sum of the longest diameter (LD) of TLs, taking as a reference the Baseline sum LD. For non-TLs, it is defined as the persistence of >=1 non-TL and no new TLs or non-TLs.
Time frame: From Baseline (Day 1) up to 6 months, evaluated every 12 weeks
Results 1:
Arm/Group Title: Letrozole + Placebo
Arm/Group Description: Letrozole tablets in the dose of 2.5 milligrams (mg) plus matching placebo were administered orally once daily for 6 months prior to surgery.
Overall Number of Participants Analyzed: 48
Measure Type: Number
Unit of Measure: percentage of participants CR: 2
PR: 58
Results 2:
Arm/Group Title: Letrozole + Lapatinib
Arm/Group Description: Letrozole tablets in the dose of 2.5 mg plus lapatinib ditosylate monohydrate tablets in the dose of 1500 mg were administered orally once daily for 6 months prior to surgery.
Overall Number of Participants Analyzed: 41
Measure Type: Number
Unit of Measure: percentage of participants CR: 12
PR: 54
|
Contradiction
|
The interventions in the primary trial and the secondary trial are applied daily for a period of several months.
|
INTERVENTION 1:
0.005% Estriol Vaginal Gel
Route: Vaginal. Administration by an applicator inserted deep inside the vagina Dose: 1 g of gel, containing 50 Mcg of estriol Dosage schedule: Weeks 1-3: single daily application Weeks 4-12: twice weekly administration
INTERVENTION 1:
One-port
intervention is placement of one-port tissue expander at time of reconstruction
Allergen one-port tissue expander placement: patients will be randomized to receive a one port or two port tissue expander for breast reconstruction
|
Contradiction
|
The same dose of trastuzumab was used for the interventions in the primary trial and the secondary trial.
|
INTERVENTION 1:
Phase I: Cyclophosphamide, Doxil, Trastuzumab
Patients receive oral cyclophosphamide once daily on days 1-28 and pegylated doxorubicin HCl liposome IV over 90 minutes on day 1. Treatment repeats every 4-6 weeks in the absence of disease progression or unacceptable toxicity. Some patients with HER2/neu 3+ disease may also receive trastuzumab IV over 30-90 minutes weekly or every 3 weeks at the discretion of the treating physician.
pegylated liposomal doxorubicin hydrochloride: Given IV
cyclophosphamide: Given orally
trastuzumab: Given IV
INTERVENTION 1:
Phase I: Dasatinib 100mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2
Cohort 1: Eligible patients were enrolled and treated with 4-week cycles of trastuzumab 2 mg/kg IV weekly (following a loading dose of 4 mg/kg in cycle 1) and paclitaxel 80 mg/m2 weekly x 3 weeks followed by a rest period of 7 days. Dasatinib 100mg was administered orally once daily (QD). Treatment was repeated on Day 1 of a 28-day cycle until radiographic or symptomatic progression or unacceptable toxicity occured. Only in the phase I, the first cycle lasted 38 days.
|
Contradiction
|
Patients with incurable and unresectable Breast Cancer are eligible for the primary trial, unless it is metastatic.
|
Inclusion Criteria:
Documented progression of incurable, unresectable, LABC, or mBC, defined by the investigator: progression must occur during or after most recent treatment for LABC/mBC or within 6 months of completing adjuvant therapy
|
Contradiction
|
Helen had stage III ovarian cancer 2 years prior, from which she is still recovering, she is excluded from the primary trial.
|
Exclusion Criteria:
Other prior malignancy. The following is allowed: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the participant is currently in complete remission, or any other cancer (including breast cancer) for which the participant has been disease-free for 5 years.
|
Entailment
|
the primary trial studies changes in tumour diameter, whereas the secondary trial investigates changes in heart failure rate.
|
Outcome Measurement:
Primary Endpoint : Compare Best Overall Response Rate (ORR) (According to Response Evaluation Criteria in Solid Tumor [RECIST] 1.1 Criteria) at Week 24 of MYL-1401O Plus Taxane Versus Herceptin® Plus Taxane in the ITT1 Population
Tumor measurements were perform by centralized blinded reviewers using RECIST 1.1 criteria. Per RECIST 1.1: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph node must have reduction in short axis to <10 mm.Partial Response (PR): >/= 30% decrease sum of the diameters of target lesions from baseline sum diameters.
Progressive Disease (PD): </= 20% increase in the sum of the diameters of target lesions, from the smallest sum on study with at least a 5 mm absolute increase in the sum of all lesions. The appearance of one or more new lesions* denotes disease progression.
Stable Disease (SD): Neither sufficient decrease or increase. Evaluation of Non-Target Lesions Complete Response (CR): Disappearance of all non-target lesions. Non-complete Response/Non-Progressive Disease: Persistence of one or more non-target lesions. Progressive Disease (PD): Substantial, unequivocal progression of existing non-target lesions.
Time frame: from time of First treatment to week 24
Outcome Measurement:
Lumbar Spine Bone Mineral Density Percent Change From Baseline at Month 12
Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry.
Time frame: 12 months
|
Contradiction
|
Both cohorts of the primary trial receive identical interventions; Pegylated Irinotecan Administered intravenously (IV) at 145 mg/m² as monotherapy once every 21 days (1 cycle), the difference between the cohorts is the type of cancers that patients are diagnosed with, cohort 1 is NSCLC, whereas cohort 2 is mBC.
|
INTERVENTION 1:
Cohort A - Pegylated Irinotecan to Treat NSCLC
Patients with non-small cell lung carinoma (NSCLC) will receive pegylated irinotecan intravenously (IV) over 90 minutes every 21 days in the absence of disease progression or unacceptable toxicity.
Pegylated Irinotecan: Administered intravenously (IV) at 145 mg/m² as monotherapy once every 21 days (1 cycle)
INTERVENTION 2:
Cohort C - Pegylated Irinotecan to Treat mBC
Patients with metastatic breast cancer (MBC) to brain will receive pegylated irinotecan intravenously (IV) over 90 minutes every 21 days in the absence of disease progression or unacceptable toxicity.
Pegylated Irinotecan: Administered intravenously (IV) at 145 mg/m² as monotherapy once every 21 days (1 cycle)
|
Entailment
|
the primary trial is investigating Cognitive behavioural therapy, a type of psychotherapy, in contrast the secondary trial studies Trastuzumab, a type of chemotherapy.
|
INTERVENTION 1:
Stage 1 Clinical Management
The group will receive clinical management treatment only each session.
Clinical Management: Clinical management is a clear contrast method of psychological therapy, which is a half-structured interview and lasting for 20-25 minutes each session. Clinical management will be assigned to both experimental group and controlled group in the first stage of intervention.
Following are major elements:
Talk to the subjects to find their main problems; introduce knowledge and medication knowledge about cancer and depression; subjects reporting use of drugs for cancer and depression and a variety of signs and symptoms of the reaction. Encourage patients to adhere to drug treatment and to comply with this research program; The operation of CBT and clinical management should be conducted by the same person as far as possible.
INTERVENTION 2:
Stage 1 CBT
The experimental group will receive CBT each session.
CBT and clinical management: The subjects will receive standardized CBT treatment regularly for 9 sessions(once per week in the first month and once half a month in the second and third months), and each session will last for about 60 minutes.The treatment includes three steps:Concept stage (the first and second sessions): establishment of therapeutic relationships with the subjects; Skills acquisition and repeat stage (the third session to the 8th session): clarification of sources of stress, patients' cognitive and behavioral response to stress. Application and complete price segment (the 9th session): return visit to test efficacy of psychological intervention.
INTERVENTION 1:
Neratinib 240, Prior Trastuzumab
Neratinib: 80mg capsules and 40mg coated tablets taken orally in prescribed dose of 240mg daily, as long as tolerated and disease does not worsen in participants with prior trastuzumab treatment.
INTERVENTION 2:
Neratinib 240, No Prior Trastuzumab
Neratinib: 80mg capsules and 40mg coated tablets taken orally in prescribed dose of 240mg daily, as long as tolerated and disease does not worsen in participants with no prior trastuzumab treatment.
|
Contradiction
|
There is no difference in results or cohort size between cohort 1 and 2 of the primary trial, the increase in Gy has no notable effect.
|
Outcome Measurement:
Feasibility of PBI Directed External Radiotherapy as Measured by Percentage of Participants Achieving a Dosimetrically Satisfactory Treatment Plan
-The study will be deemed infeasible if more than 4 patients cannot be given treatment because her tumor is such that a dosimetrically satisfactory treatment plan cannot be devised for her.
Time frame: Within 1 year of protocol registration
Results 1:
Arm/Group Title: Cohort 1 (36 Gy)
Arm/Group Description: 36 Gy in 9 fractions BID x 4 1/2 treatment days
Partial Breast Irradiation (PBI)
Overall Number of Participants Analyzed: 50
Measure Type: Number
Unit of Measure: percentage of participants 100
Results 2:
Arm/Group Title: Cohort 2 (40 Gy)
Arm/Group Description: 40 Gy in 10 fractions BID over 5 treatment days
Partial Breast Irradiation (PBI)
Overall Number of Participants Analyzed: 50
Measure Type: Number
Unit of Measure: percentage of participants 100
|
Entailment
|
Patients with HER2 + breast cancer are eligible for both the primary trial and the secondary trial. However, only patients with stage 1-2 breast cancer are eligible for the primary trial, and patients with stage 3-4 are eligilbe for the secondary trial.
|
Inclusion Criteria:
Participants with a confirmed diagnosis of clinical stage 1 or 2 breast cancer
Inclusion Criteria:
Stage IIIB, IIIC, or IV erbB2 (HER2) positive breast cancer
|
Entailment
|
the secondary trial and the primary trial both require their patients to receive their respective interventions on a daily basis.
|
INTERVENTION 1:
AB-101
Apply to both nipple/areola regions approximately 1 hour prior to sexual activity
AB-101: Apply approximately 1 hour prior to sexual activity
INTERVENTION 2:
Placebo
Apply to both nipple/areola regions approximately 1 hour prior to sexual activity
Placebo: Apply approximately 1 hour prior to sexual activity
INTERVENTION 1:
Letrozole + MRI
Protocol Therapy will consist of 6 months of letrozole, administered orally at a dose of 2.5 mg/day. Patients will have a bilateral MRI for disease evaluation at months 3 and 6.
|
Contradiction
|
Patients needing active supportive care can participate in the primary trial.
|
Inclusion Criteria:
Patients must have a performance status of 0-2 by Zubrod criteria
|
Contradiction
|
The the secondary trial intervention is applied to the palms and soles twice daily, the primary trial participants are not administered any medication on the skin of the hands or feet, but rather onto the breast or chest wall.
|
INTERVENTION 1:
Lapatinib Plus Paclitaxel
Participants received lapatinib 1500 mg orally OD with paclitaxel, administered as a 1-hour IV infusion at a dose of 80 mg/m^2 on Days 1, 8, and 15 (±2 days) of a 28-day treatment cycle for at least 6 months. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
INTERVENTION 1:
Urea/Lactic Acid Cream
Patients receive topical urea/lactic acid-based cream applied to palms and soles twice daily.
INTERVENTION 2:
Placebo Cream
Patients receive placebo cream applied to palms and soles twice daily.
|
Contradiction
|
27.6% of Patients Who Have Fatty Acid Synthase (FASN) Expression in the primary trial treated with Minocycline Hydrochloride did not have Pathological Complete Response.
|
Outcome Measurement:
Percentage of Patients With Pathological Complete Response (pCR) in Patients Who Have Fatty Acid Synthase (FASN) Expression
pCR is defined as no invasive disease in the breast of axilla at the time of definitive surgery. A patient is considered to have FASN expression if the positivity was >= 15% at the baseline or after 4-7 days of Omeprazole monotherapy. FASN expression is evaluated using immunohistochemistry in core biopsy samples. The percent of patients with FASN expression that have pCR will be calculated with an exact 95% confidence interval.
Time frame: Up to 6 months
Results 1:
Arm/Group Title: High Dose Omeprazole Treatment
Arm/Group Description: Patients will be treated with omeprazole 80 mg orally BID beginning 4-7 days prior to chemotherapy and continuing until surgery.
Overall Number of Participants Analyzed: 29
Measure Type: Number
Unit of Measure: percentage of participants 72.4 (52.8 to 87.3)
|
Contradiction
|
In the primary trial group A has a higher percentage of patients with >25% increase in tumor area at 3 months after treatment than group B.
|
Outcome Measurement:
Central Nervous System (CNS) Progression-free Survival(PFS)
The number of patients that are documented to have progression free survival at 3 months after treatment. Progression free is define as <25% increase in tumor area.
PFS will be measured from the date of entry into the trial to the date of documented progression of brain metastases or death.
Time frame: 3 months after treatment
Results 1:
Arm/Group Title: Epothilone B: Group A
Arm/Group Description: Group A: Patients with progressive, radiographically measurable parenchymal brain metastases after whole brain radiation therapy (WBRT). Patupilone will be administered as a single intravenous infusion over 20 minutes, once every 3 weeks. Patupilone will be administered at a dose of 10 mg/m2 (q3weeks) with actual body weight.
Overall Number of Participants Analyzed: 45
Measure Type: Number
Unit of Measure: participants 12
Results 2:
Arm/Group Title: Epothilone B: Group B
Arm/Group Description: Group B: an exploratory cohort of patients, with either leptomeningeal metastases (LMD) or unirradiated, asymptomatic brain metastasis from breast cancer (BCBM).Patupilone will be administered as a single intravenous infusion over 20 minutes, once every 3 weeks. Patupilone will be administered at a dose of 10 mg/m2 (q3weeks) with actual body weight.
Overall Number of Participants Analyzed: 10
Measure Type: Number
Unit of Measure: participants 2
|
Contradiction
|
In total the secondary trial recorded only 3 more cases of Pyrexia than the primary trial.
|
Adverse Events 1:
Total: 7/42 (16.67%)
Febrile neutropenia 1/42 (2.38%)
Left venrticular dysfunction 1/42 (2.38%)
Cardiac valve disease 1/42 (2.38%)
Diarrhoea 0/42 (0.00%)
Abdominal pain 1/42 (2.38%)
Colitis 0/42 (0.00%)
Nausea 0/42 (0.00%)
Vomiting 0/42 (0.00%)
Pyrexia 0/42 (0.00%)
Influenza like illness 1/42 (2.38%)
Oedema peripheral 1/42 (2.38%)
Fatigue 0/42 (0.00%)
Adverse Events 2:
Total: 7/42 (16.67%)
Febrile neutropenia 0/42 (0.00%)
Left venrticular dysfunction 1/42 (2.38%)
Cardiac valve disease 0/42 (0.00%)
Diarrhoea 0/42 (0.00%)
Abdominal pain 0/42 (0.00%)
Colitis 0/42 (0.00%)
Nausea 0/42 (0.00%)
Vomiting 0/42 (0.00%)
Pyrexia 2/42 (4.76%)
Influenza like illness 0/42 (0.00%)
Oedema peripheral 0/42 (0.00%)
Fatigue 0/42 (0.00%)
Adverse Events 1:
Total: 21/209 (10.05%)
Anaemia 0/209 (0.00%)
Febrile neutropenia 0/209 (0.00%)
Thrombocytopenia 0/209 (0.00%)
Acute myocardial infarction 0/209 (0.00%)
Cardiac failure 0/209 (0.00%)
Diplopia 0/209 (0.00%)
Gastric haemorrhage 0/209 (0.00%)
Nausea 0/209 (0.00%)
Oral pain 0/209 (0.00%)
Vomiting 1/209 (0.48%)
Mucosal inflammation 0/209 (0.00%)
Pain 1/209 (0.48%)
Adverse Events 2:
Total: 29/216 (13.43%)
Anaemia 2/216 (0.93%)
Febrile neutropenia 2/216 (0.93%)
Thrombocytopenia 2/216 (0.93%)
Acute myocardial infarction 1/216 (0.46%)
Cardiac failure 1/216 (0.46%)
Diplopia 1/216 (0.46%)
Gastric haemorrhage 1/216 (0.46%)
Nausea 1/216 (0.46%)
Oral pain 2/216 (0.93%)
Vomiting 2/216 (0.93%)
Mucosal inflammation 1/216 (0.46%)
Pain 0/216 (0.00%)
|
Contradiction
|
Patients with cancer cells that have metastasised into less than 3 lymph nodes, with at least one larger than 2mm, cannot enter the primary trial.
|
Inclusion Criteria:
By pathologic evaluation, ipsilateral nodes must be pN1 (pN1mi, pN1a, pN1b, pN1c), pN2a, pN3a, or pN3b (only if due to microscopic involvement of internal mammary node detected by sentinel lymph node dissection and with more than 3 positive axillary lymph nodes).
|
Contradiction
|
Less patients in cohort 2 of the primary trial had an unusual amount of fluid around the lungs than in cohort 1.
|
Adverse Events 1:
Pleural effusion *0/24 (0.00%)
Adverse Events 2:
Pleural effusion *2/30 (6.67%)
|
Contradiction
|
A higher number of cohort 2 participants from the primary trial experienced fever, compared to cohort 1.
|
Adverse Events 1:
Fever * 2/41 (4.88%)
Adverse Events 2:
Fever * 0/5 (0.00%)
|
Contradiction
|
Only Black women are eligible for the primary trial, as long as they do not have uncontrolled or symptomatic brain metastases.
|
Inclusion Criteria:
Self-identified Black, African or African American women of 18 years of age with proven diagnosis of advanced adenocarcinoma of the breast (locoregionally recurrent or metastatic disease)
Exclusion Criteria:
Current use of food or drugs known to be potent inhibitors or inducers of CYP3A4
Active uncontrolled or symptomatic brain metastases. Previously treated and clinically stable, as per Investigator's judgment, brain metastases are permitted.
|
Entailment
|
Patients with a palpable breast lesions and axillary lymph nodes are eligible for the primary trial.
|
Palpable or nonpalpable breast lesion
No palpable axillary lymph node(s)
|
Contradiction
|
participants of cohort 1 in the primary trial and all participants of the secondary trial take 1 milligram of anastrozole PO QD.
|
INTERVENTION 1:
Arimidex Group
Anastrozole(ARIMIDEX): 1 mg once daily oral dose
INTERVENTION 1:
anastrozole : 1 milligram tablet PO QD for 14 days
|
Entailment
|
the primary trial and the secondary trial measure the DLT of their respective interventions, using the same time frame.
|
Outcome Measurement:
Dose Limiting Toxicity Incidence of Neratinib in Combination With Paclitaxel
Dose Limiting Toxicity in subjects with solid tumors treated with neratinib, administered daily, in combination with paclitaxel 80 mg/m² IV on days 1, 8, and 15 of a 28 day cycle.
Time frame: From first dose date through day 28
Outcome Measurement:
Number of Participants With Dose Limiting Toxicities (DLT)
Number of participants with DLT in the first cycle (28 days) for the determination of the maximum tolerated dose (MTD). Important Limitations and Caveats are provided in the respective section.
Time frame: 28 days
|
Entailment
|
Less than 5% of patients undergoing the intervention in the primary trial had adverse events, in comparison almost 10% patients in cohort 1 of the secondary trial experienced an adverse event, and more than 30% of those in cohort 2 of the secondary trial had adverse events.
|
Adverse Events 1:
Total: 4/95 (4.21%)
Adverse Events 1:
Total: 3/31 (9.68%)
Adverse Events 2:
Total: 8/25 (32.00%)
|
Entailment
|
The the secondary trial intervention is applied to the palms and soles twice daily, the primary trial participants are not administered any medication topically.
|
INTERVENTION 1:
Lapatinib Plus Paclitaxel
Participants received lapatinib 1500 mg orally OD with paclitaxel, administered as a 1-hour IV infusion at a dose of 80 mg/m^2 on Days 1, 8, and 15 (±2 days) of a 28-day treatment cycle for at least 6 months. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
INTERVENTION 1:
Urea/Lactic Acid Cream
Patients receive topical urea/lactic acid-based cream applied to palms and soles twice daily.
INTERVENTION 2:
Placebo Cream
Patients receive placebo cream applied to palms and soles twice daily.
|
Entailment
|
Patients whose breast cancer has spread into both the skin and the chest wall are eligible for the secondary trial, but not the primary trial.
|
T1-3, any N disease
No inflammatory breast cancer or other T4 features
Inclusion Criteria:
Histologically confirmed, HER2-positive advanced and/or metastatic breast cancer not amenable to curative therapy
|
Entailment
|
Women classified as low-risk of developing breast cancer within the next 5 years by the Gail model , and no Family history consistent with hereditary breast cancer, are eligible for the primary trial.
|
Inclusion Criteria:
Gail risk >= 1.7% and/or relative risk >= 3 times that for 5-year age group
Family history consistent with hereditary breast cancer, as indicated by 1 of the following criteria:
|
Contradiction
|
Cohort 1 of the primary trial had a longer PFS than cohort 2. However the patient with the longest PFS was in cohort 2.
|
Outcome Measurement:
Progression Free Survival
[Not Specified]
Time frame: From the date of randomization to date of first documented disease progression (i.e., the date on which a radiologic procedure or clinical evaluation was performed) or the date of death due to any cause, if before progression, assessed up to 39 months.
Results 1:
Arm/Group Title: A (Sorafenib + Gemcitabine or Capecitabine)
Arm/Group Description: Sorafenib will be administered (400 mg; 2 tablets x 200 mg) orally twice daily (approximately every 12 hours); Gemcitabine will be administered 1000 mg/m2 pm Days 1 and 8 of a 21 day cycle; Capecitabine will be administered orally at a dose of 1,000 mg/m2 twice daily, within 30 minutes after a meal, for 14 days followed by a 7 day rest period (without capecitabine)
Gemcitabine: Gemcitabine will be administered 1000 mg/m2 pm Days 1 and 8 of a 21 day cycle
Sorafenib: Sorafenib will be administered (400 mg; 2 tablets x 200 mg) orally twice daily (approximately every 12 hours)
Capecitabine: Capecitabine will be administered orally at a dose of 1,000 mg/m2 twice daily, within 30 minutes after a meal, for 14 days followed by a 7 day rest period (without capecitabine).
Overall Number of Participants Analyzed: 81
Median (95% Confidence Interval)
Unit of Measure: Days 103 (83 to 128)
Results 2:
Arm/Group Title: B (Placebo + Gemcitabine or Capecitabine)
Arm/Group Description: Placebo will be administered ( 2 tablets ) orally twice daily (approximately every 12 hours); Gemcitabine will be administered 1000 mg/m2 pm Days 1 and 8 of a 21 day cycle; Capecitabine will be administered orally at a dose of 1,000 mg/m2 twice daily, within 30 minutes after a meal, for 14 days followed by a 7 day rest period (without capecitabine)
Gemcitabine: Gemcitabine will be administered 1000 mg/m2 pm Days 1 and 8 of a 21 day cycle
Placebo: Placebo will be administered (400 mg; 2 tablets x 200 mg) orally twice daily (approximately every 12 hours)
Capecitabine: Capecitabine will be administered orally at a dose of 1,000 mg/m2 twice daily, within 30 minutes after a meal, for 14 days followed by a 7 day rest period (without capecitabine).
Overall Number of Participants Analyzed: 79
Median (95% Confidence Interval)
Unit of Measure: Days 81 (48 to 95)
|
Contradiction
|
Accelerated partial Breast breast irradiation is used in some form for both cohorts of the secondary trial, but not at all in the primary trial.
|
INTERVENTION 1:
Sentinel Lymph Node Biopsy With Radiolabeled Methylene Blue
One arm diagnostic using 1 mCi of 125-I Methylene blue dye to find sentinel lymph nodes
INTERVENTION 1:
Whole Breast Irradiation (WBI)
Conventional whole breast irradiation (WBI)
Whole breast irradiation (WBI): Conventional whole breast irradiation (WBI)
INTERVENTION 2:
Partial Breast Irradiation (APBI)
Accelerated partial breast irradiation (APBI)
Accelerated partial breast irradiation (APBI): Accelerated partial breast irradiation (APBI) using intensity modulated radiotherapy (IMRT)
|
Contradiction
|
1 patient in the primary trial was affected by Sepsis.
|
Adverse Events 1:
Total: 17/40 (42.50%)
Anaemia 2/40 (5.00%)
Febrile Neutropenia 3/40 (7.50%)
Neutropenia 2/40 (5.00%)
Thrombocytopenia 5/40 (12.50%)
Pericardial Effusion 1/40 (2.50%)
Abdominal Pain Lower 1/40 (2.50%)
Disease Progression 6/40 (15.00%)
Fatigue 1/40 (2.50%)
Pyrexia 3/40 (7.50%)
Septic Shock 1/40 (2.50%)
Streptococcal Infection 1/40 (2.50%)
|
Entailment
|
There were no pain related adverse events observed in the primary trial.
|
Adverse Events 1:
Total: 3/25 (12.00%)
Anemia 0/25 (0.00%)
Sinus tachycardia 0/25 (0.00%)
Pericardial effusion 1/25 (4.00%)
Gastrointestinal disorders - Other, specify -stomatitis) 0/25 (0.00%)
Vomiting 1/25 (4.00%)
Fever 0/25 (0.00%)
Injection site reaction 1/25 (4.00%)
Catheter related infection 0/25 (0.00%)
Activated partial thromboplastin time prolonged 0/25 (0.00%)
Adverse Events 2:
Total: 2/23 (8.70%)
Anemia 1/23 (4.35%)
Sinus tachycardia 1/23 (4.35%)
Pericardial effusion 0/23 (0.00%)
Gastrointestinal disorders - Other, specify -stomatitis) 1/23 (4.35%)
Vomiting 0/23 (0.00%)
Fever 1/23 (4.35%)
Injection site reaction 1/23 (4.35%)
Catheter related infection 1/23 (4.35%)
Activated partial thromboplastin time prolonged 1/23 (4.35%)
|
Entailment
|
Adele is an 85 year old woman with Stage IV histologically confirmed ER+ breast cancer with an ECOG of 0, she has a life expectancy below 6 months and a history of thrombotic events. She is eligible for the primary trial
|
Inclusion Criteria:
Must be female with histologically confirmed breast cancer
Stage II-IV disease
ER and/or PR positive
ECOG Performance Status 0-1
Postmenopausal
|
Contradiction
|
the primary trial tests two different dental imaging modalities, namely Mammography and gamma imaging.
|
INTERVENTION 1:
Mammography Only
For this reporting arm, the interpretation and analysis was done with mammography only.
INTERVENTION 2:
Gamma Imaging
For this reporting arm, the interpretation and analysis was done with gamma imaging only.
|
Contradiction
|
the primary trial results show that Zoledronic Acid Upfront is a better treatment than Zoledronic Acid Delayed-start for preventing any change in Lumbar Spine (L1-L4) Bone Mineral Density (BMD).
|
Outcome Measurement:
Percent Change From Baseline in Lumbar Spine (L1-L4) Bone Mineral Density (BMD)
Bone mineral density (BMD) measurements were assessed by dual energy x-ray absorptiometry (DXA). The DXA devices of participating sites were cross-calibrated and the DXA results were compiled and analyzed by a central reader. Percent change = 100*((BMD at Month 12 - Baseline BMD)/Baseline BMD)). Missing data at month 12 were imputed by using the last observation carried forward (LOCF) method. Post-baseline non-missing data from month 6 were carried forward to month 12. Data prior to month 6 were not carried forward.
Time frame: Baseline, 12 months
Results 1:
Arm/Group Title: Zoledronic Acid Upfront
Arm/Group Description: Participants in the upfront arm received Zoledronic Acid 4 mg i.v. on Day 1 and every 6 months until disease progression (recurrence)or the end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily.
Letrozole : Participants received 2.5 mg daily.
Zoledronic Acid : Participants received Zoledronic Acid 4 mg IV 15-minute infusion every 6 months.
Overall Number of Participants Analyzed: 253
Mean (Standard Deviation)
Unit of Measure: Percentage of BMD 1.955 (3.3658)
Results 2:
Arm/Group Title: Zoledronic Acid Delayed-start
Arm/Group Description: In lieu of a placebo arm, which was considered unethical for this trial, a delayed start arm was used. Participants who met certain clinical criteria indicating risk of lumbar spine or total hip fracture, or experienced clinical fracture unrelated to trauma or any asymptomatic fracture discovered at the Month 36 scheduled visit, were started on zoledronic acid 4 mg i.v. and for every 6 months until disease progression (recurrence) or end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily.
Letrozole : Participants received 2.5 mg daily.
Zoledronic Acid : Participants received Zoledronic Acid 4 mg IV 15-minute infusion every 6 months.
Overall Number of Participants Analyzed: 256
Mean (Standard Deviation)
Unit of Measure: Percentage of BMD -2.325 (3.9542)
|
Contradiction
|
the primary trial and the secondary trial investigate different outcome measures for different interventions.
|
Outcome Measurement:
Pharmacokinetics (PK) of Oral Itraconazole
To determine the pharmacokinetics (PK) of oral itraconazole in patients with MBC by measuring mean trough plasma levels at steady state at weeks 2 and 4.
Time frame: pre-dose at Weeks 2 and 4
Results 1:
Arm/Group Title: Itraconazole
Arm/Group Description: oral itraconazole 200mg a day until disease progression or unacceptable toxicities.
Overall Number of Participants Analyzed: 12
Mean (Standard Deviation)
Unit of Measure: ng/mL Week 2 Intraconazole Concentration: 230.7 (216.8)
Week 4 Intraconazole Concentration: 305.8 (334.8)
Week 2 6-OH Itraconazole Concentration: 454.8 (429.3)
Week 4 6-OH Itraconazole Concentration: 501.6 (502.6)
Outcome Measurement:
Dose Escalation: To Evaluate the Safety and Tolerability of Escalating Doses of the MM-121 Plus Paclitaxel Combination Via Reporting of Dose-limiting Toxicity (DLT)
To establish the safety of escalating doses of MM-121 in combination with paclitaxel in order to determine the recommended phase 2 dose. Dose-escalation conducted using standard 3+3 model to determine maximum tolerated dose. Reports of Dose-Limiting Toxicities (DLTs) were assessed to determine the MTD.
Time frame: From date of first dose to 30 days after termination, the longest 163 weeks
|
Entailment
|
The difference in median Overall Survival (OS) of Patients between the two cohort of the primary trial was less than one month, the patient with the longest OS was in cohort 1.
|
Outcome Measurement:
Overall Survival (OS) of Patients
To compare Overall Survival (OS) of patients who receive 145 mg/m2 NKTR-102 given once every 21 days (q21d) with OS of patients who receive Treatment of Physician's Choice (TPC). Overall survival is defined as the time from the date of randomization to the date of death from any cause. Patients will be followed until their date of death or until final database closure. Patients who are lost-to-follow-up or are alive at the time of analysis will be censored at the time they were last known to be alive or at the date of event cut-off for OS analysis.
Time frame: Within 3 years from study start
Results 1:
Arm/Group Title: NKTR-102
Arm/Group Description: In Group A, NKTR-102 will be administered at a dose level of 145 mg/m2 on a q21d schedule as a 90-minute intravenous (IV) infusion on Day 1 of each treatment cycle.
Overall Number of Participants Analyzed: 92
Median (95% Confidence Interval)
Unit of Measure: months 7.8 (6.1 to 10.2)
Results 2:
Arm/Group Title: Treatment of Physician's Choice (TPC)
Arm/Group Description: In Group B, TPC will be administered per standard of care. Patients randomized to TPC will receive single-agent IV chemotherapy, limited to choice of one of the following 7 agents: eribulin, ixabepilone, vinorelbine, gemcitabine, paclitaxel, docetaxel, or nab-paclitaxel.
Overall Number of Participants Analyzed: 86
Median (95% Confidence Interval)
Unit of Measure: months 7.5 (5.8 to 10.4)
|
Contradiction
|
The Lapatinib group of the primary trial had a smaller Percentage Change From Baseline in Urinary N-telopeptide of Type I Collagen than the Odanacatib 5 mg group
|
Outcome Measurement:
Percentage Change From Baseline in Urinary N-telopeptide of Type I Collagen (u-NTx) at Week 4
u-NTx is a biochemical index of bone resorption. Participants provided urine specimens on Day 1 (baseline) and at Week 4 for measurement of u-NTx.
Time frame: Baseline and Week 4
Results 1:
Arm/Group Title: Single IV Infusion of ZA 4 mg
Arm/Group Description: Participants received a single IV infusion of ZA 4 mg at the start of treatment and a once-daily odanacatib matching placebo tablet for 4 weeks.
Overall Number of Participants Analyzed: 14
Mean (95% Confidence Interval)
Unit of Measure: Percentage change -73 (-80 to -62)
Results 2:
Arm/Group Title: Once-daily Odanacatib 5 mg
Arm/Group Description: Participants received a once-daily odanacatib 5 mg tablet for 4 weeks and a single IV infusion of ZA matching placebo at the start of treatment.
Overall Number of Participants Analyzed: 27
Mean (95% Confidence Interval)
Unit of Measure: Percentage change -77 (-82 to -71)
|
Contradiction
|
57% of patients in cohort 1 of the primary trial had Pathological Complete Response Rates at Surgery.
|
Outcome Measurement:
Pathological Complete Response Rates at Surgery
[Not Specified]
Time frame: at surgery approximately 5 months after initial treatment
Results 1:
Arm/Group Title: Cohort 1
Arm/Group Description: Avastin 10 mg/kg IV over 90 minutes day -14 Abraxane 100 mg/m2 IV over 30 minutes weekly x 12 weeks with Carboplatin at AUC 6 over 30 min IV and Avastin 15 mg/kg IV over 30-90 minutes weeks 1,4,7, and 10 Avastin 10 mg/kg IV over 30-60 minutes cycles 1-3 (omit dose with cycle 4) Doxorubicin 60 mg/m2* and Cyclophosphamide 600 mg/m2 IV q2weeks x 4 cycles Definitive surgery Avastin 10 mg/kg IV over 30-60 minutes q2weeks x 34 weeks
Cohort 1 and Cohort 2: Abraxane 100 mg/m2 IV over 30 minutes weekly x 12 weeks with Carboplatin at AUC 6 over 30 min IV and Avastin 15 mg/kg IV over 30-90 minutes weeks 1,4,7, and 10 (in Cohort 2, omit dose of Avastin on week 10)
Overall Number of Participants Analyzed: 28
Measure Type: Number
Unit of Measure: participants 16
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Entailment
|
Gemcitabine is not used in the primary trial, and used only in cohort 2 of the secondary trial.
|
INTERVENTION 1:
Experimental
cyclophosphamide: chemotherapy
doxorubicin hydrochloride: chemotherapy
adjuvant therapy: chemotherapy
radiation therapy: chemotherapy
INTERVENTION 1:
Arm A: Nab-Paclitaxel + Gemcitabine
Participants received nab-Paclitaxel 125 mg/m^2 on Days 1 and 8 by intravenous (IV) administration followed by gemcitabine 1000 mg/m^2 on Days 1 and 8 by IV administration of each 21-day treatment cycle. Participants continued treatment until progressive disease (PD), unacceptable toxicity, required palliative radiotherapy or surgical intervention of lesion(s), withdrawal from study treatment, withdrawal of study consent, participant refusal or the investigator felt it was no longer in the best interest of the participant to continue on treatment
INTERVENTION 2:
Arm B: Nab-Paclitaxel + Carboplatin
Participants received nab-Paclitaxel 125 mg/m^2 on Days 1 and 8 by IV administration followed by carboplatin area under the curve 2 (AUC 2) on Days 1 and 8 in each 21-day treatment cycle. Participants continued treatment until progressive disease (PD), unacceptable toxicity, required palliative radiotherapy or surgical intervention of lesion(s), withdrawal from study treatment, withdrawal of study consent, participant refusal or the investigator felt it was no longer in the best interest of the participant to continue on treatment.
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Contradiction
|
There is no overlap in treatments used in the primary trial and the secondary trial.
|
INTERVENTION 1:
MAESTRO
Baseline
INTERVENTION 1:
AeroForm Tissue Expansion
AeroForm Tissue Expansion inflation with carbon dioxide by remote control
AeroForm Tissue Expansion: The AeroForm Patient Controlled Tissue Expander is a breast tissue expander implanted following mastectomy and activated by remote control to release small doses of carbon dioxide from an internal reservoir to fill and inflate the expander.
INTERVENTION 2:
Saline Tissue Expansion
Saline Tissue Expansion inflated by needle injections of saline
Saline Tissue Expansion: A saline tissue expander is a breast tissue expander which is implanted following mastectomy and inflated over time using needle injections to fill and inflate the expander with saline.
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Entailment
|
Patients intracranial metastasis may be eligible for the primary trial.
|
Exclusion Criteria:
No metastatic disease to the Central Nervous System
|
Contradiction
|
The majority of the primary trial subjects either had Progressive disease or undetermined CNS objective response rate.
|
Outcome Measurement:
The Number of Participants With Central Nervous System (CNS) Best Overall Response
Summary of CNS Objective Response (Lapatinib Monotherapy - MITT Population)
Response to lapatinib in patients with progressive brain metastases from ErbB2-overexpressing breast cancer.
The primary indicator of drug efficacy was CNS objective response rate. A CNS objective response was defined as either a Complete response (CR) or Partial response (PR), as assessed by volumetric analysis of brain Magnetic resonance imaging (MRI), provided there was no progression of systemic disease outside of the CNS, increasing steroid requirements, or worsening of Neurological signs and symptoms (NSS)
A CNS objective response rate was defined as a 50% volumetric reduction in sum of CNS target lesions, with no new or progressive CNS or non-CNS lesions, no increases in tumor-related steroid requirements and no worsening of neurological signs or symptoms
Time frame: time from baseline to data cutoff (25 Sept 2007); approximately 2 years
Results 1:
Arm/Group Title: Cohort A
Arm/Group Description: 750mg lapatinib administered orally twice daily. Cohort A subjects had Eastern Cooperative Oncology Group (ECOG) performance status 0-1, and one or two prior trastuzumab-containing regimens, in total, for treatment of breast cancer in adjuvant and/or metastatic settings
Overall Number of Participants Analyzed: 94
Measure Type: Count of Participants
Unit of Measure: Participants Complete response (CR): 0 0.0%
Partial response (PR): 6 6.4%
Stable disease (SD): 40 42.6%
Progressive disease (PD): 40 42.6%
Unknown: 8 8.5%
Results 2:
Arm/Group Title: Cohort B
Arm/Group Description: 750mg lapatinib administered orally twice daily. Cohort B subjects had ECOG performance status 2 and/or more than 2 prior trastuzumab-containing regimens for treatment of breast cancer in the adjuvant and/or metastatic settings.
Overall Number of Participants Analyzed: 143
Measure Type: Count of Participants
Unit of Measure: Participants Complete response (CR): 0 0.0%
Partial response (PR): 9 6.3%
Stable disease (SD): 46 32.2%
Progressive disease (PD): 70 49.0%
Unknown: 18 12.6%
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Entailment
|
the primary trial records several central nervous system related adverse events in its patients, whereas the secondary trial does not.
|
Autoimmune disorder *1/30 (3.33%)
Immune system disorder *1/30 (3.33%)
Adverse Events 1:
Total: 7/52 (13.46%)
Febrile neutropenia (fever of unknown origin without clinically or microbiologically documented infe * 0/52 (0.00%)
Atrial Fibrillation * 1/52 (1.92%)
Sepsis * 1/52 (1.92%)
Muscle weakness upper limb * 1/52 (1.92%)
Dizziness * 1/52 (1.92%)
Seizure * 1/52 (1.92%)
Nervous system disorders - Other, specify * [1]1/52 (1.92%)
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Contradiction
|
In the primary trial, all cases of Enteritis, Vertigo and Cardiac failure occurred in cohort 2.
|
Adverse Events 1:
Total: 52/133 (39.10%)
Thrombocytopenia 2/133 (1.50%)
Anaemia 1/133 (0.75%)
Disseminated intravascular coagulation 0/133 (0.00%)
Atrial thrombosis 1/133 (0.75%)
Cardiac failure 0/133 (0.00%)
Vertigo 0/133 (0.00%)
Vomiting 3/133 (2.26%)
Nausea 1/133 (0.75%)
Colitis 1/133 (0.75%)
Constipation 1/133 (0.75%)
Enteritis 0/133 (0.00%)
Abdominal pain 0/133 (0.00%)
Adverse Events 2:
Total: 16/67 (23.88%)
Thrombocytopenia 0/67 (0.00%)
Anaemia 0/67 (0.00%)
Disseminated intravascular coagulation 1/67 (1.49%)
Atrial thrombosis 0/67 (0.00%)
Cardiac failure 1/67 (1.49%)
Vertigo 1/67 (1.49%)
Vomiting 0/67 (0.00%)
Nausea 1/67 (1.49%)
Colitis 0/67 (0.00%)
Constipation 0/67 (0.00%)
Enteritis 1/67 (1.49%)
Abdominal pain 2/67 (2.99%)
|
Entailment
|
Mark complained he had a racing heart twice in the last month and he is therefore excluded from the primary trial.
|
Exclusion Criteria:
Clinically significant, uncontrolled heart disease and/or recent cardiac events.
|
Contradiction
|
the primary trial and the secondary trial both administer treatments to their patients through IV.
|
INTERVENTION 1:
Treatment (MEDI4736, Tremelimumab)
Patients receive anti-B7H1 monoclonal antibody MEDI4736 IV over 1 hour and tremelimumab IV over 1 hour on day 1. Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity. Four weeks after the last combination dose, patients continue to receive anti-B7H1 monoclonal antibody MEDI4736 every 2 weeks for up to 18 additional doses in the absence of disease progression or unacceptable toxicity. Patients achieving PD or clinical benefit (CR, PR, or SD) may be retreated with anti-B7H1 monoclonal antibody MEDI4736 for an additional 52 weeks.
Anti-B7H1 Monoclonal Antibody MEDI4736: Given IV
Laboratory Biomarker Analysis: Correlative studies
Pharmacological Study: Correlative studies
Tremelimumab: Given IV
INTERVENTION 1:
Zoledronic Acid 5 mg IV
Zometa (Zoledronic Acid) 5 mg IV given over 15 minutes as a one time dose. Follow-up at month 1 & every 2 months to month 12 for serum & urine markers of bone destruction (NTx & CTx).
|
Entailment
|
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