E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Her2-Negative, Metastatic or Locally Recurrent Breast Cancer |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10027475 |
E.1.2 | Term | Metastatic breast cancer |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To estimate the treatment effect as measured by progression free survival (PFS) of subjects receiving AMG 386 (at two doses) in combination with paclitaxel + bevacizumab relative to paclitaxel + bevacizumab + placebo. |
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E.2.2 | Secondary objectives of the trial |
• To compare the treatment effect as measured by PFS of subjects receiving openlabel AMG 386 in combination with paclitaxel relative to paclitaxel + bevacizumab + placebo • To compare the treatment effect as measured by PFS of subjects receiving AMG 386 in combination with paclitaxel and bevacizumab relative to paclitaxel + AMG 386 • To evaluate the safety and tolerability of the combination and non-bevacizumab regimens • To estimate other measures (objective response rate, duration of response, overall survival, time to progression, time to response, and percentage change from baseline in the sum of the longest diameters of target lesions) of treatment effect • To evaluate the pharmacokinetics (PK) of AMG 386 and bevacizumab when used in combination • To estimate the incidence of anti-AMG386 antibody formation |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Disease Related • Subjects must have histologically or cytologically confirmed adenocarcinoma of the breast with locally recurrent or metastatic disease. Locally recurrent disease must not be amenable to resection with curative intent. • Measurable or non-measurable disease per modified RECIST guidelines (see Appendix G). • Complete radiology and tumor measurement within 28 days prior to randomization: - Chest: CT / MRI scan with intravenous contrast if the contrast is not medically contraindicated - Abdomen: CT / MRI scan with intravenous contrast if the contrast is not medically contraindicated - Pelvis: CT / MRI scan with intravenous contrast if the contrast is not medically contraindicated - Head or Brain: CT / MRI scan - Bone: Whole body Bone Scintigraphy - Demographic • Female 18 years of age or older at the time the written informed consent is obtained • Subjects of child-bearing potential and sexually active must use an accepted and effective non-hormonal method of contraception (i.e., double barrier method [e.g. condom plus diaphragm]) from signing the informed consent through 6 months
- General • Able to tolerate intravenous infusions • ECOG of 0 or 1 (within 14 days prior to randomization)
- Laboratory Adequate organ and hematological function as evidenced by the following laboratory studies within 28 days prior to randomization: • Hematological function, as follows: - Absolute neutrophil count (ANC) ≥ 1.5 x 109/L - Platelet count ≥ 100 x 109/L and ≤ 850 x 109/L - Hemoglobin ≥ 9 g/dL - PTT or a PTT and INR ≤ 1.0 x ULN per institutional laboratory range • Renal function, as follows: - Calculated creatinine clearance > 40 cc/min according to the Cockcroft- Gault formula
GFR (mL/min) = (140–age) x actual body weight (kg) (x 0.85 for females) -------------------------------------------- 72 x serum creatinine (mg/dL)
- Urinary protein quantitative value of ≤ 30 mg in urinalysis or ≤ 1+ on dipstick, unless quantitative protein is < 1000 mg in a 24 hour urine sample • Hepatic function, as follows: - Total bilirubin ≤ 2.0 x ULN per institutional laboratory range - SGOT (AST) and SGPT (ALT) ≤ 2.5 x ULN per institutional laboratory range (≤ 5 x ULN if liver metastases are present) • Cardiac function, as follows: - Normal sinus rhythm (no significant ECG changes) - Left ventricular ejection fraction ≥ LLN, as determined by echocardiogram or MUGA scan, according to institutional standards within 28 days prior to randomization |
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E.4 | Principal exclusion criteria |
- Disease Related • Inflammatory Breast Cancer • Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 peripheral neuropathy > grade 1 at randomization • History of arterial or venous thrombosis, including transient ischemic attack (TIA), within 1 year prior to randomization • Adjuvant or neoadjuvant taxane treatment within 12 months of randomization any other adjuvant chemotherapy regimen must be discontinued at least 21 days prior to randomization • Prior chemotherapy, vaccine, or biological therapy for locally recurrent or metastatic breast cancer (prior endocrine therapy is permitted) • Prior radiation therapy, radiofrequency ablation, percutaneous cryotherapy or hepatic chemoembolization on all sites of disease unless disease progression was subsequently documented prior to 14 days of randomization • Overexpression of HER-2 (gene amplification by FISH or 3+ over expression by immunohistochemistry). - Eligibility of subjects with 2+ immunohistochemistry must be confirmed by a negative FISH assay • Current or prior history of central nervous system metastasis • History of bleeding diathesis or clinically significant bleeding within 6 months prior to randomization • Major surgical procedure within 28 days prior to randomization • Open breast biopsy within 14 days prior to randomization • Minor surgical procedure, placement of access device, or fine needle aspiration within 7 days of first dose • Exclude subjects with a history of prior malignancy, except: - Malignancy treated with curative intent and with no known active disease present for ≥ 3 years before enrollment and felt to be at low risk for recurrence by treating physician - Adequately treated non-melanomatous skin cancer or lentigo maligna without evidence of disease - Adequately treated cervical carcinoma in situ without evidence of disease
• Clinically significant cardiac disease within 12 months prior to randomization, including myocardial infarction, unstable angina, grade 2 or greater peripheral vascular disease, cerebrovascular accident, transient ischemic attack, congestive heart failure, or arrhythmias not controlled by outpatient medication • Non-healing wound, ulcer or fracture • Ongoing or active infection • Known hypersensitivity to paclitaxel or drugs using the vehicle cremophor • Known hypersensitivity to bacterial proteins, or any of the drugs required in this study • Known positive test for human immunodeficiency virus (HIV), hepatitis C, or hepatitis B surface antigen • Known active or chronic hepatitis • Uncontrolled hypertension as defined as systolic blood pressure ≥ 150 mm Hg and diastolic blood pressure ≥ 90 mm Hg. Anti-hypertensive medications are allowed if the subject is stable on their current dose at the time of randomization.
- Medications • Currently or previously treated with any VEGF or VEGFr inhibitor including, but not limited to, bevacizumab, SU11248 (sunitinib), PTK787 (vatalinib), AZD 2171, AEE-788, BAY 43-9006 (sorafenib) and motesanib diphosphate (AMG 706). • Concurrent or prior (within 1 week before randomization) anticoagulation therapy, excluding aspirin and anti-platelet agents. The concurrent use of low molecular weight heparin or low dose warfarin (ie, ≤ 1 mg daily) for prophylaxis against thrombosis is acceptable while on study • Currently or previously treated with angiopoietin inhibitors, or inhibitors of TIE-1 or TIE-2 including, but not limited to, AMG 386, XL880, XL820 • Treatment with immune modulators such as cyclosporine or tacrolimus within 30 days prior to randomization • Concomitant therapy with any hormonal agent such as raloxifene, tamoxifen, or other selective estrogen receptor modulators (SERMS), given for breast cancer prevention or for osteoporosis. Subjects must have discontinued these agents 14 days prior to randomization
- General • Any condition which in the investigator’s opinion makes the subject unsuitable for study participation • Participation (treatment phase) in other investigational device or administration of other investigational treatments within 30 days prior to randomization • Pregnant (ie, positive beta-human chorionic gonadotropin test) or is breast feeding • Previously enrolled into this study • Inability to comply with protocol and/or not available for follow-up assessments
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression-free survival (PFS): time from randomization date to date of disease progression per the modified RECIST criteria or death. Subjects not meeting criteria for progression by the analysis data cutoff date will be censored at their last evaluable disease assessment date. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of study is when all subjects have completed the treatment period or long-term follow-up (maximum 48 months from the date the last subject is randomized), whichever is later. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |