E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
HER2 Negative Locally Recurrent or Metastatic Breast Cancer |
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E.1.1.1 | Medical condition in easily understood language |
Breast Neoplasms
Breast Tumors
Breast Cancer
Locally Recurrent and Metastatic Breast Cancer |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10027475 |
E.1.2 | Term | Metastatic breast cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
The primary objective of the study is to determine if treatment with paclitaxel and AMG 706 is superior to paclitaxel plus AMG 706 placebo in subjects with HER2 negative locally recurrent or metastatic breast cancer, based on objective response rates. |
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E.2.2 | Secondary objectives of the trial |
• To estimate the differences in progression- free survival time, clinical benefit, overall survival and duration of response between Arm A (paclitaxel plus AMG 706 placebo) and Arm B (paclitaxel plus AMG 706).
• To estimate the differences in objective response rate, progression- free survival time, clinical benefit, overall survival and duration of response between Arm B (paclitaxel plus AMG 706) and Arm C (paclitaxel plus bevacizumab)
• To evaluate safety and tolerability in the three treatment arms |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Written informed consent must be obtained prior to any study-related procedures.
2. 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.
3. Measurable disease per RECIST ( Response Evaluation Criteria in Solid Tumor) guidelines.
4. Complete radiology and tumor measurement within 4 weeks (28 days) prior to registration:
a. Chest: CT scan with intravenous contrast if the contrast is not medically contraindicated.
b. Abdomen: CT scan with intravenous and oral contrast if the contrast is not medically contraindicated.
c. Pelvis: CT scan with intravenous and oral contrast if the contrast is not medically contraindicated.
d. Brain: CT scan or MRI
e. Bone: Whole body Bone Scintigraphy.
5. Tumor (primary or metastatic) must be HER2 negative by fluorescence in-situ hybridization (FISH) or chromogenic in-situ hybridization (CISH) or 0, 1+ overexpression by immuno- histochemistry.
6. Female 18 years of age or older at the time the written informed consent is obtained.
7. ECOG Performance Status of 0 or l.
8. Adequate organ and hematological function as evidenced by the following laboratory studies within 2 weeks (14 days) of study registration, unless stated otherwise:
a. Cardiac function
b. Hematological function
c. Renal function
d. Hepatic function
9. Subjects of child- bearing potential and sexually active must provide a negative pregnancy test within 7 days prior to registration and use an accepted and effective non- hormonal method of contraception during study treatment and up to 6 months after last dose of study |
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E.4 | Principal exclusion criteria |
Disease Related
1. Adjuvant or neoadjuvant taxane treatment within 12 months of randomization. Any other adjuvant chemotherapy regimen must be discontinued at least 3 weeks (21 days) prior to study registration.
2. Prior chemotherapy for locally recurrent or metastatic breast cancer ( prior endocrine therapy is permitted).
3. Prior radiation therapy, radiofrequency ablation, percutaneous cryotherapy or hepatic chemoembolization on all sites of measurable disease unless progression was subsequently documented on at least one of these sites.
Medications
4. Currently or previously treated with bevacizumab or small molecule inhibitors of VEGF including, but not limited to, SU11248 (sunitinib), PTK787 (vatalinib), AZD 2171, AZD 6474, AEE- 788, BAY 43- 9006 (sorafenib) and AMG 706.
5. Treatment with coumadin anticoagulants, (other than low dose prophylaxis for central venous catheters < 1mg/ d) within 7 days prior to study registration.
6. Treatment with rifampin, carbamazepine, rifabutin or phenobarbital within 14 days prior to study registration.
General
7. Any condition which in the investigator’s opinion makes the subject unsuitable for study participation
8. Participation in other investigational device drug trials, or administration of other investigational treatments within 30 days prior to study registration.
9. Pregnant ( i. e., positive beta- human chorionic gonadotropin test) or breast feeding. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Endpoint as defined by RECIST
Objective Response Rate: the percentage of subjects assigned to a treatment arm with a confirmed best independent review committee.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary analysis for the objective response rate will be performed when all subjects who are receiving protocol specified therapy have at least their second radiological image (i.e., the radiological imaging at week 16). An updated analysis will be performed when every subject on the study receiving protocol specified therapy have at least 10 months after first dose of study treatment. |
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E.5.2 | Secondary end point(s) |
• To estimate the differences in progression-free survival time, clinical benefit, overall survival and duration of response between Arm A (paclitaxel plus placebo) and Arm B (paclitaxel plus motesanib).
• To estimate the differences in objective response rate, progression-free survival time, clinical benefit, overall survival and duration of response between Arm B (paclitaxel plus motesanib) and Arm C (paclitaxel plus bevacizumab).
• To evaluate safety and tolerability in the 3 treatment arms.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The primary analysis for the objective response rate will be performed when all subjects who are receiving protocol specified therapy have at least their second radiological image (i.e., the radiological imaging at week 16). An updated analysis will be performed when every subject on the study receiving protocol specified therapy have at least 10 months after first dose of study treatment. |
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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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
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 | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
AMG 706 arms are double-blind, Bevacizumab arm is open-label |
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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.8.2.4 | Number of treatment arms in the trial | 3 |
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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 36 |
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 | No |
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 |
Australia |
Canada |
Hong Kong |
India |
New Zealand |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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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last end of study treatment visit of last subject |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |