| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally Recurrent or Metastatic Breast Cancer |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10006187 |
| E.1.2 | Term | Breast cancer |
|
| 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 response rate of ixabepilone/bevacizumab combination in each of the following 2 schedules relative to the reference arm of paclitaxel plus bevacizumab:
• Ixabepilone administered every week for 3 weeks followed by 1 week rest plus
bevacizumab administered every 2 weeks (Arm A) and
• Ixabepilone administered every 3 weeks plus bevacizumab administered every
3 weeks (Arm B). |
|
| E.2.2 | Secondary objectives of the trial |
• To determine the week 24 PFS rate
• To estimate the progression free survival for the 3 treatment arms
• To determine time to response for the 3 treatment arms
• To determine the duration of response for the 3 treatment arms
• To estimate overall survival for the 3 treatment arms
• Determine the safety and tolerability of these schedules in this subject population for the 3 treatment arms |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Signed written informed consent
2) Men or women ages ≥ 18 years
3) Histologic or cytologic confirmed diagnosis of invasive adenocarcinoma originating in the breast with evidence of locally recurrent or metastatic disease.
4) At least one target lesion per RECIST criteria (Protocol Section 3.3). Locally recurrent disease must not be amenable to resection with curative intent. Previously radiated area(s) must not be the only site of disease.
5) Subjects must not have received cytotoxic chemotherapy for locally recurrent/metastatic disease. (Subjects may have received adjuvant or neo adjuvant chemotherapy)
6) Subjects who received prior adjuvant or neoadjuvant taxane therapy must have relapsed ≥ 12 months after completing therapy.
7) Subjects must not have breast cancer known to over express or amplify Her-2 (i.e., 3+ by immunohistochemistry and/or FISH positive).
8) Prior hormonal therapy in adjuvant, recurrent or metastatic setting is allowed, but this must have been discontinued at least 2 weeks prior to randomization.
9) Karnofsky performance status (PS) of 80-100 (or ECOG, PS of 0-1).
10) Estimated life expectancy of at least 12 weeks.
11) Recovery (except for alopecia) from recent therapy, including chemotherapy, immunotherapy, biological therapy or investigational product. Any such therapy must have been completed at least 3 weeks prior to randomization and at least 6 weeks from use of nitrosourea, or mitomycin.
12) Recovery from recent surgery and radiation therapy. At least one week must have elapsed from minor surgery (e.g. placement of venous access device or fine needle aspiration) and/or focal/palliative radiation therapy; at least 3 weeks from radiation, at least 4 weeks from major surgery, and at least 8 weeks from liver resection, thoracotomy or neurosurgery.
13) Absolute neutrophil count (ANC) ≥ 1500/mm3,
14) Hemoglobin ≥ 9 g/dL,
15) Platelets ≥ 100,000/mm³
16) Total bilirubin ≤ 1.5 x times the upper limit of normal (ULN)
17) AST or ALT ≤ 2.5 x ULN
18) Normal PTT and either INR or PT <1.5 x ULN
19) Serum creatinine ≤ 1.5 x ULN or 24-hour creatinine clearance > 60 mL/min (measured or calculated by Cockcroft-Gault method)
20) Urine dipstick for proteinuria < 2+ (negative, trace or +1). Subjects discovered to have ≥ 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate ≤ 1g of protein in 24 hours to be eligible. |
|
| E.4 | Principal exclusion criteria |
1) WOCBP unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and up to 6 months after treatment with bevacizumab.
2) Women who are pregnant or breastfeeding
3) Women with a positive pregnancy test on enrollment or prior to study drug administration.
4) Sexually active fertile men, whose partners are WOCBP, not using an adequate method of birth control.
5) Evidence of baseline sensory or motor neuropathy.
6) Serious intercurrent infections or non-malignant medical illnesses that are uncontrolled or the control of which may be jeopardized by this therapy.
7) History of abdominal fistula, GI perforation, intra-abdominal abscess, or serious gastric ulcer or bone fracture within 6 months prior to study entry.
8) Any prior history of hypertensive crisis or hypertensive encephalopathy.
9) Significant vascular disease (e.g., aortic aneurysm, aortic dissection).
10) Clinically significant cardiovascular disease (e.g. unstable angina, New York Heart Association Class II or greater congestive heart failure, uncontrolled hypertension (>150/90), myocardial infarction or cerebral vascular accidents) within 6 months prior to study entry.
11) Baseline LVEF by MUGA or echocardiogram for subjects with prior exposure to anthracyclines not within institutional normal limits.
12) Symptomatic peripheral vascular disease.
13) Prior history of high dose chemotherapy with bone marrow transplant or peripheral blood stem cell transplant within the previous 2 years.
14) Prior treatment with an epothilone (or epothilone analogue) or any antiangiogenic agent.
15) Evidence of bleeding diathesis or coagulopathy.
16) Concurrent non-healing wound, ulcer or fracture.
17) Any current or previous history of brain and/or leptomeningeal metastases including evidence of cerebral edema by computerized tomography (CT) or magnetic resonance imaging (MRI). Head CT or MRI must be obtained within 4 weeks prior to randomization.
18) Psychiatric disorders or other conditions rendering the subject incapable of complying with the requirements of the protocol.
19) Any concurrent active malignancy other than non-melanoma skin cancer or carcinoma in situ of the cervix. (Subjects with a history of previous malignancies but without evidence of disease for 5 years will be allowed to enter the trial).
20) Known human immunodeficiency viral (HIV) infection.
21) Known allergy to any of the study drugs or their excipients such as, prior severe HSR to agents containing Cremophor®EL; or allergies to Chinese hamster ovary cell proteins or other recombinant humanized antibodies.
22) Subjects must not continue or institute treatment with the following strong inhibitors of CYP3A4 from 72 hours prior to the initiation of study therapy until end of treatment with ixabepilone or paclitaxel: amprenavir, delavirdine, voriconazole, itraconazole, ketoconazole, indinavir, nelfinavir, ritonavir, and saquinavir.
23) Other concurrent anti-tumor chemotherapy, hormonal therapy, immunotherapy regimens or radiation therapy, standard or investigational (see Protocol Section 6.4.2).
24) Aspirin (>325 mg/day), or non-steroidal anti inflammatory medications and other medications known to inhibit platelet function (e.g. dipyridamole, ticlopidine, clopidogrel or cilostazol) within 10 days of randomization.
25) Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious disease) illness. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- The primary efficacy endpoint is the overall response rate (RR) defined for each arm as the number of subjects with best tumor response on-study of CR or PR divided by the number of randomized subjects in the arm. Secondary endpoints are 24 week PFS rate, time to response, duration of response and overall survival.
- Exploratory analyses will assess the impact on QOL using the EORTC QLQ-C30© and the Herth Hope Index© for all randomized subjects, who meet the PRO evaluation criteria (see Protocol Section 3.3.11).
- The safety profile of the three treatment arms will be assessed through summaries of adverse events, serious adverse events, deaths, adverse events leading to discontinuation and laboratory abnormalities in hematology, liver function and renal parameters for all treated subjects. |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Quality Of Life measures: EORTC QLQ-C30© and Herth Hope index© |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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 | No |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 |
|
| 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
|
Subjects will continue treatment until documented disease progression or unacceptable toxicity.
Subjects will be followed for survival for 20 months from the last subject accrued.
For details re. follow-up duration, refer to Protocol Section 6.2.8.
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| 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 | 2 |
| 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 |
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