| 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 (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 and at least 4 weeks from major surgery.
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 (subjects on therapeutic dose warfarin are not allowed to participate; low dose warfarin or low molecular weight heparin for prophylactic use is permitted).
19) Serum creatinine ≤ 1.5 x ULN or 24-hour creatinine clearance > 60 mL/min
(measured or calculated by Cockcroft-Gault method)
20) Negative or trace proteinuria on dipstick. (If proteinuria on dipstick is ≥ 1+, a 24 hr urine collection is required to confirm < 500mg proteinuria in 24 hrs) |
|
| 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 8 weeks after treatment withdrawal.
2) Women who are pregnant or breastfeeding
3) Women with a positive pregnancy test on enrollment or prior to study drug
administration.
4) Evidence of baseline sensory or motor neuropathy.
5) Serious intercurrent infections or non-malignant medical illnesses that are
uncontrolled or the control of which may be jeopardized by this therapy.
6) History of abdominal fistula, GI perforation, intra-abdominal abscess, or serious
gastric ulcer or bone fracture within 6 months prior to study entry.
7) Clinically significant cardiovascular disease (e.g. unstable angina, congestive heart
failure, uncontrolled hypertension (>150/90), myocardial infarction or cerebral
vascular accidents) within 6 months prior to study entry.
8) Prior history of high dose chemotherapy with bone marrow transplant or peripheral blood stem cell transplant within the previous 2 years.
9) Prior treatment with an epothilone (or epothilone analogue) or bevacizumab.
10) History of bleeding diathesis, pulmonary embolism, deep vein thrombosis or use of therapeutic anticoagulants as therapy. (Low dose anticoagulant therapy to maintain vascular access is allowed)
11) Concurrent non-healing wound or fracture.
12) 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.
13) Psychiatric disorders or other conditions rendering the subject incapable of complying with the requirements of the protocol.
14) 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).
15) Known human immunodeficiency viral (HIV) infection.
16) 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.
17) 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: amiodarone, clarithromycin, amprenavir,
delavirdine, voriconazole erythromycin, fluconazole, itraconazole, ketoconazole,
indinavir, nelfinavir, ritonavir, and saquinavir.
18) Other concurrent anti-tumor chemotherapy, hormonal therapy, immunotherapy
regimens or radiation therapy, standard or investigational (see Section 6.4.2).
19) 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.
20) 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 | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Information not present in EudraCT |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Information not present in EudraCT |
| E.6.7 | Pharmacodynamic | Information not present in EudraCT |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| 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 | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| 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 | 2 |
| 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
|
Off study visit procedures should be completed within 30 days after the last dose of study drug.
For subjects with continuing study drug toxicities, a follow up visit will be required at
least every 4 weeks until all study related toxicities resolve to baseline, stabilize, or are deemed irreversible. Subjects who come off study for reasons other than progression should be followed every 3 months until progression is documented. |
|
| 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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