| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with advanced metastatic colorectal cancer (MCRC) |
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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 | 10061451 |
| E.1.2 | Term | Colorectal 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 |
Part 1: To define the recommended dose of brivanib that can be safely administered in combination with Erbitux and irinotecan to K-Ras wild type subjects with advanced metastatic colorectal cancer (MCRC).
Part 2: To compare median duration of progression free survival (PFS) in the 2 treatment arms |
|
| E.2.2 | Secondary objectives of the trial |
• To estimate the thrombosis related event rate in each treatment arm, and using data from Part I and Part II
• To describe any preliminary evidence of anti-tumor activity as measured by response rate duration of response, and progression free-survival for each treatment arm
• To assess the PK of BMS-540215 in subjects following administration of either brivanib alone or in combination with irinotecan
• To assess the PK of irinotecan and the active metabolite SN-38 in subjects when given alone and in combination with brivanib
• To assess the effects of brivanib and irinotecan on EMCP
• To assess correlation of FDG-PET and progression free survival as assessed by CT/MRI using modified WHO criteria
• To assess any treatment effect on changes in Collagen IV and sVEGFR2
• To obtain blood and paraffin-embedded tumor samples for the purpose of identifying predictive markers of biological response utilizing enzyme-linked ELISA, and/or other techniques
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|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Signed Written Informed Consent
a) Voluntary signed and dated written informed consent form in accordance with regulatory and institutional guidelines obtained before the performance of any protocol-related procedures not part of normal subject care.
2) Target Population
a) Able to comply with visits/procedures required by protocol.
b) Life expectancy at least 3 months.
c) Subjects with histological or cytological confirmed diagnosis of metastatic CRC.
d) Part 1: Subjects who have progressive or refractory disease after treatment with one or more chemotherapy regimens, not including adjuvant therapy.
e) Part 2: Subjects who have progressive or refractory disease after treatment with only one chemotherapy regimen, not including adjuvant therapy.
f) Subjects who have bi-dimensionally measurable disease by CT or MRI
g) Subjects in both parts of the study may have received a prior irinotecan or a prior Erbitux containing regimen, but they may not have received a prior regimen containing both irinotecan and Erbitux.
h) Exactly one prior anti-angiogenesis therapy alone or as part of a multidrug
regime is permitted
i) ECOG performance status 0-1 (Appendix 3)
j) Subject must be available for follow-up
k)Archived tumor must be confirmed to be K-Ras wild type by means of mutation analysis performed on representative samples of diagnostic tumor tissue by a central reference laboratory
3) Age and Sex
a) Men and women, over age 18. Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 12 weeks after the last dose of investigational product in such a manner that the risk of pregnancy is minimized. WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea ≥ 12 consecutive months; or women on hormone replacement therapy [HRT] with documented serum follicle stimulating hormone [FSH] level > 35 mIU/mL). Even women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence or where their partner is sterile (eg, vasectomy) should be considered to be of childbearing potential. WOCBP must have a negative serum (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of investigational produc |
|
| E.4 | Principal exclusion criteria |
1) Sex and Reproductive Status
a) WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to12 weeks after the last dose of investig product
b) WOCBP using a prohibited contraceptive method
c) Women who are pregnant or breastfeeding
d) Women with a positive pregnancy test on enrollment or prior to investigational product administration
e) Sexually active fertile men not using effective birth control if their partners are WOCBP
2) Target Disease Exceptions
a) Subjects with known brain metastasis
b) Subjects with signs or symptoms suggestive of brain metastasis are not eligible unless brain metastases are ruled out by CT or MRI
3) Medical History and Concurrent Diseases
a) Subjects with implantable porta-cath devices or central venous access are allowed in this study, but catheter prophylaxis with low dose warfarin is not permitted. A 14 day wash out period after stopping warfarin prophylaxis is required prior to starting study treatment.
b) Any history of thrombo-embolic disease requiring therapeutic anticoagulation
c) Subjects with concomitant second malignancies (except non-melanoma skin cancers, in situ bladder or cervical cancers) are excluded unless a complete remission was achieved at least 5 years prior to study entry and no additional therapy is required or anticipated to be required during the study period
d) Subjects with history of poor wound healing or non healing ulcers
e) Uncontrolled or signif. cardiovascular disease including:
• Myocardial infarction within 12 months
• Uncontrolled angina within 12 months
• Class III-IV New York Heart Association (NYHA) congestive heart failure
• LVEF < 45%
• Uncontrolled hypertension (Systolic BP > 150 and diastolic BP > 100 mmHg for 24 hours). BP must be below 150/100 mmHg at screening.
• History of stroke, TIA, or other ischemic event
• Valvular heart disease CTCAE Grade ≥ 2 (asymptomatic; moderate regurgitation or stenosis by imaging).
f) A serious uncontrolled medical disorder or active infection which would impair the ability of the subject to receive protocol therapy or whose control may be jeopardized by the complications of this therapy
g) Any psychiatric or other disorders such as dementia that would prohibit the subjects from understanding or rendering informed consent or from fully complying with protocol treatment and follow-up
h) Inability to swallow tablets or any gastrointestinal disease that may impact the absorption of the drug (i.e. recent gastrointestinal surgery such as a whipple procedure, mal-absorption syndrome.)
i) Subjects requiring the use of a feeding tube
j) Inability to tolerate multiple blood sampling/or tolerate venous access
k) Any other sound medical, psychiatric, and/or social reason as determined by the Investigator
l) Subjects with chronic inflammatory bowel disease and/or bowel obstruction
4) Physical and Laboratory Test Findings
a) Absolute neutrophil counts < 1,500/mm3, platelet count < 100,000/mm3, or hemoglobin < 9 g/dL.
b) serum total bilirubin > 1.5 times the institutional upper limits of normal or ALT or AST > 2.5 times the institutional upper limits of normal (> 5 times IULN for subjects with documented liver metastases).
c) serum creatinine > 1.5 times the institutional upper limits of normal or calculated creatinine clearance < 50 mL/min/1.73m2
d) Subjects who are positive for UGT1A1 genotype *28/*28 (TA7/TA7)
5) Allergies and Adverse Drug Reactions
a) History of allergy to brivanib its drug class or related compounds
b) Subjects with known or suspected allergy to irinotecan or cetuximab.
6) Prohibited Treatments and/or Therapies
a) Exposure to any investigational drug within 4 weeks of enrollment
b) Other concurrent chemotherapy, hormonal therapy, immunotherapy regimens or radiotherapy, standard or investigational • Subjects may continue to receive hormone replacement therapy
c) Prior exposure to brivanib , or combination treatment with Erbitux® and
irinotecan.
d) Current medication with any anticoagulants including coumadin, heparin, or low-molecular weight heparins. A 14 day wash out period is required before start of study therapy
e) Use of Erythropoietin stimulating agents (ESA) are not permitted while on study. Subjects requiring augmentation of hemoglobin/hematocrit may receive transfusions as clinically indicated
7) Other Excl. Criteria
a) Prisoners or subjects who are involuntarily incarcerated.
b) Subjects who are compulsory detained for treatment of either a psychiatric or physical illness
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety assessments: will be based on adverse event reports and the results of vital signs measurements, 2-D ECHO, physical examinations, and clinical laboratory tests. The incidence of adverse events will be tabulated and reviewed for potential significance and clinical importance. The incidence of TRE’s for each treatment will be estimated from data in Parts 1 and 2.
Efficacy: Tumor response will be evaluated according to modified WHO criteria for Part 1 and 2. Progression Free Survival (PFS) and Duration of Overall Response will be calculated for subjects in Part 2. FDG-PET in Part 2: pharmacodynamic changes in tumor metabolic activity measured by the changes in FDG PET SUV will be assessed at baseline, and at the end of Cycle 2. The parameters evaluated are SUVMean, SUVPeak and SUVmax. Derived outcomes from measurements across different lesions will also be calculated. Metabolic response rates based on EORTC criteria will also be provided. |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | 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 | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 | 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 30 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 30 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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