E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Subjects with Advanced Solid Tumors |
|
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 | 10065252 |
E.1.2 | Term | Solid tumor |
|
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 |
Compare progression free survival (PFS) for brivanib versus placebo in subjects with advanced solid tumor with FGF-2 over-expression and who have obtained stable disease after 12 weeks of treatment with brivanib separately for each tumor type. |
|
E.2.2 | Secondary objectives of the trial |
• To determine the objective response rate (RR), duration of response (DOR), time to response (TTR), disease stabilization rate (DSR), and change in tumor size in FGF+ subjects • To evaluate the safety of brivanib when given as mono-therapy • To assess other biomarker studies and correlate with clinical outcomes (Collagen IV, VEGF, VEGFR-2, sFGF). • To investigate associations between exposure to BMS-540215 and changes in biomarkers |
|
E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pharmacogenetics Blood Sample Amendment 01 (version 1.0, dated 28-Jan-2008)
The objective of this Amendment is to permit the collection and storage of blood samples for use in future exploratory pharmacogenetic research studies. BMS will use DNA obtained from the blood sample and health information collected from the main clinical trial, CA182026 case report form, to study the association between genetic variation and drug response. BMS may also use the DNA to study the causes and further progression of oncology diseases. Samples from this and other clinical studies may also be used in conjunction to accomplish this objective. |
|
E.3 | Principal inclusion criteria |
1) Target population
a) Able to comply with visits/procedures required by protocol. b) Life expectancy at least 3 months. c) Histologic or cytologic confirmed diagnosis of a solid tumor which is unresectable and locally advanced or metastatic in which no approved effective therapy exists or for subjects who are intolerable to such therapy. The initial enrollment will focus on non-small cell lung, gastric/esophageal adenocarcinoma, soft tissue sarcoma, transitional cell carcinoma, and pancreatic cancer including ampulla of Vater tumors. Upon evaluation of preliminary data and recommendation from the Steering Committee, one or more of the following tumor types may be substituted: refractory prostate cancer, ovarian cancer, breast cancer, endometrial carcenoma, melanoma or head and neck cancer. d) Measurable disease as defined in section 6.4.1.2. e) Adequate tumor sample for FGF-2 assay as defined by historical pathology report or local pathologist review (Appendix 6). f) Adequate bone marrow, renal and hepatic function. g) ECOG performance status 0 or 1 (Appendix 4). h) Adequate recovery (baseline or Grade 1 for major toxicities) from recent therapy. At least 1 week must have elapsed from the time of a minor surgery, and at least 8 weeks for major surgery or radiation therapy. i) At least 3 weeks must have elapsed from the last dose of chemotherapy or targeted agents providing the subject has recovered from all toxicities. At least 8 weeks must have elapsed from the last dose of bevacizumab prior to beginning protocol therapy
2) Age and sex a) Men and women age 18 or older. 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. |
|
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 to 12 weeks after the last dose of investigational product. b) Women who are pregnant or breastfeeding c) Women with a positive pregnancy test on enrollment or prior to investigational product administration. d) Sexually active fertile men not using effective birth control if their partners are WOCBP (including up to 12 weeks after the last dose of investigational product). 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. c) Subjects with centrally cavitating lung lesions. 3) Medical History and Concurrent Diseases a) History of thrombo-embolic disease within the last six months requiring therapeutic anticoagulation b) Subjects with previous 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. c) Subjects with history of poor wound healing or non healing ulcers d) Uncontrolled or significant cardiovascular disease including: • Myocardial infarction within 12 months • Uncontrolled angina within 12 months • Class III-IV New York Heart Association (NYHA) congestive heart failure (Appendix 7) • Valvular heart disease CTCAE grade ≥ 2 (asymptomatic; moderate regurgitation or stenosis by imaging) • Uncontrolled hypertension (Systolic BP > 150 or diastolic BP > 100 mmHg for 24 hours) despite optimized anti-hypertensive therapy. BP must be below 150/100 mmHg at screening. Subjects with a history of hypertension who are receiving treatment with calcium channel blockers that are CYP3A4 substrates should be changed to an alternative antihypertensive medication before study entry (Appendix 3). • History of stroke, TIA, or other ischemic event e) 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 f) 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 g) Inability to swallow tablets or untreated malabsorption syndrome h) Inability to tolerate multiple blood sampling/or tolerate venous access i) Any other medical, psychiatric, and/or social reason as determined by the Investigator
4) Physical and Laboratory Test Findings a) Absolute neutrophil counts < 1,500/mm3, platelet count < 80,000/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 d) Hyponatremia with sodium < 125mEq/L e) Albumin < 2.5 g/dl 5) Allergies and Adverse Drug Reactions a) History of allergy to brivanib its drug class, or related compounds 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 7) Other Exclusion Criteria a) Prisoners or subjects who are involuntarily incarcerated b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
Safety: The safety endpoints will consist of frequencies 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. All subjects who receive study medication will be included in the safety evaluation. Adverse events and other symptoms will be graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0, dated 09 August 2006.
Efficacy: Tumor response will be evaluated according to Modified WHO criteria.
Pharmacokinetic: Measurements of pharmacokinetic concentrations for BMS 540215 will be based on plasma samples on specified study days and times.
Pharmacodynamic: Measurements of Collagen IV and sVEGFR2 from plasma samples by ELISA will be used for pharmacodynamic analysis.
Exploratory/Proteomic and Genomic : Measurements of Collagen IV, and sVEGFR2 from plasma samples by ELISA will also be used for predictive markers analyses. SNPs will be evaluated from blood and tumor samples. Levels of FGF-2 protein will be evaluated from tumor samples by IHC.
|
|
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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | Information not present in EudraCT |
E.6.9 | Dose response | Information not present in EudraCT |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
E.6.13 | Others | Information not present in EudraCT |
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 | Yes |
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
| 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 | 11 |
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
| |
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 | 2 |
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 | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |