| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Progressive or recurrent non-small cell lung cancer (NSCLC) after treatment with one to two lines of cytotoxic chemotherapy |
|
| 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 | 10061873 |
| E.1.2 | Term | Non-small cell lung 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 compare the Progression-free survival (PFS) in subjects receiving BMS-690514 relative to erlotinib. |
|
| E.2.2 | Secondary objectives of the trial |
• To estimate the objective response rate (ORR) in subjects receiving BMS-690514 or erlotinib
• To compare the Overall survival (OS) in subjects receiving BMS-690514 or erlotinib
• To estimate the PFS rate and tumor size change at 6 weeks (using CT/MRI) in subjects receiving BMS-690514 or erlotinib
• To assess the safety and tolerability of both BMS-690514 and erlotinib
• To estimate the association between efficacy and EGFR copy number measured by FISH for both BMS-690514 and erlotinib
• To obtain samples for population pharmacokinetics of BMS-690514 in previously chemotherapy treated NSCLC patients. |
|
| 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 |
(1) Pharmacogenetics Blood Sample Amendment 01 (version 1.0 dated 30-Jul-08):
Objective:
- 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, CA187017 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.
(2)CA187-017 Site-Specific Protocol Amendment 2 (version 1.0, dated 19-Sep-08):
A Double-Blind Randomized, Parallel Two-Arm Phase II Trial of BMS-690514 versus Erlotinib in Chemotherapy Refractory Non-Small Cell Lung Cancer Patients - FDG-PET Sub-Study
Objectives:
- To assess metabolic tumoral changes by FDG-PET imaging.
- To explore whether a metabolic response, measured by FDG-PET, provides early predication of treatment outcome (ie, tumor response, PFS or OS). |
|
| E.3 | Principal inclusion criteria |
1) Signed Written Informed Consent
2) Target Population
a) Able to comply with visits/procedures required by protocol.
b) ECOG performance status 0 or 1. See Protocol Appendix 7.
c) Life expectancy at least 3 months.
d) Confirmed NSCLC by histologic or cytologic methods and radiographic proof of disease.
e) Adequate amount of tumor sample (archival or fresh) must be available for molecular biomarker evaluation and adequacy confirmed by local pathologist review. See Protocol Appendix 9.
f) Received one or two chemotherapy regimens (none given as adjuvant treatment) with progression or recurrent disease (at least one of these platinum containing).
g) Patients must have ended their prior chemotherapy for at least 4 weeks prior to study entry. Patients must have completed therapy with bevacizumab or cetuximab at least 4 weeks prior to study entry.
h) Patients who received radiotherapy must have completed treatment at least 2 weeks prior to study entry.
i) Adequate bone marrow function defined as:
♦ Absolute neutrophil count > 1500/mm³.
♦ Hemoglobin > 10 g/dL (The use of erythropoietin stimulating agents is permitted.)
♦ Platelet count > 100,000/mm³.
j) Adequate renal parameters defined as:
♦ Blood urea nitrogen of < 30 mg/dL.
♦ Serum creatinine of < 1.0 mg/dL or 24 hour creatinine clearance > 60 mL/minute. For patients older than 70 years of age a 24 hour urine collection must indicate a creatinine clearance of > 60 mL/minute.
♦ Serum magnesium between 1.5 and 2.5 mg/dL (supplementation to achieve this range is acceptable).
♦ Serum potassium between 3.5 and 5.0 mEq/L (supplementation to achieve this range is acceptable).
k) Adequate hepatic parameters defined as:
♦ AST ≤ 2.5 times the institutional ULN.
♦ ALT ≤ 2.5 times the institutional ULN.
♦ Alkaline phosphatase ≤ 2 times the institutional ULN.
♦ Total bilirubin ≤ 2 times the institutional. ULN
l) In the presence of documented liver metastases, the hepatic parameters will be defined as:
♦ AST ≤ 3.5 times the institutional ULN.
♦ ALT ≤ 3.5 times the institutional ULN.
♦ Alkaline phosphatase ≤ 2.5 times the institutional ULN.
♦ Total bilirubin ≤ 2 times the institutional ULN.
m) not applicable (see Protocol Amendment 4)
n) Stable control of blood pressure with a systolic blood pressure consistently below 150 mmHg and a diastolic blood pressure consistently below 90 mmHg on antihypertensives. Subjects with a history of hypertension who are receiving treatment with calcium channel blockers that are CYP3A4 substrates must be changed to an alternative antihypertensive medication and be stable on the new medication for at least 4 weeks before study entry.
o) Brain metastases that have remained stable in size on CT or MRI, have not progressed for 4 weeks, and have no evidence of neurologic impairment.
3) Age and Sex
a) Men and women, age ≥18 years.
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) Patients with symptomatic brain metastases.
b) Patients with signs or symptoms suggestive of spinal cord compression.
c) Patients with signs or symptoms suggestive of intractable back pain due to compressive or destructive mass.
d) Any condition that requires emergent treatment using steroids and/or radiation therapy or emergent surgery.
e) Patients who have central pulmonary tumor close to large vessels.
3) Medical History and Concurrent Diseases
a) ECOG performance status of ≥ 2.
b) History of transient ischemic accident, cerebrovascular accident, thrombotic or thromboembolic event (pulmonary embolus or deep venous thrombosis) within the last 6 months.
c) Patients with previous malignancies (except non-melanoma skin cancers, in situ bladder or cervical cancers/dysplasia) are excluded unless a complete remission was achieved at least 2 years prior to study entry and no additional therapy is required or anticipated to be required during the study period.
d) Patients with history of hemoptysis greater than 10 mL/day within the last 30 days.
e) Uncontrolled or significant cardiovascular disease including:
♦ Myocardial infarction within 6 months.
♦ Uncontrolled angina within 6 months.
♦ Class III-IV New York Heart Association (NYHA) congestive heart failure
♦ Uncontrolled hypertension (Systolic BP > 150 or diastolic BP > 90 mmHg for 24 hours) despite optimized anti-hypertensive therapy. BP must be below 150/90 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 and be stable on the new medication for at least 4 weeks before study entry.
f) Any history of uncontrolled diarrhea, Crohn’s disease or ulcerative colitis that may be exacerbated by the use of EGFR TKIs.
g) 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.
h) 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.
i) Inability to swallow tablets, untreated malabsorption syndrome or gastrointestinal surgery that results in inability to properly absorb protocol therapy.
j) Any surgery within 4 weeks of study enrollment.
k) Patients who are HIV+.
l) Inability to tolerate multiple blood sampling/or tolerate venous access.
m) Any other medical, psychiatric, and/or social reason as determined by the Investigator.
4) Physical and Laboratory Test Findings
a) Absolute neutrophil counts < 1500/mm³, platelet count < 100,000/mm³, or hemoglobin < 10 g/dL.
b) Serum total bilirubin > 2 times the institutional upper limits of normal or ALT or AST > 2.5 times the institutional upper limits of normal (> 3.5 times IULN for subjects with documented liver metastases).
5) Allergies and Adverse Drug Reactions
a) History of allergy to erlotinib, BMS-690514, or any other EGFR/VEGFR TKI.
6) Prohibited Treatments and/or Therapies
a) Other concurrent chemotherapy, hormonal therapy, immunotherapy regimens or radiotherapy, standard or investigational.
b) Prior exposure to erlotinib, gefitinib, experimental EGFR or VEGFR TKI, BMS- 690514 or panitumumab.
c) Concurrent use of steroid therapy except for low dose oral steroids used for control of brain metastases.
d) Concurrent use of CYP3A4 strong inducers is prohibited. Caution must be used with all inhibitors, except for grapefruit and grapefruit juice which are prohibited.
See Appendix 3.
e) Therapeutic anticoagulation with Vitamin K antagonists (eg warfarin).
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) |
- The primary endpoint of the trial is to compare PFS in subjects receiving BMS-690514 relative to erlotinib. The direct comparison will allow for the assessment of the efficacy and safety of BMS-690514 compared to erlotinib.
- Secondary endpoints to be followed will include OS, ORR, PFS rate and tumor size change at week 6 and safety. Tumor and plasma will be collected for biomarker assessments |
|
| 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 |
| Outcomes research assessments (EORTC QLQ-C30 and LC13) |
|
| 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) | 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 15 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| 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 | 15 |
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