E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with pretreated locally advanced or metastatic Non-small Cell Lung Cancer (NSCLC) |
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MedDRA Classification |
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 assess efficacy of BMS-275183 in pretreated NSCLC patients as measured by the tumor response rate according to the SWOG criteria. |
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E.2.2 | Secondary objectives of the trial |
• To further characterize the qualitative and quantitative toxicities of BMS-275183 in the same patient population. • To assess the response duration. • To assess the progression free survival time. • To assess the overall survival time. • To assess the plasma pharmacokinetics of BMS-275183 at the recommended dose of 100 mg/m² given orally on a twice weekly schedule. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Signed written informed consent 2) The subject population will consist of patients with histologically or cytologically confirmed locally advanced or metastatic NSCLC who failed only one prior chemotherapy regimen. 3) Prior chemotherapy with a minimum of two chemotherapy cycles given at a full dose. Prior chemo-radiation is not allowed unless the patient received a full dose of chemotherapy concomitantly with the radiation or the concomitant chemo-radiation was preceded or followed by a minimum of two cycles of the same chemotherapy administered at a full dose. That chemotherapy must be a taxane for cohort I, a platinum based but non taxane containing regimen for cohort II and any chemotherapy regimen and one EGFR-TKI inhibitor compound for cohort III patients. 4) Prior treatment with EGFR-TKI inhibitor is allowed only for patients in cohort 3. Prior treatment with a VEGFr inhibitor is allowed for all the patients. The VEGFr inhibitor cannot be in addition an EGFR inhibitor. 5) Prior chemotherapy may have been administered in adjuvant, neoadjuvant or advanced setting but only one prior chemotherapy regimen is allowed to which the patient must have failed treatment (i.e.: disease recurrence in adjuvant setting or tumor progression in advanced stages). 6) Patients must have at least one measurable lesion according to the SWOG criteria. 7) Prior anti cancer treatment must have been discontinued at least 3 weeks prior to study enrollment and the patient must have recovered from the acute toxicities of the prior treatment. 8) Prior radiation therapy must be completed at least 2 weeks prior to study enrollment and the patient must have recovered from its toxicities. 9) Prior curative surgery must have been completed at least 10 weeks, and prior palliative surgery must have been completed at least 2 weeks, prior to study enrollment. 10) Performance status of 0 or 1 on the ECOG scale or 90-100 on the Karnofsky scale (see Protocol Appendix 2). Adequate organ function is defined as: i) Adequate bone marrow function: absolute Neutrophil count of at least 1.5 x 10 9/L, platelets ≥ 100 x 10 9 /L, and hemoglobin ≥ 9 g/dl ii) Adequate hepatic function: Bilirubin less than or equal to the upper limit of normal (ULN), AST, ALT ≤ 1.5 times ULN, and alkaline phosphatase ≤ 2.5 ULN iii) Renal: Plasmatic creatinine < 1.5xULN
11) Estimate life–expectancy of a least 8 weeks 12) Men and women, age ≥ 18 years 13) Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 8 weeks after the study in such a manner that the risk of pregnancy is minimized
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E.4 | Principal exclusion criteria |
Sex and Reproductive Status 1) WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and up to 8 weeks after the study. 2) Women who are pregnant or breastfeeding 3) Women with a positive pregnancy test on enrollment or prior to study drug administration.
Target Disease Exceptions 4) Prior brain metastases, unless previously treated adequately, the patient is asymptomatic and no longer requires corticosteroids, and a minimum of 4 weeks has elapsed since the treatment of the brain lesions.
Medical History and Concurrent Diseases 5) Second primary malignancy that is detectable at the time of consideration for study enrollment 6) Prior history of a major gastrointestinal surgery or malabsorption that could potentially influence the absorption of BMS-275183 7) Recent significant cardiovascular disease (i.e., myocardial infarction, unstable angina within 6 months, or any history of significant degree congestive heart failure with or without medical treatment, any history of clinically significant atrial or ventricular arrhythmias, any history of Grade 2 or 3 heart block). 8) QTc prolongation > 500 msec at the baseline 9) Serious concomitant systemic disorders that would compromise the safety of the patient or compromise the patient’s ability to complete the study 10) Prior treatment with BMS-275183 11) Active infection that, in the opinion of the investigator, is not compatible with the conduct of the study.
Physical and Laboratory Test Findings 12) Inability or unwillingness to swallow the oral BMS-275183 13) NCI CTC AE Grade ≥ 2 peripheral neuropathy at study entry. 14) Significant weight loss, (i.e. ≥ 10%, over the previous 6 weeks before study entry)
Prohibited Therapies and/or Medications 15) Concomitant medication with efflux transporter PGP inhibitors such as Benzimidazoles (benzimidazoles includes PPIs such as omeprazole, esomeprazole, lansoprazole, pantoprazole) or prior medication with such drugs within seven days from study drug administration 16) Concomitant medication with a CYP 3A4 inhibitor or inducer (see Protocol Appendix 3). 17) Concomitant medication with Metoclopramide
Other Exclusion Criteria 18) Prisoners or subjects who are compulsorily detained
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy Analyses: Patients will be evaluated for tumor response according to the SWOG criteria on a scheduled basis every 8 weeks. Patients may continue to receive additional cycles of therapy until progressive disease (PD), intolerable toxicity or a maximum of 8 cycles. In case of partial response (PR)/complete response (CR), tumor response must be confirmed at least 4 weeks later. Patients will be considered as evaluable for response if they have a histologically or cytologically confirmed NSCLC and have received a minimum of 2 cycles of study drug. Patients who received less than two cycles of study drug due to reasons of toxicity or early progression will also be considered as response evaluable (SWOG criteria).
Safety Analyses: Patients will be evaluated for safety if they have received at least one dose of study drug; worst toxicity grades per patient will be tabulated for selected adverse events and laboratory measurements. Data will be analyzed separately for each cohort and also for combined cohorts. An independent safety review board will review the safety data during the conduct of the trial and ensure that any safety issues are identified and addressed.
Pharmacokinetics Analyses: PK parameters of BMS-275183 will be estimated from plasma concentration versus time data with population PK modeling. The parameters to be assessed include: Cmax, Tmax, AUC(INF), T-HALF, Cmin and CL/F. Individual subject PK parameter values will be derived from a nonlinear mixed effects model developed from Phase I concentration versus time data.
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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 | No |
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 | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
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 | No |
E.8.1.1 | Randomised | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
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) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
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 | 21 |
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 |
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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
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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 | 11 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 11 |
E.8.9.2 | In all countries concerned by the trial days | 0 |