| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced non-small cell lung cancer. |
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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 | 10029514 |
| E.1.2 | Term | Non-small cell lung cancer NOS |
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| 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 the ixabepilone plus carboplatin arm to that in the paclitaxel plus carboplatin arm for the subgroup of subjects with βIII tubulin positive tumors (βIII tubulin positive subgroup).
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| E.2.2 | Secondary objectives of the trial |
• To compare the PFS for the entire population in the 2 arms • To estimate the PFS for the βIII tubulin negative subgroup in the 2 arms • To estimate the Week 18 progression free survival rate (PFSR-18) in the 2 arms (entire population, βΙΙΙ tubulin positive subgroup and βΙΙΙ tubulin negative subgroup) • To estimate the response rate (RR) in both arms (entire population, βΙΙΙ tubulin positive subgroup and βΙΙΙ tubulin negative subgroup) • To estimate the overall survival (OS) in both arms (entire population, βΙΙΙ tubulin positive subgroup and βΙΙΙ tubulin negative subgroup) • Evaluate the safety of the ixabepilone plus carboplatin combination • Evaluate the impact of the treatment on subject symptoms.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Signed Written Informed Consent. 2) Target Population a) Histologically confirmed NSCLC (squamous cell, adenocarcinoma, large cell or bronchoalveolar carcinoma); b) Stage IIIB with pleural effusion, or Stage IV NSCLC, or recurrent disease following surgery and/or radiation therapy; c) Available paraffin embedded tissue to measure the expression levels of βIII tubulin (also see Protocol Section 5.2); d) Measurable disease by RECIST guidelines, with at least 1 target lesion outside any previous radiotherapy field (also see Protocol Section 6.4.1); e) Karnofsky performance status (KPS) of 70 - 100 (see Protocol Appendix 3); f) Life expectancy of at least 3 months; g) Accessible for treatment and follow-up. Subjects enrolled in this trial must be treated at the participating center(s). 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 4 weeks after end of investigational products in such a manner that the risk of pregnancy is minimized. In general, the decision for appropriate methods to prevent pregnancy should be determined by discussions between the Investigator and the study subject.
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| 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 periodand for up to 4 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. 2) Target Disease Exceptions a) Uncontrolled brain metastases (active brain metastases including evidence of cerebral edema by CT scan or MRI, or progression from prior imaging study, any requirement for steroids, or clinical symptoms of/from brain metastases. Subjects with known metastases must have a baseline imaging scan within 4 weeks of randomization). 3) Medical History and Concurrent Diseases a) Peripheral neuropathy > Grade 1; b) Less than 4 weeks from prior radiation therapy or loco-regional surgeries to randomization date (less than 1 week from focal/palliative RT, or minor surgery); c) Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent or completing questionnaires; d) A serious uncontrolled medical disorder that, in the opinion of the investigator, would impair the ability of the subject to receive protocol therapy; e) Any concurrent malignancy other than non-melanoma skin cancer, or carcinoma in situ of the cervix; f) Known HIV positive. 4) Physical and Laboratory Test Findings a) Hematologic function (all baseline laboratory information must be obtained within 14 days prior to randomization): i) Absolute neutrophil count (ANC) < 1500 cells/mm³; ii) Hemoglobin < 9.0 g/dL; iii) Platelets < 100,000 cells/mm³ b) Hepatic function: i) Total bilirubin greater than Upper Limit of Normal (ULN) as defined by the institution (with the exception of elevation due to Gilbert’s syndrome); ii) Aspartate transaminase (AST) or alanine transaminase (ALT) > 2.5 x ULN. c) Serum creatinine ≥ 1.5 mg/dL; d) Renal function with a calculated creatinine clearance (CrCl) based on Cockcroft and Gault < 50 mL/min (see calculation algorithm under Protocol Section 4.2.2). 5) Allergies and Adverse Drug Reactions a) Known prior severe hypersensitivity reactions to agents containing Cremophor EL. 6) Prohibited Treatments and/or Therapies a) Any prior antineoplastic systemic regimens. Subjects must not initiate any concurrent antineoplastic therapy (ie, chemotherapy, hormonal therapy, immunotherapy, radiation therapy, herbal regimens or standard or investigational agents for treatment of NSCLC); b) Subjects must not continue treatment with strong inhibitors or inducers of CYP3A4 (see Protocol Section 5.5.1 for further details). 7) Other Exclusion Criteria ) 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.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary aim of this study is to test the hypothesis that the progression free survival (PFS) in the ixabepilone plus carboplatin arm is superior to that in the paclitaxel plus carboplatin arm for the βIII tubulin positive subgroup. As a secondary analysis, the PFS for the entire population will be compared between the 2 arms at the same time of the analysis of the primary endpoint. The following secondary analysis of efficacy will be performed for both the βIII tubulin positive subgroup and the entire population for randomized subjects: 18 week progression free survival rate, overall survival, response rate and the disease control rate, time to response and duration of the best response, and safety analysis. Additional exploratory pharmacogenomic analyses will be performed. |
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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 | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
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| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
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| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 23 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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
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| Lo studio terminera' quando si sara' verificato l'80% delle morti. |
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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 | 9 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 9 |
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