E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 13.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10027406 |
E.1.2 | Term | Mesothelioma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To compare the overall survival associated with L-001079038 plus best supportive care versus that associated with placebo plus best supportive care for the treatment of patients with advanced malignant pleural mesothelioma who have failed at least one prior chemotherapy that has included pemetrexed in combination with either cisplatin or carboplatin regimen, and to determine the overall safety and toxicity of L-001079038 in this population |
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E.2.2 | Secondary objectives of the trial |
To compare between L-001079038 plus best supportive care versus placebo plus best supportive care for the treatment of patients with advanced malignant mesothelioma who have failed at least one prior chemotherapy that included pemetrexed in combination with either cisplatin or carboplatin regimen with respect to: a. Progression-free-survival b. Overall ORR; c Time-to-progression; d. Dyspnea score of lung cancer symptom scale modified for mesothelioma (LCSS-Meso) at Week 12; and e. Percent change from baseline in forced vital capacity (FVC) at Week 12.
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
a. Patient must have a histologically and/or cytologically confirmed diagnosis of epithelial, sarcomatoid, or mixed histology malignant pleural mesothelioma and: In countries where premetrexed is an approved mesothelioma treatment, the patient's mesothelioma has progressed or relapsed following treatment with at least one prior chemotherapy regimen with premetrexed and either cisplatin or carboplatin. OR In countires where premetrexed is not approved for mesothelioma, the patient's mesothelioma has progressed or relapsed following treatment with at least one prior chemotherapy regimen. OR In the opinion of the investigator, premetrexed is not the preferred therapy for the patient, and the patient's mesothelioma has progressed or relapsed following treatment with at least one prior chemotherapy regimen.
b. Patient must have received no more then 2 prior systemic therapy regimens. c. Patient must have an area of pleural thickness measured by using the modified RECIST that is at least 1.5 cm in diameter on a spiral computerized tomography (CT) scan. d. Patient is at least 18 years. e. Patient has a karnofsky performance scale status of ≥70 f. Patient has adequate bone marrow function without current use of colony stimulating factors g. Patient has adequate coagulation h. Patient has adequate liver function i. Patient has adequate kidney function.
Extension Phase Any patient who was previously enrolled on MK-0683 P014 who did not experience progression of malignant pleural mesothelioma while receiving treatment with vorinostat will have the option to enroll in a Treatment Extension Phase of the study. This option will be available if the investigator believes that the patient may benefit from treatment with open label vorinostat to treat their malignant pleural mesothelioma. Investigators will have up to three months from the time that they are notified of the final study results to enroll patients into the Treatment Extension Phase. The following patients may enroll in the Treatment Extension Phase • patients who are receiving treatment with vorinostat and have not experienced progression of mesothelioma • patients who were randomized to the placebo arm and meet the eligibility criteria for the Treatment Extension Phase outlined in Section I. D. 3 • for those patients assigned to vorinostat who have discontinued study therapy for reasons other than progression of mesothelioma, it is left to the investigator's discretion as to whether the potential benefit outweighs potential risks associated with using vorinostat b. Female patient must either be post-menopausal or surgically sterilized or willing to use 2 adequate barrier methods of contraception to prevent pregnancy or agrees to abstain from heterosexual activity throughout the Treatment Extension Phase starting with Day 1 of the Treatment Extension Phase and for at least 30 days after the last dose of vorinostat. Male patient must agree to use an adequate method of contraception for the duration of the Treatment Extension Phase. Patient has the ability to understand and willingness to sign the Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved informed consent form. For those patients who are not currently receiving vorinostat as the study therapy when they transition to the Treatment Extension Phase, the following inclusion criteria regarding performance status and organ function as determined by laboratory testing must be fulfilled: d. Patient has a Karnofsky performance scale status of ≥70 (see Appendix 1). e. Patient has adequate bone marrow function without current use of colony stimulating factors: • Absolute neutrophil count (ANC) ≥1000 /μL, • Platelets ≥100,000 /μL, • Hemoglobin ≥9.0 g/dL. f. Patient has adequate coagulation: • Prothrombin time ≤1.5 x the upper limit of normal (ULN) unless receiving therapeutic anticoagulation. g. Patient has adequate liver function: • ALT (SGPT) and AST (SGOT) ≤2.5 x ULN; or ≤5 x ULN if enzyme abnormalities are due to liver metastases, • Bilirubin ≤1.5 x ULN. h. Patient has adequate renal function: • Creatinine ≤1.5 x ULN.
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E.4 | Principal exclusion criteria |
a. Patient had prior treatment with an HDAC inhibitor (e.g., Depsipeptide, MS 275, LAQ-824, PXD-101, and valproic acid). Patients who have received such agents for other indications (eg epilepsy) may enroll after a 30-day wash-out. b. Patient has an active infection or had received intravenous antibiotic, antiviral, or antifungal medications within 2 weeks prior to the start of study drug. c. Patients with a "currently active" second malignancy other than non-melanoma skin cancers and carcinoma in situ of the cervix are not eligible. Patients are not considered to have a "currently active" second malignancy if they have completed therapy for the second malignancy and are disease free from prior malignancies for >5 years. d. Patient has uncontrolled brain metastases, e.g., previously treated brain metastases that is not stable in the last 6 weeks. e. Patient has a known human immunodeficiency virus (HIV) infection or HIV-related malignancy. f. Patient is pregnant or breastfeeding. g. Patient has a known allergy to any component of the study drug. H. Patient has a history of gastrointestinal surgery or other procedures that might, in the opinion of the investigator, interfere with the absorption or swallowing of the study drug. i. Patient has any poorly controlled intercurrent illness or circumstances that could limit compliance with the study. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint of this study is overall survival. Survival is generally considered to be the best measurement of an oncology drug’s effectiveness. |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Information not present in EudraCT |
E.6.8 | Bioequivalence | Information not present in EudraCT |
E.6.9 | Dose response | Information not present in EudraCT |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Yes |
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) | Information not present in EudraCT |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
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 | Information not present in EudraCT |
E.8.1.4 | Double blind | Yes |
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) | No |
E.8.2.2 | Placebo | Yes |
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.8.5 | The trial involves multiple Member States | Yes |
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 | Information not present in EudraCT |
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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The first interim analysis will occur after 50 patients have had 18 weeks of follow-up. The second interim analysis will occur after 220 patients have had 18 weeks of follow-up. The third interim analysis will occur after approximately 270 events have occurred. |
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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 | |
E.8.9.1 | In the Member State concerned months | 26 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 26 |