| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Malignant pleural mesothelioma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer of the lining of the lung |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10035603 |
| E.1.2 | Term | Pleural 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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The principal research question for the phase I study is to find the maximum tolerated dose of Ganetespib, and use this information with the number of chemotherapy cycles administered to determine the most appropriate dose of Ganetespib for the phase II trial. For the phase II study, the principle research question is to determine whether adding Ganetespib to pemetrexed and cisplatin using the dose from the Phase I part of the study, versus pemetrexed and cisplatin chemotherapy improves progression free survival (first disease progression or death of any cause). |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary research questions for the Phase I study are; how safe is adding Ganetespib to the standard treatment and the disease response. The secondary research questions for the Phase II study are; how safe is adding Ganetespib to the standard treatment, does it improves the chances of the tumour shrinking and does it help people with the disease to live longer, the length of treatment the patients have and their reasons for stopping early. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| 1. Pathological confirmation of malignant pleural mesothelioma 2. Measurable disease using meso-modified RECIST criteria (Scan must be within 28 days of registration/randomisation) 3. Performance status ECOG 0-1 4. Age at least 18 years 5. Adequate haematological status: a. Haemoglobin 10g/dl or greater b. Neutrophil count ≥1.5 x 109/L c. Platelets ≥100 x 109 /L 6. Adequate organ function: a. Bilirubin ≤1.5x ULN, ALP ≤2.5x ULN, ALT or AST ≤1.5x ULN b. Serum creatinine ≤1.5 x ULN or calculated creatinine clearance ≥ 60ml/min (C&G or EDTA) 7. Negative serum pregnancy test for female patients within 1 week prior to starting the first dose ganetespib. 8. Male subjects and women of child bearing potential must agree to use an acceptable method of birth control for the duration of the trial and for 6 months after the last trial treatment cycle has finished. 9. Ability to understand and willing to sign the written informed consent to participate (including donation of diagnostic biopsy tissue for research) 10. Ability to comply with the requirements of the protocol |
|
| E.4 | Principal exclusion criteria |
| 1. Prior exposure to other investigational or commercial agents or therapies administered with the intent of treating the patient’s malignancy. This includes crizotinib, other ALK-targeted agents, and any Hsp90 inhibitor (e.g. ganetespib). Prior valproic acid is acceptable but only if there has been at least 30 days wash-out period 2. Evidence of CNS metastases that in the opinion of the investigator should receive local treatment prior to systemic cytotoxic chemotherapy 3. Uncontrolled intercurrent illness including but not limited to: • Symptomatic neurological illness • Active uncontrolled systemic infection considered opportunistic, life threatening or clinically significant at the time of treatment • Significant pulmonary disease or hypoxia • Psychiatric illness/social situations that would limit compliance with trial requirements •Human immunodeficiency virus (HIV)-positive patients •Known hepatitis B or C infection •Uncontrolled diabetes mellitus 4. Known serious cardiac illness including but not confined to: • Uncontrolled congestive heart failure (CHF), New York Heart Association class • II/III/IV, with a history of dyspnoea, orthopnea or oedema that requires current treatment with angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, beta-blockers or diuretics. NOTE: Use of these medications for the treatment of hypertension is allowed. • Baseline QTc > 470 msec or history of QT prolongation while taking other medications • High-risk uncontrolled arrhythmias (e.g., ventricular arrhythmias, high-grade atrioventricular (AV)-block, supra-ventricular arrhythmias which are not adequately rate-controlled) • Arrhythmias that require current treatment with the following anti-arrhythmic drugs: flecainide, moricizine or propafenone • A myocardial infarction within the last 6 months or unstable angina 5. The patient has a history of prior malignant tumour, unless the patient has been without evidence of disease for at least three years, or the tumour was a non-melanoma skin tumour or in situ cervix carcinoma 6. Pregnant women or those who are lactating 7. Pre-planned surgery or procedures that would interfere with the conduct of the trial 8. Patients who have had surgery (does not include pleurodesis or pleurectomy) within 28 days of randomisation should not be included 9. Previous treatment with systemic chemotherapy 10. Receipt of extensive radiation therapy, systemic chemotherapy, or other anti-neoplastic therapy within 4 weeks before enrolment is not allowed. However, drain site radiotherapy is allowed 11. Significant weight loss (≥10% body weight) within the 4 weeks prior to Cycle 1 Day 1. 12. Patients who have had a yellow fever vaccination in the previous 30 days. 13. Other medications, severe acute/chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the subject inappropriate for entry into this study. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| For the Phase I Study - the primary outcome measures are; 1. to find the maximum tolerated dose (MTD) of ganetespib in combination with standard cisplatin/pemetrexed in patients with mesothelioma. 2. the number of patients with a dose limiting toxicity 3. the number of cycles of cisplatin/pemetrexed given For the Phase II Study - the primary outcome measure is; 1 Progression-free survival (PFS). PFS is an appropriate primary endpoint for phase II trials of mesothelioma. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The first primary endpoint (to find the MTD) in the phase I will be evaluated after accrual of the required number of patients per cohort plus 2 cycles of chemotherapy. All other endpoints for the phase I and II will be evaluated at the end of the trial. PFS will also be evaluated at the end of the trial unless accrual is much slower than expected - at which point the PFS will be examined for futility after about half the number of expected events have occurred or half the patients have been recruited and followed up for at least 2 months (whichever occurs first). |
|
| E.5.2 | Secondary end point(s) |
| In the Phase I study the Secondary end points are; •To examine the number of cycles of pemetrexed/cisplatin chemotherapy administered. • To examine the frequency of all Adverse Events graded by NCI-CTCAE version 4. • To evaluate the incidence of Dose Limiting Toxicities (DLTs) according to each ganetespib dose cohort. • To examine the objective tumour response according to meso-modified RECIST, and the overall response rate. • To examine biomarkers for response, progression and survival within a translational research substudy For the Phase II Study - the secondary outcome measures are; • To examine the frequency of all Adverse Events graded by NCI-CTCAE version 4, in particular those with ≥ grade 3 • To examine the objective tumour response according to meso-modified RECIST, and the overall response rate. • To examine overall survival. • To examine the number of chemotherapy cycles (pemetrexed/cisplatin) completed; and for patients who stop before 6 cycles, the reasons for stopping early. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| All endpoints for the phase I and II will be evaluated at the end of the trial. |
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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 | Yes |
| 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 | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| 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 | No |
| E.8.1.5 | Parallel group | No |
| 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.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 0 |
| 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 | No |
| 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
|
| Completion of all trial procedures by participants (e.g. last follow−up visit). In the Phase I study this will be 30 days after day 30 of the last treatment cycle received. In the Phase II study patients are to be followed up every 6 weeks for the first year (and then every 12 weeks thereafter) until death or the trial results are reported, whichever is sooner. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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