Ganetespib With Pemetrexed-cisplatin, in Patients With Malignant Pleural Mesothelioma (MESO-02)

Primary Outcome Measures:

• Maximum Tolerated Dose of Ganetespib [ Time Frame: 6 Months ] [ Designated as safety issue: Yes ]
  • Primary endpoint (phase I): Dose-limiting toxicities during Cycles 1 & 2; and number of cycles of pemetrexed-cisplatin given.
  • The Phase I trial will consist of three ganetespib dose cohorts, each with 3 or 6 patients:
    • Cohort 1: 100mg/m2 IV on day 1 and day 8 of each cycle
    • Cohort 2: 150mg/m2 IV on day 1 and day 8 of each cycle
    • Cohort 3: 200mg/m2 IV on day 1 and day 8 of each cycle
  • Primary endpoint (phase II): Progression free survival

Secondary Outcome Measures:

• Progression Free Survival [ Time Frame: 24 Months ] [ Designated as safety issue: Yes ]
  • Secondary endpoints (phase I):
    • To examine the number of cycles of pemetrexed/cisplatin/(cisplatin) chemotherapy administered.
    • To examine the objective tumour response according to meso-modified RECIST, and the overall response rate.
  • Secondary endpoints (phase II):
    • To examine the frequency of all Adverse Events graded by NCI-CTCAE version 4, in particular those with grade 3 or 4 events.
    • To examine the objective tumour response according to meso-modified RECIST, and the overall response rate.
    • To examine overall survival.

Eligibility Criteria

• Inclusion Criteria:
  1. Pathological confirmation of malignant pleural mesothelioma
  2. Measurable disease using meso-modified RECIST criteria (This 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:
     • Haemoglobin 10g/dl or greater
     • Neutrophil count ≥1.5 x 109/L
     • Platelets ≥100 x 109 /L
  6. Adequate organ function:
     • Bilirubin ≤1.5x ULN, ALP ≤2.5x ULN, ALT or AST ≤1.5x ULN
     • Serum creatinine ≤1.5 x ULN or calculated creatinine ≥ 50ml/min (C&G or EDTA) (appendix 4)
  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. (See section 5.3.3 for details)
  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
• 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 edemathat requires current treatment with angiotensin converting enzyme inhibitors,angiotensin II receptor blockers, beta-blockers or diuretics. NOTE: Use of thesemedications for the treatment of hypertension is allowed.
     • Baseline QTc > 470 msec or history of QT prolongation while taking othermedications
     • Left ventricular ejection fraction (LVEF) < 45 %
     • High-risk uncontrolled arrhythmias (e.g., ventricular arrhythmias, high-gradeatrioventricular (AV)-block, supra-ventricular arrhythmias which are notadequately 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. 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
  10. Significant weight loss (≥10% body weight) within the 4 weeks prior to Cycle 1 Day 1.
  11. Patients who have had a yellow fever vaccination in the previous 30 days.
  12. 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.