Malignant pleural mesothelioma (MPM) is a rapidly lethal cancer arising from the parietal pleural mesothelium, and is associated with exposure to asbestos.

Once a rare disease, it is increasing in incidence in the UK and is presently more common than cervical cancer. MPM is characterized by local invasion of adjacent structures including the chest wall, mediastinum, diaphragm and pericardium resulting in progressive shortness of breath.

Median survival with best supportive care alone is approximately 6-9 months and most cases of mesothelioma present in the advanced setting. Therefore this trial will be looking at whether a new drug, Ganetespib has any improvement on survival for these types of patients.

Inclusion Criteria:

1. Histopathological confirmation of malignant pleural mesothelioma

2. Measurable disease using meso-modified RECIST criteria (CT 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 100g/L or greater
   • Neutrophil count ≥2.0 x 10^9/L
   • Platelets ≥100 x 10^9 /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 clearance ≥ 60ml/min (C&G or EDTA)

7. Chemotherapy naïve

8. Negative serum pregnancy test for female patients of child bearing potential.

9. 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.

10. Ability to understand and willing to sign the written informed consent to participate (including donation of diagnostic biopsy tissue for research)

11. 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. Serum potassium, magnesium, and calcium levels no more than 10% outside the Sites normal reference ranges

5. Known serious cardiac illness including but not confined to:

   • Clinically unstable cardiac disease, including unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, active myocardial ischemia, or indwelling temporary pacemaker
   • Ventricular tachycardia or a supraventricular tachycardia that requires treatment with a Class Ia anti-arrhythmic drug (e.g., quinidine, procainamide, disopyramide) or Class III anti-arrhythmic drug (e.g., sotalol, amiodarone, dofetilide). Use of other anti-arrhythmic drugs is permitted.
   • Use of medications that have been linked to the occurrence of torsades de pointes
   • Second- or third-degree atrioventricular (AV) block unless treated with a permanent pacemaker
   • Complete left bundle branch block (LBBB)
   • History of long QT Syndrome or a family member with this condition
   • QTc >470ms (average of triplicate ECG recordings); a consistent method of QTc calculation must be used for each patient's QTc measurements. QTcF (Fridericia's formula) is preferred

6. 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

7. Pregnant women or those who are lactating

8. Pre-planned surgery or procedures that would interfere with the conduct of the trial

9. Patients who have had surgery (does not include pleurodesis or pleurectomy) within 28 days of randomisation should not be included

10. Previous treatment of mesothelioma with systemic chemotherapy

11. 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

12. Significant weight loss (≥10% body weight) within the 4 weeks prior to Cycle 1 Day 1.

13. Patients who have had a yellow fever vaccination in the previous 30 days.

14. 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.