A Phase I/II Study of First Line Vorinostat With Pemetrexed-cisplatin, in Patients With Malignant Pleural Mesothelioma
Mesothelioma is a rapidly lethal cancer which is increasing in incidence year on year. A
projected doubling of cases has been predicted within the next two decades in Europe and the
disease is usually diagnosed only after it has become advanced.
As yet the standard treatment for advanced mesothelioma, chemotherapy (cytotoxic drugs), is
only for disease control and symptom management. A Phase I study of a drug called Vorinostat
recently looked in to its effect, when given with standard cytotoxic drugs, on advanced
solid tumours. The data for this study showed that this treatment caused a response in the
tumours of patients with mesothelioma.
The study aims to examine the efficacy and safety of first-line vorinostat when used
concurrently with cisplatin/pemetrexed.
In the proposed trial, we will initially conduct an initial run-in phase I study, to find
the maximum tolerated dose, before embarking on the randomised phase II trial. The study is
therefore in two stages:
Phase I study: to find the maximum tolerated dose of vorinostat in this patient group. Both
safety (ie the observed number of Dose Limiting Toxicities per cohort and the overall
toxicity profile) and the number of chemotherapy cycles administered will be used to
determine the final dose of vorinostat to be used in the subsequent phase II study.
Randomised Phase II study: to evaluate the efficacy and safety of vorinostat (using the dose
from the phase I study) versus placebo in combination with cisplatin and pemetrexed. The
Phase II study will use a placebo and double-blinding to ensure that neither the patient nor
the research team are aware of the allocated treatment, which should allow for accurate
comparison of the two treatment arms and reduce the potential for researcher bias. Patients
will be randomized 1:1 to the two treatment arms.
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment
Phase I only - Dose-limiting toxicities
After 2 cycles of chemotherapy. (6 weeks after start of treatment)
Queen's University of Belfast
United Kingdom: Medicines and Healthcare Products Regulatory Agency