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A Phase I/II Study of First Line Vorinostat With Pemetrexed-cisplatin, in Patients With Malignant Pleural Mesothelioma

Phase 1/Phase 2
18 Years
Not Enrolling
Malignant Pleural Mesothelioma

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Trial Information

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.

Inclusion Criteria:

- Pathological confirmation of malignant pleural mesothelioma

- Measurable disease using modified RECIST criteria with at least one lesion ≥ 1cm
using spiral CT in a single dimension. This scan must be within 28 days of

- Performance status ECOG 01

- Age > 18

- Able to swallow oral medication

- Adequate haematological status

- Adequate organ function

- Negative serum or urine pregnancy test. Male subject agrees to use an acceptable
method of birth control for the duration of the study and contraception must be used
by women of child bearing potential.

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

- Ability to comply with the requirements of the protocol

Exclusion Criteria:

- Other investigational or commercial agents or therapies administered with the intent
of treating the patient's malignancy.

- Evidence of CNS metastases that in the opinion of the investigator should receive
local treatment prior to systemic cytotoxic chemotherapy

- Uncontrolled intercurrent illness

- 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 nonmelanoma
skin tumour or insitu cervix carcinoma.

- Prior exposure to vorinostat or another HDAC inhibitor is not allowed. Prior valproic
acid is acceptable but only if there has been at least 30 days washout period

- Preplanned surgery or procedures that would interfere with the conduct of the study.

- Patients who have had surgery within 28 days of randomisation

- Receipt of extensive radiation therapy, systemic chemotherapy, or other
antineoplastic therapy within 4 weeks before enrolment is not allowed. However, drain
site radiotherapy is allowed.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Outcome Measure:

Phase I only - Dose-limiting toxicities

Outcome Time Frame:

After 2 cycles of chemotherapy. (6 weeks after start of treatment)

Safety Issue:


Principal Investigator

Dean Fennell

Investigator Role:

Principal Investigator

Investigator Affiliation:

Queen's University of Belfast


United Kingdom: Medicines and Healthcare Products Regulatory Agency

Study ID:




Start Date:

Completion Date:

Related Keywords:

  • Malignant Pleural Mesothelioma
  • mesothelioma
  • vorinostat
  • Mesothelioma