Neoplasms

All Conditions

Respiratory Tract (Lung and Bronchial) Diseases

Rare Diseases

Mesothelioma

Mesothelioma, Malignant

Adenoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neoplasms, Mesothelial

Lung Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Pleural Neoplasms

Lung Diseases

Respiratory Tract Diseases

Malignant Mesothelioma

Antineoplastic Agents

All Drugs and Chemicals

Pembrolizumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Patients will receive an initial dose of pembrolizumab in week 1 dosed at 200 mg. They will then receive SBRT dosed at 30 Gy in 3 fractions (#) alternate days in week 3. Treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks.

An additional 12 patients will be recruited for this cohort. Patients will receive an initial dose of pembrolizumab at 200 mg in week 1. This will be followed in by SBRT dosed at 30 Gy in 3 fractions (#) alternate days in week 3. Treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks.

Pembrolizumab will be continued dosed at 200 mg given every 3 weeks

Drug: Pembrolizumab Pembrolizumab in week 1 dosed at 200 mg (prior to SBRT) and then treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks.

Stereotactic Body Radiotherapy (SBRT) 30 Gy 3 fractions (#)

Stereotactic Body Radiotherapy (SBRT)

This is a multi-centre non-randomised open-label phase 1 trial of pembrolizumab given in combination with SBRT to part of a pleural-based lesion in patients with unresectable MPM. This study will recruit up to 18 patients whose MPM has progressed beyond first-line of palliative chemotherapy, with a platinum-based doublet, and now requires further palliative systemic treatment, or have declined first-line palliative chemotherapy, however must have been considered suitable for a platinum doublet chemotherapy.

The study will be conducted in two parts; an initial safety phase (Part A), followed by an expansion cohort (Part B). The initial safety phase (Part A) is based on a 3+3 design such that patients will be treated in a cohort of 3-6 patients. A maximum of 6 patients will be allocated to Part A exploring SBRT 30 Gy in 3 fractions in combination with pembrolizumab. If there is more than one DLT in the first 3 patients or two or more DLTs in the first 6 patients, this treatment combination will be deemed as being unacceptable and it would lead to termination of the study. During the expansion cohort (Part B), 12 patients will have SBRT 30 Gy in 3 fractions with pembrolizumab to obtain additional safety and response data. Maintenance pembrolizumab will continue until disease progression, unacceptable toxicities, the patient withdraws consent to the trial, or the patient has completed 35 cycles of treatment. A maximum of 18 patients will be treated in the study.

All patients will receive pembrolizumab on cycle (C) 1 day (D) 1, in Part A and B of the study. All patients will receive SBRT on C1D15, C1D17 and C1D19, as per SBRT protocol. Patients in part A will receive SBRT 30 Gy in 3#. Patients in Part B will receive 30 Gy in 3 fractions if considered safe after part A. All patients in Part A and Part B will receive pembrolizumab dosed at 200 mg every 3 weeks, until disease progression, unacceptable toxicities, the patient withdraws consent from the trial or the patient has completed 35 cycles of treatment.

In the initial safety cohort, a minimum of 3 patients will be treated at the SBRT dose of 30Gy in 3 fractions combined with pembrolizumab. The gap left between the treatments of each subsequent patient will start after the second cycle of Pembrolizumab in the previous dosed patient to mitigate against multiple patients suffering from acute toxicity. The DLT period for this study is 12 weeks from the last dose of SBRT (i.e. at C6D1). Patients included in Part A will be considered by the Safety Review Committee (SRC) once the 3rd and 6th patient in the Part A cohort has completed the DLT period. If 0 out of 3 patients experience a DLT, or if 1 out of 3 patients experience a DLT in Part A, then the cohort will be expanded to 6 patients. If 1 in 6 patients experience a DLT, then it will be acceptable to move forward to the expansion cohort (Part B).

However, if ≥ 2 in 6 patients (or more than 1 in the first 3 patients) experience a DLT then the maximum administered dose (MAD) will have been reached. If the MAD is seen at a dose level of 30 Gy in 3# then the study will be terminated.

While waiting for 3 or 6 patients to complete the DLT period, no additional patients will be recruited. Further patients can only be recruited after the SRC has reviewed the toxicity data for the cohort to proceed to Part B. Patients obtaining complete response or having completed 35 cycles of pembrolizumab must discontinue and may recommence for additional 17 cycles upon subsequent disease, the CI/PI will need to discuss with the sponsor and MSD, on a case by case basis for the continuation of pembrolizumab

Initial safety phase followed by an Expansion phase

Pembrolizumab and Hypofractionated Stereotactic Radiotherapy in Patients With Malignant Pleural Mesothelioma

To characterise TILs and tumour antigens in the tumour biopsies. These immunohistochemistry analyses will include, but not necessarily be limited to, the following markers: CD4, CD8, FOXp3, PD-1, PD-L1, and PD-L2. To identify biomarkers that correlate with immunological response to therapy.

Hypothesis: SBRT in MPM can be safely administered in combination with pembrolizumab without significant dose limiting acute toxicity.

To correlate the number of patients that responded to the treatment with their tumour PD-1/PD-L1 expression.

Spots Global Cancer Trial Database for external beam stereotactic body radiotherapy