Clinical Trials /

Pembrolizumab and Hypofractionated Stereotactic Radiotherapy in Patients With Malignant Pleural Mesothelioma

NCT04166734

Description:

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.

Related Conditions:
  • Malignant Pleural Mesothelioma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab and Hypofractionated Stereotactic Radiotherapy in Patients With Malignant Pleural Mesothelioma
  • Official Title: Pembrolizumab and Hypofractionated Stereotactic Radiotherapy in Patients With Malignant Pleural Mesothelioma

Clinical Trial IDs

  • ORG STUDY ID: CCR4583
  • NCT ID: NCT04166734

Conditions

  • Advanced Malignant Pleural Mesothelioma

Interventions

DrugSynonymsArms
PembrolizumabKeytrudaInitial safety cohort

Purpose

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.

Detailed Description

      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
    

Trial Arms

NameTypeDescriptionInterventions
Initial safety cohortOtherPatients 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.
  • Pembrolizumab
Expansion cohortOtherAn 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

Eligibility Criteria

        Inclusion Criteria:

          1. Patients should be ≥18 years old on the day of signing the informed consent.

          2. Patients must have a histological or cytological diagnosis of MPM.

          3. Patients should have non-radically treatable MPM (i.e. not being considered for
             extrapleural pneumonectomy or pleurectomy and decortication).

          4. Patients must have measurable disease as assessed by mRECIST (i.e. at least a 1 cm
             rind of MPM at 2 sites on 3 different levels).

          5. Patients must have had disease progression or be intolerant of standard first-line
             palliative chemotherapy for MPM. Patients who have declined first-line palliative
             chemotherapy must have been suitable for platinum-doublet combination chemotherapy.

          6. Patient should have an ECOG performance status 0-1.

          7. Patients should be able to tolerate a course of stereotactic radiotherapy as assessed
             by the investigator.

          8. Patients should have pleural based disease, away from critical structures, and
             suitable for treatment to part of lesion with SBRT for pleural mesothelioma.

          9. Patients must have adequate organ function including MRC dyspnoea score <3 and
             adequate baseline lung function tests, with an FEV1 > 0.8L or >30% of predicted and a
             TLCO > 30%.

         10. Demonstrate adequate organ function (based on bloods within 10 days of C1D1).

         11. Have provided tissue from an archival tissue sample or newly obtained tissue sample.

         12. Female patient of childbearing potential should have a negative serum pregnancy within
             72 hours prior to receiving the first dose of study medication (C1D1). Female patients
             of childbearing potential should be willing to use highly effective methods of
             contraception for the course of the study through 120 days after the last dose of
             study medication. Female of childbearing potential is defined as women following
             menarche and until becoming post-menopausal unless permanently sterile. Permanent
             sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral
             oophorectomy. A postmenopausal state is defined as no menses for 12 months without an
             alternative medical cause.

         13. Male patients should agree to use an adequate method of contraception starting with
             the first dose of study therapy through 120 days after the last dose of study therapy.

         14. Be willing to provide informed consent for the trial.

        Exclusion criteria

          1. Patients who have taken any investigational medicinal product or have used an
             investigational device within 4 weeks of the first dose of pembrolizumab. Patients are
             allowed to participate in additional observational studies.

          2. Patients who have received prior chemotherapy, targeted small molecule therapy or
             radiotherapy within 4 weeks prior to the first dose of pembrolizumab.

          3. Patients with a diagnosis of immunodeficiency or be receiving systemic steroid therapy
             (>7.5 mg of prednisone / >1 mg of dexamethasone or their equivalent dose) or any other
             form of immunosuppressive therapy within 7 days prior to the first dose.

          4. Patients with evidence of active autoimmune disease requiring systemic treatment
             within the past 3 months or a documented history of clinically severe autoimmune
             disease, or a syndrome that requires systemic steroids or immunosuppressive agents or
             an autoimmune disease that is currently quiescent off any treatment, but deemed at
             risk of a significant flare if treated on this protocol.

          5. Patients who have received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2,
             anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody
             (including ipilimumab or any other antibody or drug specifically targeting T-cell
             co-stimulation or checkpoint pathways).

          6. Patients with evidence of active central nervous system (CNS) metastases and/or
             carcinomatous meningitis. Patients with previously treated brain metastases may
             participate provided the brain metastases are stable and there is no evidence of new
             or enlarging brain metastases.

          7. Patients who have had previous radiotherapy to the thorax or other neighbouring region
             that would preclude the safe administration of SBRT for MPM.

          8. Patients with evidence of interstitial lung disease or active, non-infectious
             pneumonitis.

          9. Patients with evidence of additional malignancy that is progressing or requires active
             treatment.

         10. Patients with a history or current evidence of any condition, therapy, or laboratory
             abnormality that might confound trial results, interfere with the patient's
             participation or is not in the best interest of the patient.

         11. Patients with psychiatric or substance abuse disorders that would interfere with
             patients participation.

         12. Patients who are pregnant / breastfeeding or expecting to conceive within the duration
             of the trial, starting with the screening visit through 120 days after the last dose.

         13. Patients with a history of HIV, HIV 1/2 antibodies, Hepatitis B or Hepatitis C.

         14. Patients with any active infection requiring systemic treatment

         15. Patients who have received a live vaccine within 30 days prior to the first dose of
             trial treatment.

         16. Patients with known hypersensitivity to the active substance pembrolizumab or to any
             of the excipients listed in the IB.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Toxicity rate, stated as the number of patients who have had a Dose Limiting Toxicity calculated along with an exact binomial 95% confidence interval. All toxicities will be graded by CTCAE v5.0, tabulated by type, grade and dose level.
Time Frame:12 weeks from the last dose of SBRT
Safety Issue:
Description:Hypothesis: SBRT in MPM can be safely administered in combination with pembrolizumab without significant dose limiting acute toxicity.

Secondary Outcome Measures

Measure:Number of patients of toxicity (adverse events) using CTC AE v5.0, tabulated by type, grade and dose level
Time Frame:defined as up to 12 weeks after the last fraction of stereotactic radiotherapy
Safety Issue:
Description:
Measure:Overall response rate (ORR) in Malignant pleural mesothelioma using RECIST v1.1 and mRECIST
Time Frame:at 6 and 12 months
Safety Issue:
Description:
Measure:Responses rates in epithelioid versus sarcomatoid histological subtypes of MPM using RECIST v1.1 and mRECIST
Time Frame:at 6 and 12 months
Safety Issue:
Description:
Measure:Response rates in relation to tumour PD-1/PD-L1 expression
Time Frame:12 months
Safety Issue:
Description:To correlate the number of patients that responded to the treatment with their tumour PD-1/PD-L1 expression.
Measure:Overall survival (OS) (proportion of patients)
Time Frame:at 6 and 12 months
Safety Issue:
Description:To measure the OS
Measure:Progression free survival (PFS) (proportion of patients).
Time Frame:at 6 and 12 months
Safety Issue:
Description:To measure the PFS
Measure:Disease control rate (DCR) in Malignant pleural mesothelioma using RECIST v1.1 and mRECIST
Time Frame:at 6 and 12 months
Safety Issue:
Description:
Measure:Duration of response (DOR) in Malignant pleural mesothelioma using RECIST v1.1 and mRECIST
Time Frame:at 6 and 12 months
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Royal Marsden NHS Foundation Trust

Trial Keywords

  • Advanced malignant pleural mesothelioma
  • mesothelioma
  • pembrolizumab
  • radiotherapy
  • SBRT
  • External Beam Stereotactic Body Radiotherapy

Last Updated

November 15, 2019