Pembrolizumab and Hypofractionated Stereotactic Radiotherapy in Patients With Malignant Pleural Mesothelioma (MESO-PRIME)

• ClinicalTrials.gov Identifier: NCT04166734
• Recruitment Status: Recruiting
• First Posted: November 18, 2019
• Last Update Posted: April 12, 2021
• Sponsor: Royal Marsden NHS Foundation Trust
• Collaborator: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Royal Marsden NHS Foundation Trust

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Advanced Malignant Pleural Mesothelioma	Drug: Pembrolizumab; Radiation: Stereotactic Body Radiotherapy (SBRT)	Phase 1

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 18 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: Initial safety phase followed by an Expansion phase
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pembrolizumab and Hypofractionated Stereotactic Radiotherapy in Patients With Malignant Pleural Mesothelioma
• Actual Study Start Date: January 26, 2021
• Estimated Primary Completion Date: August 2023
• Estimated Study Completion Date: August 2024

Arms and Interventions

Arm	Intervention/treatment
Initial safety cohort; 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.	Drug: Pembrolizumab; 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.; Other Name: Keytruda; Radiation: Stereotactic Body Radiotherapy (SBRT); Stereotactic Body Radiotherapy (SBRT) 30 Gy 3 fractions (#); Other Name: SBRT
Expansion cohort; 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.	Drug: Pembrolizumab; 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.; Other Name: Keytruda; Radiation: Stereotactic Body Radiotherapy (SBRT); Stereotactic Body Radiotherapy (SBRT) 30 Gy 3 fractions (#); Other Name: SBRT

Outcome Measures

Primary Outcome Measures :

1. 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 ]
   Hypothesis: SBRT in MPM can be safely administered in combination with pembrolizumab without significant dose limiting acute toxicity.

Secondary Outcome Measures :

1. 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 ]
2. Overall response rate (ORR) in Malignant pleural mesothelioma using RECIST v1.1 and mRECIST [ Time Frame: at 6 and 12 months ]
3. Responses rates in epithelioid versus sarcomatoid histological subtypes of MPM using RECIST v1.1 and mRECIST [ Time Frame: at 6 and 12 months ]
4. Response rates in relation to tumour PD-1/PD-L1 expression [ Time Frame: 12 months ]
   To correlate the number of patients that responded to the treatment with their tumour PD-1/PD-L1 expression.
5. Overall survival (OS) (proportion of patients) [ Time Frame: at 6 and 12 months ]
   To measure the OS
6. Progression free survival (PFS) (proportion of patients). [ Time Frame: at 6 and 12 months ]
   To measure the PFS
7. Disease control rate (DCR) in Malignant pleural mesothelioma using RECIST v1.1 and mRECIST [ Time Frame: at 6 and 12 months ]
8. Duration of response (DOR) in Malignant pleural mesothelioma using RECIST v1.1 and mRECIST [ Time Frame: at 6 and 12 months ]

Other Outcome Measures:

1. 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. [ Time Frame: 12 months ]
   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.
2. To analyse peripheral blood samples for ctDNA [ Time Frame: Cycle1 Day1, Cycle 2 Day 1, Cycle 5 Day1 and End of treatment (an average of 7 months) ]
   To assess for levels of ctDNA

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Contacts

Contact: Fiona McDonald, Oncologist; +44 (0)20 8915 6083; Fiona.McDonald@rmh.nhs.uk

Contact: Sarah Webb; +44 (0) 20 8915 6667; mesoprime.trial@rmh.nhs.uk

Locations

United Kingdom

Royal Marsden NHS Foundation Trust; Recruiting

Chelsea, United Kingdom

Contact: Fiona McDonald 02086439414 fiona.mcdonald@rmh.nhs.uk

Principal Investigator: Fiona McDonald

Beatson West of Scotland Cancer Centre; Recruiting

Glasgow, United Kingdom, G12 0YN

Contact: Maria Nicol 01413017223 Maria.Nicol@ggc.scot.nhs.uk

Principal Investigator: Stephen Harrow

Sponsors and Collaborators

Royal Marsden NHS Foundation Trust

Merck Sharp & Dohme LLC

More Information

• Responsible Party: Royal Marsden NHS Foundation Trust
• ClinicalTrials.gov Identifier: NCT04166734
• Other Study ID Numbers: CCR4583
• First Posted: November 18, 2019
• Last Update Posted: April 12, 2021
• Last Verified: April 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Royal Marsden NHS Foundation Trust:

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

Additional relevant MeSH terms:

Mesothelioma; Mesothelioma, Malignant; Adenoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Mesothelial; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Pleural Neoplasms; Lung Diseases; Respiratory Tract Diseases; Pembrolizumab; Antineoplastic Agents, Immunological; Antineoplastic Agents