Pembrolizumab Plus Lenvatinib In Second Line and Third Line Malignant Pleural mesotheLioma Patients (PEMMELA)

• ClinicalTrials.gov Identifier: NCT04287829
• Recruitment Status: Recruiting
• First Posted: February 27, 2020
• Last Update Posted: January 17, 2023
• Sponsor: The Netherlands Cancer Institute
• Collaborator: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): The Netherlands Cancer Institute

Tracking Information

• First Submitted Date: November 15, 2019
• First Posted Date: February 27, 2020
• Last Update Posted Date: January 17, 2023
• Actual Study Start Date: March 1, 2021
• Estimated Primary Completion Date: December 5, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 29, 2022)

Objective response rate defined by Modified RECIST 1.1 criteria for pleural mesothelioma [ Time Frame: Through study completion, an average of 1 year ]

Complete response and partial response

Original Primary Outcome Measures (submitted: February 25, 2020)

Objective response rate defined by Modified (i)RECIST criteria for pleural mesothelioma [ Time Frame: Through study completion, an average of 1 year ]

Complete response and partial response

Current Secondary Outcome Measures (submitted: February 25, 2020)

• Safety of pembrolizumab- lenvatinib [ Time Frame: Up to 90 days after last study drug intake ]
  Number of participants with treatment-related adverse events as assessed by CTCAE v5.0
• Describe the disease control rate (DCR) at 3 and 6 months [ Time Frame: From date of registration until 6 months ]
  a percentage of the total number of patients in the study who are evaluable for the primary endpoint who have best overall response of CR or PR or SD.
• Objective response rate (ORR) [ Time Frame: Assessed up to 60 months ]
  Number of patients with a partial or complete response
• Progression-free survival [ Time Frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months ]
  To describe PFS by independent radiological review

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: February 25, 2020)

Immunological status [ Time Frame: before study and after 6 weeks of treatment ]

The immunological status in the tumors before study and after 6 weeks of treatment with pembrolizumab +lenvatinib. This research will include PD-L1 status, mutational load and other potential biomarkers (e.g. micro vessel density count).

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: Pembrolizumab Plus Lenvatinib In Second Line and Third Line Malignant Pleural mesotheLioma Patients
• Official Title: PEMbrolizumab Plus Lenvatinib In Second Line And Third Line Malignant Pleural MEsotheLiomA Patients(PEMMELA)
• Brief Summary: There is no standard second line treatment in malignant pleural mesothelioma (MPM). Pembrolizumab has shown to be active in in small phase II studies in MPM. Its activity however, is limited, with a response rate up to 20%. Since the arrival of nivolumab plus ipilimumab as first line standard of care treatment in mesothelioma, no treatment options are investigated in this group of patients in the second line. So, there is a need for new treatment combinations with drugs that might exhibit a synergistic interaction with pembrolizumab.
• Detailed Description: There is no standard second line treatment in malignant pleural mesothelioma (MPM). Pembrolizumab has shown to be active in in small phase II studies in MPM. Its activity however, is limited, with a response rate up to 20%. So, there is a need for new treatment combinations with drugs that might exhibit a synergistic interaction with pembrolizumab. The mechanisms of actions of lenvatinib, which has a broad spectrum of activities, predicts many synergistic interactions with PD-1 blocking. The aim of this study is to characterize the potential clinical activity, toxicity and biomarkers of outcome of pembrolizumab - lenvatinib in patients with recurrent MPM.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Mesotheliomas Pleural

Intervention

• Drug: Pembrolizumab
  Infusion
• Drug: Lenvatinib
  Capsule

Study Arms

Experimental: pembrolizumab and lenvatinib

Patients will receive pembrolizumab 200mg/iv (fixed dose) every 3 weeks and lenvatinib 20mg QD in a three weekly cycle.

Treatment continues until disease progression by modified RECIST 1.1 for MPM, severe toxicity, serious intercurrent illness, patient request for discontinuation, need or use for any other anti-cancer agent other than protocol treatment, except for palliative radiotherapy, for a maximum period of 35 cycles

Interventions:

• Drug: Pembrolizumab
• Drug: Lenvatinib

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: September 29, 2022): 58
• Original Estimated Enrollment (submitted: February 25, 2020): 36
• Estimated Study Completion Date: December 5, 2024
• Estimated Primary Completion Date: December 5, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Histologically or cytologically diagnosed malignant pleural mesothelioma, age at least 18 years

2. Progressive disease after at least 1 and maximal 2 prior systemic treatment lines:

   • Cohort 1: patients, in which one of the lines contains a platinum-based doublet (both cisplatin and carboplatin are allowed) for unresectable MPM (CLOSED)
   • Cohort 2: patients with only in which one of the lines contains nivolumab-ipilimumab immunotherapy as first line treatment for unresectable MPM. No prior chemotherapy.
3. Measurable disease. At least one measurable lesion according to Modified RECIST 1.1 for pleural mesothelioma. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions
4. WHO-ECOG performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to date of allocation
5. Adequate organ function
6. Ability to understand the study and give signed informed consent (or legally acceptable representative if applicable) prior to beginning of protocol specific procedures including the approval of the thoracoscopy or transthoracic pleural biopsy before the first treatment cycle and an optional biopsy before the third treatment cycle
7. No presence of clinically relevant treatment-related toxicity from previous chemotherapy, targeted therapy and/or radiotherapy. Note: Participates must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants with ≤2 neuropathy may be eligible
8. No active uncontrolled infection, severe cardiac dysfunction (i.e. unstable angina, history of myocardial infarction within the past 12 months prior to screening, congestive heart failure > NYHA II, serious cardiac arrhythmia), unstable peptic ulcer, unstable diabetes mellitus or other seriously disabling condition
9. Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP ≤150/90 mmHg at screening ad no change in hypertensive medication within 1 week before the cycle 1/day1.
10. No prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with another agent agents direct to another stimulatory or co-inhibitory T-cell receptor (eg CTLA-4, OC-40, CD137) or TKI or antibody targeting angiogenesis in the first cohort. Patients who have been treated with autologous tumor cell vaccination (eg. Dendritic cell-based immunotherapy) will be eligible in the first cohort. (First cohort is closed).
11. No concomitant administration to any other experimental drugs under investigation ≤ 4 weeks prior to first admission of pembrolizumab- lenvatinib
12. No prior radiotherapy within 2 weeks before start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids as therapy for radiation induced toxicities. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
13. No major injuries and/or surgery within the past 4 weeks prior to first study dose with incomplete wound healing

Exclusion Criteria:

1. presence of clinically relevant treatment-related toxicity from previous chemotherapy, targeted therapy and/or radiotherapy. Note: Participates must have recovered from all AEs due to previous therapies to 5Grade 1 or baseline. Participants with 52 neuropathy may be eligible
2. active uncontrolled infection, severe cardiac dysfunction (i.e. unstable angina, history of myocardial infarction within the past 12 months prior to screening, congestive heart failure > NYHA II, serious cardiac arrhythmia), unstable peptic ulcer, unstable diabetes mellitus or other seriously disabling condition
3. prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with another agent agents direct to another stimulatory or co-inhibitory T-cell receptor (eg CTLA-4, OC-40, CD137) or TKI or antibody targeting angiogenesis in the first cohort. Patients who have been treated with autologous tumor cell vaccination (eg. Dendritic cell-based imnnunotherapy) will be eligible in the first cohort. (CLOSED)
4. concomitant administration to any other experimental drugs under investigation 5 4 weeks prior to first admission of pembrolizumab- lenvatinib

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: S Burgers, PhD; 0031205129111; s.burgers@nki.nl

Contact: L Douma, MD; 0031205129111; l.douma@nki.nl

• Listed Location Countries: Netherlands

Administrative Information

• NCT Number: NCT04287829
• Other Study ID Numbers: N19PEM
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: The Netherlands Cancer Institute
• Original Responsible Party: Same as current
• Current Study Sponsor: The Netherlands Cancer Institute
• Original Study Sponsor: Same as current
• Collaborators: Merck Sharp & Dohme LLC

Investigators

• Principal Investigator: S Burgers, PhD; NKI-AvL

• PRS Account: The Netherlands Cancer Institute
• Verification Date: September 2022