Neoadjuvant Durvalumab and Tremelimumab With and Without Chemotherapy for Mesothelioma

Objectives: The investigators will test whether combination of chemoimmunotherapy or dual agent immunotherapy alone improves efficacy for patients with MPM. Primary Objectives: The primary objective is to test whether the combination of platinum-based chemotherapy and pemetrexed with durvalumab / tremelimumab or durvalumab / tremelimumab alone improves recurrence-free survival for patients with resectable MPM compared to historical, published data for surgery with chemotherapy. Secondary Objective(s): The secondary objectives are to determine the safety of and whether the platinum-based chemotherapy and pemetrexed with durvalumab / tremelimumab or durvalumab / tremelimumab alone improves response rate, resectability, major pathological response, and complete pathological response. Exploratory Objective(s): The exploratory objectives are to determine the safety of and whether the platinum-based chemotherapy and pemetrexed with durvalumab / tremelimumab or durvalumab / tremelimumab alone improves response rate, resectability, major pathological response, and complete pathological response for patients with epithelioid and non-epithelioid histologies. The scientific exploratory objectives include: 1. Develop an NGS plasma assay of common mutations identified from our previous grant cycle to prospectively measure minimal residual disease (MRD) after resection as a potential, novel biomarker test in mesothelioma. 2. Determine the predictive role of BH3 profiling in patients undergoing neoadjuvant ICI followed by surgery: With patient samples collected from our neoadjuvant ICI trial, the investigators will test whether BH3 profiling from pre-treatment tumor biopsies and PBMC predicts clinical, radiological, and pathological responses to ICIs. The investigators will identify TAMs from the TiME in MPM tumor samples before and after treatment to compare differences in polarization induced by ICI in clinical and pathologically responding versus non-responding patients.

Study Design: The study will be a two-arm, randomized non-comparative Phase Ib/IIa study of induction dual immunotherapy with durvalumab/tremelimumab OR platinum chemotherapy (cisplatin or carboplatin) and pemetrexed chemotherapy plus dual immunotherapy with durvalumab/tremelimumab for 3 cycles in untreated, potentially resectable malignant pleural mesothelioma for all histologic subtypes and regardless PDL1 score. Patients will continue adjuvant durvalumab for up to 12 months following surgery. Tremelimumab will be given up to cycle 5 on treatment protocol. The investigators will enroll 6 patients to each arm to assess safety and resectability. If differences are not noted between the two arms, the investigators will expand enrollment to 23 patients per arm. To account for up to 10% unevaluable patients, the investigators will enroll at total of 52 patients. Safety in the first 6 patients in the chemotherapy plus immunotherapy arm will be determined by rate of attempted surgical resection. If 4 or more patients undergo surgical resection, then the study will proceed to enroll the full 23 patient cohort. If 3 or less than 3 patients undergo surgical resection, the study will be paused for PI review of the enrolled patients to determine causality of the safety events.