Efficacy of a Maintenance Treatment With TALAzoparib Following First Line Platinum-based Chemotherapy in Malignant MESOthelioma

Summary

Malignant mesothelioma is an invasive neoplasm that arises from mesothelium that lines several organs. Common primary sites of origin of mesotheliomas are the pleura (malignant pleural mesothelioma: 85%) and peritoneum (malignant peritoneal mesothelioma 15%), and rarely the pericardium and tunica vaginalis.

The standard of care recommended for malignant pleural mesotheliomas (MPM) is palliative chemotherapy based on a doublet of platinum salt and an anti-folate. The median survival of patients with pleural MPM is around 8 months with best supportive care only, 12 to 19 months when systemic chemotherapy is used with or without anti-angiogenic agents or targeted therapy. There is an unmet need for innovative approaches in pleural mesotheliomas.

Malignant peritoneal mesothelioma is an aggressive neoplasm that arises from the lining mesothelial cells of the peritoneum and spreads extensively within the confines of the abdominal cavity. Cytoreductive surgery (CRS) followed by hyperthermic intraoperative peritoneal perfusion with chemotherapy (HIPEC) is the standard curative approach when it is possible, with respect to peritoneal carcinomatosis extend. When the cytoreductive surgery is impossible, the common strategy is to prescribe systemic chemotherapy, with the objective of downsizing tumor lesions for potential subsequent CRS. The standard strategy based on cisplatin - pemetrexed combination regimen has been extrapolated from pleural mesothelioma management principles.

Genomic landscape of mesotheliomas is now well described. Pleural and peritoneal malignant mesotheliomas harbor closed genomic instability.

Strategies based on maintenance-based treatments with Poly (ADP-ribose) polymerase (PARP) inhibitors, especially olaparib, niraparib and talazoparib, have been shown effective in ovarian cancer patients, thereby leading to their approvals. The benefit has been mainly observed in patients with homologous recombination deficiencies (HRD), but also in all-comers patients in a lesser extent. It is thought that HRD induces addiction of cancer cells to PARP, thereby leading to cell death in the presence of PARP inhibitors.

As a consequence, given the prevalence of HRD, through BAP-1 mainly, in mesotheliomas, maintenance treatment with PARP-inhibitor in malignant mesothelioma patients without any progressive disease after 4 to 6 cycles of platinum-based chemotherapy may be associated with increased progression free survival, as it was shown in ovarian cancer patients.

TALAMESO aims to evaluate the efficacy of talazoparib maintenance treatment given for maximum 2 years following 4 to 6 cycles of platinum-based first line chemotherapy in terms of proportion of patients progression free 6 months after starting the maintenance, and progression-free survival, in patients with advanced malignant pleural (cohort A) or peritoneal (cohorts B1 and B2) mesotheliomas.

Cohorts B1 and B2 are meant to confirm that talazoparib can increase progression free survival in both patient populations with non-resected or incompletely resected disease (cohort B1) or with completely resected disease (cohort B2).

TALAMESO is an open-label phase II trial with 3 independent cohorts (Fleming's single-stage) including patients with advanced malignant pleural (cohort A) or peritoneal (cohort B1 and B2) mesotheliomas without any sign of disease progression after 4 to 6 cycles of platinum-based chemotherapy (including minimum 1 cycle of pemetrexed).

Conditions

• Advanced Malignant Pleural or Peritoneal Mesothelioma

Interventions

DRUG

Talazoparib

Talazoparib 1 mg a day (PO) (or 0.75 mg a day) for 2 years, started between 6 to 8 weeks after the end of chemotherapy discontinuation. Talazoparib will be given for up to 2 years, or less length of time in the case of disease progression,. unacceptable toxicity despite adequate management,patient decides to withdraw from the study, or general or specific changes in the patient's condition render the patient unacceptable for further treatment.

Sponsors & Collaborators

• Hospices Civils de Lyon

  lead OTHER

Study Design

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2020-09-01

Primary Completion

2021-03-01

Completion

2024-10-01