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Durvalumab + Standard Chemotherapy for 4 to 6 cycles, followed by Maintenance with Durvalumab

Standard Chemotherapy for 4 to 6 cycles, followed by Observation

Ipilimumab every 6 weeks and Nivolumab every 2 or 3 weeks for up to 2 years.

Durvalumab 1500 milligrams (mg) intravenous (IV) every 3 weeks + Cisplatin 75 mg/m² or Carboplatin AUC 5 IV every 3 weeks + Pemetrexed 500 mg/m² IV every 3 weeks for 4 to 6 cycles, followed by maintenance with Durvalumab 1500 mg IV every 4 weeks

Cisplatin 75 mg/m² or Carboplatin AUC 5 IV every 3 weeks + Pemetrexed 500 mg/m² IV every 3 weeks) for 4 to 6 cycles, followed by Observation

Standard Chemotherapy

Ipilimumab 1 mg/kg every 6 weeks and Nivolumab 360 mg every 3 weeks or 3 mg/kg every 2 weeks for up to 2 years

Ipilimumab and Nivolumab

Patrick Forde, MD

Anna Nowak, MD

Patients with pleural mesothelioma (PM) that cannot be surgically removed will receive standard chemotherapy (cisplatin or carboplatin and pemetrexed) given with durvalumab, a type of immunotherapy, or a treatment chosen by the study doctor, which is either standard chemotherapy or immunotherapy combination (ipilimumab and nivolumab).

Durvalumab is an antibody (a type of human protein) that works by blocking a body substance called Programmed Death-Ligand 1 (PD-L1). Blocking PD-L1 helps the body's immune system attack cancer cells. Research has shown that durvalumab can slow tumor growth and shrink tumors in some people with cancer. Previous studies of combining durvalumab and chemotherapy showed that this combination is active in advanced mesothelioma.

The purpose of this study is to see whether adding durvalumab to standard chemotherapy will improve overall survival (OS) in patients with PM.

Mesothelioma is a malignant tumor of the mesothelial surfaces primarily arising in the thoracic pleura. In the United Kingdom and USA the expected number of cases in the next few decades are 65,000 and 85,000, respectively. Once diagnosed, this disease is rarely cured with a median survival of less than a year.

This is an International, Open-Label, Multi-center, Phase III study. Patients will be randomized 1:1 to receive (a) chemotherapy given with durvalumab versus (b) physician's choice of either chemotherapy alone, or ipilimumab and nivolumab.

Experimental Arm:

- Durvalumab every 3 weeks + standard chemotherapy (cisplatin or carboplatin every 3 weeks + pemetrexed every 3 weeks) for 4 to 6 cycles, followed by durvalumab every 4 weeks until disease progression, unacceptable toxicity or patient withdrawal.

Control Arm: Physician Choice

* Standard chemotherapy (cisplatin or carboplatin every 3 weeks + pemetrexed every 3 weeks) for 4 to 6 cycles followed by observation
* Ipilimumab every 6 weeks and nivolumab every 2 or 3 weeks \[physician discretion\] for up to 2 years until disease progression, unacceptable toxicity or patient withdrawal .

Tumor assessments and Quality of Life (QOL) forms will be performed at baseline, then at weeks 6, 12, 18, 26, 34, 42, 50 and then every 12 weeks until disease progression. The QOL forms will also be repeated during the first visit after progression.

Mandatory pre-treatment tumor tissue sample (i.e., obtained during a previous procedure or biopsy) for research will also be required. Blood samples for research at 3 time points will be done.

The study is being led jointly by PrECOG as the US sponsor and University of Sydney as the international sponsor.

First-line chemotherapy with cisplatin or carboplatin and pemetrexed + durvalumab OR physician's choice of either first-line chemotherapy alone, or ipilimumab and nivolumab.

DuRvalumab With chEmotherapy as First Line treAtment in Advanced Pleural Mesothelioma

DREAM3R: DuRvalumab (MEDI4736) With chEmotherapy as First Line treAtment in Advanced Pleural Mesothelioma - A Phase 3 Randomised Trial

Defined as the time from randomisation to the date of death due to any cause.

Defined as the interval from date of randomisation to the date of first evidence of disease progression or death, whichever occurs first.

Percentage of participants with either Complete Response (CR) or Partial Response (PR) assessed according to modified Response Criteria in Solid Tumors (RECIST) 1.1 for response in malignant pleural mesothelioma.

Classify and grade participants abnormal laboratory values and/or adverse events.

European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30), Importance of QOL issues assessed using a four-point scale (1 = not at all, 4 = very much).

EORTC Quality of Life Lung Cancer Module (QLQ-LC29), Importance of QOL issues assessed using a four-point scale (1 = not at all, 4 = very much).

Euro-Quality of Life (EuroQoL) 5 dimension 5 level (EQ-5D-5L) questionnaire, comprising of 5 questions with a score from 1 (no problem) to 5 (extreme problem) and a visual analog scale from 0 (worst) to 100 (best).

Australian Sites Only: Hospitalization costs calculated by applying Australian unit costs to Australian Refined Diagnostic Related Groups (AR DRG) costs for hospitalizations.

Australian Sites Only: Scheduled costs for visits to health professionals collected via Medical Benefits Schedule (MBS).

Australian Sites Only: Scheduled costs for medications collected via the Pharmaceutical Benefits Schedule (PBS).

AstraZeneca

Thoracic Oncology Group Australasia (TOGA)

University of Sydney

PrECOG, LLC.

Pemetrexed/cisplatin will be given for up to six 3-week cycles with the addition of concurrent durvalumab every 3 weeks. The first 6 patients who are enrolled and commence treatment will be monitored for safety of the combination. Use of carboplatin in place of cisplatin will be permitted for patients who are ineligible for cisplatin due to impaired renal function at screening. For patients that receive cisplatin, carboplatin may also be substituted after Cycle 1 for cisplatin related toxicity (e.g., grade 3 ototoxicity, grade 3 nausea) at the investigator's discretion. After completion of Cycle 6 of concurrent therapy, patients with stable or responding disease per modified RECIST for malignant mesothelioma will continue on single agent durvalumab every 3 weeks until progression. Maximum duration of durvalumab treatment is 12 months starting from Cycle 1 of concurrent treatment (inclusive of any treatment delays or missed treatments).

On Day 1 of each 21 day cycle: Durvalumab 1120 mg IV will be administered before pemetrexed and cisplatin chemotherapy over approximately 60 minutes. Approximately 30 minutes after the durvalumab infusion is complete, pemetrexed 500 mg/m² IV will be administered over 10 minutes. Cisplatin 75 mg/m² IV over 2 hours will begin approximately 30 minutes after the end of pemetrexed administration. If carboplatin is substituted for cisplatin, carboplatin Area Under the Concentration-Time Curve (AUC) 5 will be infused over 30 minutes beginning approximately 15-30 minutes after the end of the pemetrexed administration. Maintenance: On Day 1 of each 21 day cycle: Durvalumab 1120 mg IV over approximately 60 minutes.

Patients with pleural mesothelioma that can not be surgically removed will receive durvalumab, in combination with standard chemotherapy of pemetrexed and cisplatin as first-line treatment.

Durvalumab is a type of drug called a monoclonal antibody (a type of protein). Laboratory tests show that it works by allowing the immune system to detect your cancer and reactivates the immune response. This may help to slow down the growth of cancer or may cause cancer cells to die.

The purpose of this study is to see whether adding durvalumab to standard chemotherapy will improve overall survival (OS).

Mesothelioma is a malignant tumor of the mesothelial surfaces primarily arising in the thoracic pleura and is estimated to cause 43,000 deaths worldwide each year with over 3300 cases occurring annually in the United States. Approximately 80% of cases of mesothelioma are due to inflammation induced by prior asbestos exposure with a lead time from exposure to development of cancer of 20-30 years.

This is a single arm, open label phase II study of the anti-PD-L1 antibody, durvalumab, in combination with standard chemotherapy. Pemetrexed and cisplatin will be given for up to six 3-week cycles with the addition of concurrent durvalumab dosed every 3 weeks. The first 6 patients who are enrolled and commence treatment will be monitored for safety of the combination. Use of carboplatin in place of cisplatin will be permitted for patients who are ineligible for cisplatin due to impaired renal function at screening, however these patients must otherwise fulfill the eligibility criteria for the study. For patients that receive cisplatin, carboplatin may also be substituted after Cycle 1 for cisplatin related toxicity (e.g., grade 3 ototoxicity, grade 3 nausea) at the investigator's discretion. After completion of Cycle 6 of concurrent therapy, patients with stable or responding disease per modified RECIST for malignant mesothelioma will continue on single agent durvalumab every 3 weeks until progression. Maximum duration of durvalumab treatment is 12 months starting from Cycle 1 of concurrent treatment (inclusive of any treatment delays or missed treatments).

Tumor assessments will be performed approximately every 6 weeks during concurrent therapy and every 9 weeks during the maintenance phase.

Mandatory pre-treatment tumor tissue sample (i.e., obtained during a previous procedure or biopsy) and blood samples (prior to Cycle 1, Cycle 2 and Cycle 5) for research will also be required.

Concurrent therapy with Durvalumab, Pemetrexed and Cisplatin (or Carboplatin) for up to 6 cycles followed by Maintenance Therapy with Durvalumab

Phase II MEDI4736 in Combination With Chemotherapy for First-Line Treatment of Unresectable Mesothelioma

Open Label, Phase II Study of Anti - Programmed Death - Ligand 1 Antibody, Durvalumab (MEDI4736), in Combination With Chemotherapy for the First-Line Treatment of Unresectable Mesothelioma

Overall survival (OS) is defined as the time from randomization to death from any cause. Patients that have not had an event reported at analysis will be censored at their date of last follow-up.

Number of participants with abnormal laboratory values and/or adverse events related to treatment.

Progression-free survival (PFS) is defined as the time from randomization to documented disease progression or death from any cause, whichever occurs first. Patients who have not experienced an event of interest by the time of analysis will be censored at the date they are last known to be alive and progression-free.

TTP measured from the time concurrent treatment with chemotherapy/durvalumab begins until radiologic or clinical progression is noted.

ORR assessed in accordance with RECIST 1.1 (modified for malignant mesothelioma).

Pemetrexed/cisplatin will be given for up to six 3-week cycles with the addition of concurrent durvalumab every 3 weeks. Use of carboplatin in place of cisplatin will be permitted for patients who are ineligible for cisplatin due to impaired renal function at screening. For patients that receive cisplatin, carboplatin may also be substituted after Cycle 1 for cisplatin related toxicity at the investigator's discretion.

Concurrent Durvalumab: On Day 1 of each 21 day cycle: Durvalumab 1120 mg IV will be administered before pemetrexed and cisplatin chemotherapy over approximately 60 minutes. Approximately 30 minutes after the durvalumab infusion is complete, pemetrexed 500 mg/m² IV will be administered over 10 minutes. Cisplatin 75 mg/m² IV over 2 hours will begin approximately 30 minutes after the end of pemetrexed administration. If carboplatin is substituted for cisplatin, carboplatin Area Under the Concentration-Time Curve (AUC) 5 will be infused over 30 minutes beginning approximately 15-30 minutes after the end of the pemetrexed administration.

After completion of Cycle 6 of concurrent therapy, patients with stable or responding disease per modified RECIST for malignant mesothelioma will continue on single agent durvalumab every 3 weeks until progression. Maximum duration of durvalumab treatment is 12 months starting from Cycle 1 of concurrent treatment.

Maintenance Durvalumab: On Day 1 of each 21 day cycle: Durvalumab 1120 mg IV over approximately 60 minutes.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
DuRvalumab With chEmotherapy as First Line treAtment in Advanced Pleural Mesothelioma	NCT04334759	Mesothelioma Pleural Mesothe... Malignant Pleur...	Durvalumab Standard Chemot... Ipilimumab and ...	18 Years -	PrECOG, LLC.
Phase II MEDI4736 in Combination With Chemotherapy for First-Line Treatment of Unresectable Mesothelioma	NCT02899195	Mesothelioma Pleural Mesothe...	Durvalumab	18 Years -	PrECOG, LLC.
Phase II MEDI4736 in Combination With Chemotherapy for First-Line Treatment of Unresectable Mesothelioma	NCT02899195	Mesothelioma Pleural Mesothe...	Durvalumab	18 Years -	PrECOG, LLC.

Spots Global Cancer Trial Database for unresectable mesothelioma