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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.

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Immunologic Factors

The effect of ipilimumab and nivolumab has previously been tested in metastatic uveal melanoma. In this study the combination with percutaneous hepatic perfusion will be performed in order to evaluate the effect.

Ipilimumab and nivolumab

Melphalan chemosaturation via percutaneous hepatic perfusion

Ellen W. Kapiteijn, MD, PhD

Mark C. Burgmans, MD, PhD

Ellen Kapiteijn, MD, PhD

Frank Speetjens, MD, PhD

Thaïs Tong, MD

Melanoma of the eye (ocular/uveal melanoma) is an uncommon type of cancer that is associated with a high mortality. It usually disseminates rapidly throughout the body, most commonly to the liver and lungs. In this study a combination therapy with immunotherapy (ipilimumab with nivolumab) and chemotherapy (melphalan) will be assessed for the treatment of disseminated uveal melanoma. Melphalan will be administered selectively to the liver via percutaneous hepatic perfusion, limiting the systemic effect of chemotherapy. With this treatment combination we aim to find a treatment for disseminated uveal melanoma, both in the liver as in the other organs.

Uveal melanoma (UM) is an uncommon malignancy (0.6-0.7 cases/100.000/year) that, in the case of metastatic stage, has a poor prognosis for response to treatment and survival. It is remarkable for its purely hematogenous pattern of dissemination, most commonly to the liver (60%) and lungs (25%). Current approaches using percutaneous hepatic perfusion (PHP) with melphalan resulted in response rates of up to 40% in the liver (1, 2) (for results of our own phase II study see paragraph 6.3.2). However, a main part of the patients developed extrahepatic disease in the follow-up, whereas the liver metastases were mainly stable.

Checkpoint inhibitors have been shown to improve overall survival in metastasized cutaneous melanoma in phase III studies (3-6), but seem to have limited activity as monotherapies in metastasized uveal melanoma (7-9). The combination of ipilimumab and nivolumab has achieved 2 out of 6 patients PR in a retrospective analysis (10). Interestingly, both patients had a liver-directed therapy (SIRT and chemoembolization) before the immunotherapy.

Combination of radio-frequency ablation (RFA) and anti-CTLA-4 enhanced antigen-loading of dendritic cells, and induced long-lasting anti-tumor immune responses in a murine melanoma model without induction of any severe side effects (11, 12). A phase Ib/II trial by Blank et al. (13) showed unconfirmed responses in some patients when RFA was combined with ipilimumab in uveal melanoma, but long-term disease stabilization was not achieved. Most of the responses were seen in extrahepatic metastases. Combining percutaneous hepatic perfusion (PHP) with checkpoint inhibitors could together lead to control of hepatic and extrahepatic disease. Therefore, we propose the current trial: Phase1b/2 Study Combining Hepatic Percutaneous Perfusion with Ipilimumab plus Nivolumab in advanced Uveal Melanoma (CHOPIN).

In the phase 1b part, safety and feasibility of combining percutaneous hepatic perfusion with 4 courses of ipilimumab and nivolumab will be investigated. In the randomized phase 2 part, efficacy as measured by progression-free survival at one year comparing PHP only versus PHP plus ipilimumab/nivolumab will be evaluated.

Open label, single center, phase Ib/randomized phase II trial, evaluating the safety and efficacy (as measured by RECIST 1.1) of the combination of PHP and ipilimumab/nivolumab in patients with unresectable hepatic and extrahepatic metastases of uveal melanoma.

PHP and Immunotherapy in Metastasized UM

Phase1b/2 Study Combining Hepatic Percutaneous Perfusion With Ipilimumab Plus Nivolumab in Advanced Uveal Melanoma

Dose limiting toxicities, maximum tolerated dose and recommended phase dose of the combination ipilimumab/nivolumab and PHP in patients with unresectable, histologically confirmed hepatic metastasis of uveal melanoma in phase Ib part.

Description of PFS according to RECIST 1.1 at one year in the PHP group versus PHP + ipilimumab/nivolumab group in the phase II part.

Description of response rate and overall survival, overall clinical response, and duration of response

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.
PHP and Immunotherapy in Metastasized UM	NCT04283890	Uveal Melanoma,...	Ipilimumab and ... Melphalan chemo...	18 Years - 75 Years	Leiden University Medical Center
PHP and Immunotherapy in Metastasized UM	NCT04283890	Uveal Melanoma,...	Ipilimumab and ... Melphalan chemo...	18 Years - 75 Years	Leiden University Medical Center

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