A Study Evaluating the Efficacy and Safety of Multiple Treatment Combinations in Patients With Melanoma (Morpheus-Melanoma)

A Study Evaluating the Efficacy and Safety of Multiple Treatment Combinations in Patients With Melanoma (Morpheus-Melanoma)

A Phase Ib/II, Open-Label, Multicenter, Randomized Umbrella Study Evaluating the Efficacy and Safety of Multiple Treatment Combinations in Patients With Melanoma (Morpheus-Melanoma)

This study will evaluate the efficacy, safety, and pharmacokinetics of treatment combinations in cancer immunotherapy (CIT)-naive participants with resectable Stage III melanoma (Cohort 1) and in participants with Stage IV melanoma (Cohort 2). The study is designed with the flexibility to open new treatment arms as new treatments become available, close existing treatment arms that demonstrate minimal clinical activity or unacceptable toxicity, and modify the participant population.

Cohort 1 participants in the nivolumab plus ipilimumab arm will receive treatment for 2 cycles (6 weeks) on Day 1 of each cycle (cycle length 21 days) until surgery, or until unacceptable toxicity or loss of clinical benefit, whichever occurs first.

Cohort 1 participants in the RO7247669 arm will receive treatment for 2 cycles (6 weeks) until surgery, or until unacceptable toxicity or loss of clinical benefit, whichever occurs first.

Cohort 1 participants in the atezolizumab plus tiragolumab arm will receive treatment for 2 cycles (6 weeks) until surgery, or until unacceptable toxicity or loss of clinical benefit, whichever occurs first.

Cohort 1 participants in the RO7247669 plus tiragolumab arm will receive treatment for 2 cycles (6 weeks) until surgery, or until unacceptable toxicity or loss of clinical benefit, whichever occurs first.

Cohort 2 participants in RO7247669 plus tiragolumab arm will receive treatment until unacceptable toxicity or loss of clinical benefit as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status.

Cohort 1 participants in the RO7247669 arm will receive treatment for 2 cycles (6 weeks) until surgery, or until unacceptable toxicity or loss of clinical benefit, whichever occurs first.

Cohort 1 participants in the RO7247669 plus tiragolumab arm will receive treatment for 2 cycles (6 weeks) until surgery, or until unacceptable toxicity or loss of clinical benefit, whichever occurs first.

pRR is defined as the proportion of participants with pathologic complete response (pCR), pathologic near complete response (pnCR), and pathologic partial response (pPR) at time of surgery, as determined by independent pathologic review.

ORR is defined as the proportion of participants with a complete response (CR) or partial response (PR) on two consecutive occasions >= 4 weeks apart, as determined by the investigator according to RECIST v1.1.

pRR is defined as the proportion of participants with pCR, pnCR, and pPR at time of surgery, as determined by local pathologic assessment.

EFS is defined as the time from randomization to any of the following events (whichever occurs first): Disease progression that precludes surgery, as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1); local, regional or distant disease recurrence; or death from any cause.

Randomization to disease progression that precludes surgery; local, regional or distant disease recurrence; or death from any cause (whichever occurs first) (up to approximately 5 years)

RFS is defined as the time from surgery to the first documented recurrence of disease or death from any cause.

Surgery to the first documented recurrence of disease or death from any cause (up to approximately 5 years)

ORR is defined as the proportion of participants with a complete response (CR) or partial response (PR) as determined by the investigator according to RECIST v1.1, prior to surgery.

Surgical complication rates according to Clavien-Dindo surgical classification after completion lymph node dissection (CLND).

PFS after randomization/enrollment, defined as the time from randomization/enrollment to the first occurrence of disease progression or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1.

Randomization/enrollment to the first occurrence of disease progression or death from any cause (whichever occurs first)(up to approximately 5 years)

OS after randomization/enrollment, defined as the time from randomization/enrollment to death from any cause.

OS after randomization/enrollment, defined as the time from randomization/enrollment to death from any cause.

Randomization/enrollment to death from any cause at specific timepoints (up to approximately 5 years)

DOR is defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1.

First occurrence of a documented objective response to disease progression or death from any cause (whichever occurs first)(up to approximately 5 years)

Disease control is defined as stable disease for >= 12 weeks or a CR or PR, as determined by the investigator according to RECIST v1.1.

Inclusion Criteria for Cohort 1: ECOG performance status (PS) of 0 or 1 Histologically confirmed resectable Stage III melanoma according to AJCC-8 and no history of in-transit metastases within the last 6 months Fit and planned for CLND Measurable disease according to RECIST v1.1 Availability of a representative tumor specimen Adequate hematologic and end-organ function For patients receiving therapeutic anticoagulation: stable anticoagulant regimen Negative HIV test, negative hepatitis B surface antibody (HBsAb), and negative total hepatitis B core antibody (HBcAb) test, and negative hepatitis C virus (HCV) at screening. Patients with a positive HIV test at screening are eligible provided they are stable on anti-retroviral therapy, have a CD4 count >= 200/μL, and have an undetectable viral load. Exclusion Criteria for Cohort 1: Mucosal, uveal and acral lentiginous melanoma Distantly metastasized melanoma History of in-transit metastases within the last 6 months Prior radiotherapy Prior immunotherapy, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies, and other systemic therapy for melanoma Treatment with investigational therapy within 28 days prior to initiation of study treatment Treatment with systemic immunostimulatory agents within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment Prior allogeneic stem cell or solid organ transplantation Known immunodeficiency or conditions requiring treatment with systemic immunosuppressive medication, or anticipation of need for systemic immunosuppressant medication during study treatment Active or history of autoimmune disease or immune deficiency Inclusion Criteria for Cohort 2: ECOG PS of 0 or 1 Life expectancy >= 3 months, as determined by the investigator Histologically confirmed Stage IV (metastatic) cutaneous melanoma according to AJCC-8 Disease progression during or following at least one but no more than two lines of treatment for metastatic disease Measurable disease according to RECIST v1.1 Availability of a representative tumor specimen Adequate hematologic and end-organ function For patients receiving therapeutic anticoagulation: stable anticoagulant regimen Negative HIV test, negative hepatitis B surface antibody (HBsAb), and negative total hepatitis B core antibody (HBcAb) test, and negative hepatitis C virus (HCV) at screening. Patients with a positive HIV test at screening are eligible provided they are stable on anti-retroviral therapy, have a CD4 count >= 200/μL, and have an undetectable viral load. Exclusion Criteria for Cohort 2: Mucosal and uveal melanoma Treatment with investigational therapy within 28 days prior to initiation of study treatment Treatment with systemic immunostimulatory agents within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment Prior allogeneic stem cell or solid organ transplantation Known immunodeficiency or conditions requiring treatment with systemic immunosuppressive medication, or anticipation of need for systemic immunosuppressant medication during study treatment Active or history of autoimmune disease or immune deficiency Symptomatic, untreated, or progressing CNS metastases Active or history of carcinomatous meningitis/leptomeningeal disease Uncontrolled tumor-related pain Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures Uncontrolled or symptomatic hypercalcemia

Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here ( https://vivli.org/ourmember/roche/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).