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

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Melanoma

Intervention / Treatment
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* Drug: Nivolumab
* Drug: Ipilimumab
* Drug: RO7247669 2100 mg
* Drug: Atezolizumab
* Drug: Tiragolumab
* Drug: RO7247669 600 mg


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cohort 1: Nivolumab + Ipilimumab<br>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. | Drug: Nivolumab<br>* Nivolumab will be administered at a dose of 3 mg/kg IV on Day 1 of each 21 day cycle.<br>Drug: Ipilimumab<br>* Ipilimumab will be administered at a dose of 1 mg/kg by IV on Day 1 of each 21 day cycle.<br>|
| Experimental: Cohort 1: RO7247669 2100 mg<br>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. | Drug: RO7247669 2100 mg<br>* RO7247669 will be administered at a dose of 2100 mg by IV infusion on Day 1 of each 21 day cycle.<br>|
| Experimental: Cohort 1: + Atezolizumab + Tiragolumab<br>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. | Drug: Atezolizumab<br>* Atezolizumab will be administered at a dose of 1200 mg IV on Day 1 of each 21 day cycle.<br>* Other names: Tecentriq, RO5541267;Drug: Tiragolumab<br>* Tiragolumab will be administered at a dose of 600 mg IV on Day 1 of each 21 day cycle.<br>* Other names: RO7092284;|
| Experimental: Cohort 1: RO7247669 2100 mg + Tiragolumab<br>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. | Drug: RO7247669 2100 mg<br>* RO7247669 will be administered at a dose of 2100 mg by IV infusion on Day 1 of each 21 day cycle.<br>Drug: Tiragolumab<br>* Tiragolumab will be administered at a dose of 600 mg IV on Day 1 of each 21 day cycle.<br>* Other names: RO7092284;|
| Experimental: Cohort 2: RO7247669 2100 mg + Tiragolumab<br>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. | Drug: RO7247669 2100 mg<br>* RO7247669 will be administered at a dose of 2100 mg by IV infusion on Day 1 of each 21 day cycle.<br>Drug: Tiragolumab<br>* Tiragolumab will be administered at a dose of 600 mg IV on Day 1 of each 21 day cycle.<br>* Other names: RO7092284;|
| Experimental: Cohort 1: RO7247669 600 mg<br>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. | Drug: RO7247669 600 mg<br>* RO7247669 will be administered at a dose of 600 mg by IV infusion on Day 1 of each 21 day cycle.<br>|
| Experimental: Cohort 1: RO7247669 600 mg + Tiragolumab<br>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. | Drug: Tiragolumab<br>* Tiragolumab will be administered at a dose of 600 mg IV on Day 1 of each 21 day cycle.<br>* Other names: RO7092284;Drug: RO7247669 600 mg<br>* RO7247669 will be administered at a dose of 600 mg by IV infusion on Day 1 of each 21 day cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathologic Response Rate (pRR) for Cohort 1 as Determined by Independent Pathologic Review | 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. | Time of surgery (Week 7) | 
| Objective Response Rate (ORR) for Cohort 2 | 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. | Enrollment/randomization up to approximately 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| pRR for Cohort 1 as Determined by Local Pathologic Assessment | pRR is defined as the proportion of participants with pCR, pnCR, and pPR at time of surgery, as determined by local pathologic assessment. | Time of surgery (Week 7) | 
| Event-Free Survival (EFS) for Cohort 1 | 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) | 
| Relapse-Free Survival (RFS) for Cohort 1 | 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) | 
| Overall Survival (OS) for Cohort 1 | OS is defined as the time from randomization to death from any cause. | Randomization to death from any cause (up to approximately 5 years) | 
| Objective Response Rate (ORR) for Cohort 1 | 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. | Prior to surgery (up to Week 6) | 
| Percentage of Participants With Adverse Events for Cohort 1 |  | Baseline through the end of the study (approximately 5 years) | 
| Percentage of Participants With Immune-Related Adverse Events for Cohort 1 | Percentage of participants with immune-related adverse events Grade >= 3 during the first 12 weeks. | Baseline to Week 12 | 
| Rate of Delayed Surgery Due to Treatment-Related Adverse Events for Cohort 1 |  | Week 8 to Week 9 | 
| Duration of Delayed Surgery Due to Treatment-Related Adverse Events for Cohort 1 |  | Week 8 to Week 9 | 
| Surgical Complication Rates for Cohort 1 | Surgical complication rates according to Clavien-Dindo surgical classification after completion lymph node dissection (CLND). | Week 7 through Follow-Up (up to approximately 6 months) | 
| Progression-Free Survival (PFS) for Cohort 2 | 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) | 
| Overall Survival (OS) for Cohort 2 | OS after randomization/enrollment, defined as the time from randomization/enrollment to death from any cause. | Randomization/enrollment to death from any cause (up to approximately 5 years) | 
| Overall Survival (OS) at Specific Timepoints for Cohort 2 | 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) | 
| Duration of Response (DOR) for Cohort 2 | 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 for Cohort 2 | 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. | Randomization up to approximately 5 years | 
| Percentage of Participants With Adverse Events for Cohort 2 |  | Baseline through the end of the study (approximately 5 years) |