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

• ClinicalTrials.gov Identifier: NCT05116202
• Recruitment Status: Completed
• First Posted: November 10, 2021
• Last Update Posted: May 1, 2024
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: October 22, 2021
• First Posted Date: November 10, 2021
• Last Update Posted Date: May 1, 2024
• Actual Study Start Date: February 2, 2022
• Actual Primary Completion Date: September 22, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 2, 2021)

• Pathologic Response Rate (pRR) for Cohort 1 as Determined by Independent Pathologic Review [ Time Frame: Time of surgery (Week 7) ]
  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.
• Objective Response Rate (ORR) for Cohort 2 [ Time Frame: Enrollment/randomization up to approximately 5 years ]
  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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: November 2, 2021)

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

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study Evaluating the Efficacy and Safety of Multiple Treatment Combinations in Patients With Melanoma (Morpheus-Melanoma)
• Official Title: 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)
• Brief Summary: 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Melanoma

Intervention

• Drug: Nivolumab
  Nivolumab will be administered at a dose of 3 mg/kg IV on Day 1 of each 21 day cycle.
• Drug: Ipilimumab
  Ipilimumab will be administered at a dose of 1 mg/kg by IV on Day 1 of each 21 day cycle.
• Drug: RO7247669 2100 mg
  RO7247669 will be administered at a dose of 2100 mg by IV infusion on Day 1 of each 21 day cycle.
• Drug: Atezolizumab
  Atezolizumab will be administered at a dose of 1200 mg IV on Day 1 of each 21 day cycle.
  Other Name: Tecentriq, RO5541267
• Drug: Tiragolumab
  Tiragolumab will be administered at a dose of 600 mg IV on Day 1 of each 21 day cycle.
  Other Name: RO7092284
• Drug: RO7247669 600 mg
  RO7247669 will be administered at a dose of 600 mg by IV infusion on Day 1 of each 21 day cycle.

Study Arms

• Active Comparator: Cohort 1: Nivolumab + Ipilimumab
  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.
  Interventions:

  • Drug: Nivolumab
  • Drug: Ipilimumab
• Experimental: Cohort 1: RO7247669 2100 mg
  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.
  Intervention: Drug: RO7247669 2100 mg
• Experimental: Cohort 1: + Atezolizumab + Tiragolumab
  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.
  Interventions:

  • Drug: Atezolizumab
  • Drug: Tiragolumab
• Experimental: Cohort 1: RO7247669 2100 mg + Tiragolumab
  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.
  Interventions:

  • Drug: RO7247669 2100 mg
  • Drug: Tiragolumab
• Experimental: Cohort 2: RO7247669 2100 mg + Tiragolumab
  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.
  Interventions:

  • Drug: RO7247669 2100 mg
  • Drug: Tiragolumab
• Experimental: Cohort 1: RO7247669 600 mg
  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.
  Intervention: Drug: RO7247669 600 mg
• Experimental: Cohort 1: RO7247669 600 mg + Tiragolumab
  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.
  Interventions:

  • Drug: Tiragolumab
  • Drug: RO7247669 600 mg

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 30, 2024): 110
• Original Estimated Enrollment (submitted: November 2, 2021): 191
• Actual Study Completion Date: March 27, 2024
• Actual Primary Completion Date: September 22, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, France, Italy, Netherlands, Spain, United States

Administrative Information

• NCT Number: NCT05116202
• Other Study ID Numbers: BO43328
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: 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).

• Current Responsible Party: Hoffmann-La Roche
• Original Responsible Party: Same as current
• Current Study Sponsor: Hoffmann-La Roche
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

• PRS Account: Hoffmann-La Roche
• Verification Date: April 2024