An Open-Label, Multicenter, Phase Ib Study to Evaluate Safety and Therapeutic Activity of RO6874281, an Immunocytokine, Consisting of Interleukin-2 Variant (IL-2v) Targeting Fibroblast Activation Protein-Α (FAP), in Combination with Pembrolizumab (Anti-PD-1), in Participants with Advanced or Metastatic Melanoma
Overview
- Phase
- Phase 1
- Intervention
- RO6874281
- Conditions
- Metastatic Melanoma
- Sponsor
- Hoffmann-La Roche
- Enrollment
- 83
- Locations
- 23
- Primary Endpoint
- Percentage of participants with adverse events
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
This is an open-label, multicenter, Phase Ib study to evaluate the safety and therapeutic activity of RO6874281 in combination with pembrolizumab. The study will consist of 3 parts: a safety run-in (Part I: Cohorts 1.1. and 1.2) and two expansion parts (Parts II and III). Part II will start once all participants in Cohort 1.1 have completed the observation period. Part III will start once all participants in Cohorts 1.1 and 1.2 have completed the observation period.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Histologically confirmed unresectable stage III or stage IV cutaneous or mucosal melanoma (AJCC v8.0).
- •Participants need to have known BRAF status.
- •CPI naïve melanoma population: Participants with unresectable stage III or stage IV cutaneous or mucosal melanoma who have not received prior treatment for advanced disease. BRAF mutation-positive patients are eligible without prior treatment or after failure of BRAF directed inhibitor therapy.
- •CPI experienced melanoma population: Participants with unresectable stage III or stage IV cutaneous melanoma. Participants must have progressed during or after treatment with anti PD-1 antibody therapy, either as monotherapy or in combination with other agent(s).
- •Participants should have adequate cardiovascular, hematological, liver, and renal function.
- •Participants with unilateral pleural effusion are eligible if they fulfill both of the following: NYHA Class 1; Forced expiratory volume 1 (FEV1) \>70% and forced vital capacity (FVC) \>70% of predicted value; participants with lung metastases should present with DLCO \>60% of predicted value.
- •Exclusion criteria:
- •Medical Conditions
- •Rapid disease progression or suspected hyperprogression (as determined by the Investigator) or threat to vital organs or critical anatomical sites requiring urgent alternative medical intervention.
- •Known active CNS metastases and/or carcinomatous meningitis/leptomeningeal disease:
Exclusion Criteria
- Not provided
Arms & Interventions
Part I Safety Run in: RO6874281 + Pembrolizumab
Cohort 1.1 (CPI naive and experienced melanoma participants): Participants will receive RO6874281 in combination with Pembrolizumab every 3 weeks (Q3W) and will be observed for 2 cycles (ie: 6 weeks) in order to confirm the safety of the proposed dose and schedule that will be used in Part II of this study. Cohort 1.2 (CPI experienced melanoma participants only): Participants will receive RO6874281 in combination with Pembrolizumab via an induction and maintenance schedule for RO6874281: QW three times (D1, D8, D15) followed by Q3W dosing (D22 and subsequent). Pembrolizumab is to be administered Q3W, starting on Day 1. Participants will be observed for 2 pembrolizumab cycles (ie: 6 weeks) in order to confirm the safety of the proposed dose and schedule that will be used in Part III of this study.
Intervention: RO6874281
Part I Safety Run in: RO6874281 + Pembrolizumab
Cohort 1.1 (CPI naive and experienced melanoma participants): Participants will receive RO6874281 in combination with Pembrolizumab every 3 weeks (Q3W) and will be observed for 2 cycles (ie: 6 weeks) in order to confirm the safety of the proposed dose and schedule that will be used in Part II of this study. Cohort 1.2 (CPI experienced melanoma participants only): Participants will receive RO6874281 in combination with Pembrolizumab via an induction and maintenance schedule for RO6874281: QW three times (D1, D8, D15) followed by Q3W dosing (D22 and subsequent). Pembrolizumab is to be administered Q3W, starting on Day 1. Participants will be observed for 2 pembrolizumab cycles (ie: 6 weeks) in order to confirm the safety of the proposed dose and schedule that will be used in Part III of this study.
Intervention: Pembrolizumab
Part II Expansion: RO6874281 + Pembrolizumab
Part II will start once all participants in Part I Cohort 1.1 have completed the observation period. Approximately 34 participants will receive RO6874281 in combination with Pembrolizumab every 3 weeks (Q3W) and will be observed for 2 cycles (ie: 6 weeks).
Intervention: RO6874281
Part II Expansion: RO6874281 + Pembrolizumab
Part II will start once all participants in Part I Cohort 1.1 have completed the observation period. Approximately 34 participants will receive RO6874281 in combination with Pembrolizumab every 3 weeks (Q3W) and will be observed for 2 cycles (ie: 6 weeks).
Intervention: Pembrolizumab
Part III Expansion: RO6874281 + Pembrolizumab
Part III will start once all participants in Part I Cohorts 1.1 and 1.2 have completed the observation period. Approximately 80 participants will be randomised to receive RO6874281 in combination with Pembrolizumab in either a Q3W or QW/Q3W schedule.
Intervention: RO6874281
Part III Expansion: RO6874281 + Pembrolizumab
Part III will start once all participants in Part I Cohorts 1.1 and 1.2 have completed the observation period. Approximately 80 participants will be randomised to receive RO6874281 in combination with Pembrolizumab in either a Q3W or QW/Q3W schedule.
Intervention: Pembrolizumab
Outcomes
Primary Outcomes
Percentage of participants with adverse events
Time Frame: Baseline to end of study (approximately 24 months)
Secondary Outcomes
- Progression Free Survival (PFS)(Time from study treatment initiation to the first occurrence of documented disease progression (based on Investigator's assessment) or death from any cause during treatment (whichever occurs first) until the end of study (approximately 24 months))
- Disease Control Rate (DCR)(Baseline to end of study (approximately 24 months))
- Duration of Response(Time from first occurrence of a documented objective response until the time of documented disease progression or death from any cause during treatment (whichever occurs first) until the end of study (approximately 24 months))
- Baseline PD-L1(Baseline to end of study (approximately 24 months))
- Complete Response Rate (CRR)(Baseline to end of study (approximately 24 months))
- Fibroblast Activation Protein-a (FAP)(Baseline to end of study (approximately 24 months))
- Change from baseline in density (cell/mm2) of immune cells including CD8+, FOXP3, and PD-L1(Baseline to end of study (approximately 24 months))
- Objective Response Rate (ORR)(Time from first occurrence of a documented objective response until the time of documented disease progression or death from any cause during treatment (whichever occurs first) until the end of study (approximately 24 months))