An Open-Label, Multicenter, Dose Escalation Phase Ib Study With Expansion Cohorts to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Therapeutic Activity of RO7009789 (CD40 Agonistic Monoclonal Antibody) in Combination With Vanucizumab (Anti-Ang2 and Anti-VEGF Bi-Specific Monoclonal Antibody, Part I) or Bevacizumab (Anti-VEGF Monoclonal Antibody, Part II) in Patients With Metastatic Solid Tumors
Overview
- Phase
- Phase 1
- Intervention
- Selicrelumab
- Conditions
- Advanced/Metastatic Solid Tumors
- Sponsor
- Hoffmann-La Roche
- Enrollment
- 94
- Locations
- 16
- Primary Endpoint
- Percentage of Participants With Adverse Events (AEs)
- Status
- Completed
- Last Updated
- 6 years ago
Overview
Brief Summary
This open-label, two-part study is designed to assess the safety, PK, PD, and therapeutic activity of Selicrelumab in combination with vanucizumab or bevacizumab in participants with metastatic solid tumors not amenable to standard treatment. Part I (dose escalation) is designed to establish the maximum tolerated dose (MTD) of Selicrelumab in this combination. Part II (expansion) is intended to characterize the safety and tolerability of Selicrelumab in combination with bevacizumab among indication-specific cohorts and to confirm the recommended dose.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Part I: Histologically confirmed advanced/metastatic solid tumor (except prostate cancer and squamous non-small cell lung cancer \[NSCLC\])
- •Part II: Histologically confirmed advanced/metastatic platinum-resistant ovarian carcinoma (aPROC), head and neck squamous cell carcinoma (HNSCC), or non-squamous NSCLC previously treated with anti-PD-L1/PD-1 inhibitor alone or in combination (e.g. atezolizumab, nivolumab, pembrolizumab, durvalumab, avelumab)
- •Checkpoint inhibitor (CPI)- experienced patients must have experienced documented disease progression on or after PD-L1/PD-1 inhibitor therapy
- •In CPI-experienced patients, the PD-L1/PD-1 inhibitor must have been part of the most recent systemic anticancer therapy administered prior to study enrollment
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
- •Life expectancy \>/= 16 weeks
- •Adequate hematologic, renal, hepatic, and cardiovascular function
- •Measurable disease per Response Evaluation Criteria in Solid Tumors, v 1.1 (RECIST v1.1)
- •Tumors must be acceptable for biopsy. Participants in Part II may be enrolled without a biopsy if the collection is not clinically feasible.
- •Agreement to use adequate contraceptive measures among men or among women of childbearing potential
Exclusion Criteria
- •Prostate cancer or squamous NSCLC
- •Recent systemic anti-cancer treatment
- •Prior treatment with anti-programmed death (PD) 1 or anti-programmed death ligand (PD-L) 1 therapeutic antibody, vanucizumab, or compounds targeting cluster of differentiation (CD) 40 less than 4 weeks or 5xt1/2 (whichever is shorter) prior to enrollment
- •Part II: Treatment targeting vascular endothelial growth factor (VEGF) or receptor within 12 months prior to enrollment
- •Systemic immunosuppressive medication within 2 weeks prior to day 1 of cycle 1
- •Chronic daily treatment with non-steroidal anti-inflammatory drugs
- •Unacceptable/unresolved toxicity from prior anti-cancer therapy
- •Patients who have had a surgical procedure or significant traumatic injury within 28 days prior to initiation of study treatment, or a core biopsy or other minor surgical procedure within 7 days prior to initiation of study treatment
- •Bisphosphonate therapy for symptomatic hypercalcemia
- •Significant vascular disease
Arms & Interventions
Part I: Selicrelumab, Vanucizumab/Bevacizumab
Participants will receive a fixed dose of vanucizumab, 2 grams via IV infusion on Days 1 and 15 of every 28-day cycle. Selicrelumab will be given SC in ascending dose levels on Day 2 of Cycles 1 to 4 and every third cycle thereafter. Treatment will continue as long as the participant experiences clinical benefit or until unacceptable toxicity, withdrawal of consent, or the end of Part I of the study (expected 24 months). Due to the discontinuation of Vanucizumab development, Participants ongoing in Part I will switch from Vanucizumab to Bevacizumab. All the dose escalation has been performed using Vanucizumab.
Intervention: Selicrelumab
Part I: Selicrelumab, Vanucizumab/Bevacizumab
Participants will receive a fixed dose of vanucizumab, 2 grams via IV infusion on Days 1 and 15 of every 28-day cycle. Selicrelumab will be given SC in ascending dose levels on Day 2 of Cycles 1 to 4 and every third cycle thereafter. Treatment will continue as long as the participant experiences clinical benefit or until unacceptable toxicity, withdrawal of consent, or the end of Part I of the study (expected 24 months). Due to the discontinuation of Vanucizumab development, Participants ongoing in Part I will switch from Vanucizumab to Bevacizumab. All the dose escalation has been performed using Vanucizumab.
Intervention: Vanucizumab
Part II: Selicrelumab, Bevacizumab
Bevacizumab will be administered via IV infusion on days 1 and 15 of every 28-day cycle. Selicrelumab will be given SC after the Bevacizumab infusion at the dose determined in the Part I of the study on Day 2 of Cycles 1 to 4 and every third cycle thereafter. Treatment will continue as long as the participant experiences clinical benefit or until unacceptable toxicity, withdrawal of consent, or the end of Part II of the study (expected 18 months).
Intervention: Selicrelumab
Part II: Selicrelumab, Bevacizumab
Bevacizumab will be administered via IV infusion on days 1 and 15 of every 28-day cycle. Selicrelumab will be given SC after the Bevacizumab infusion at the dose determined in the Part I of the study on Day 2 of Cycles 1 to 4 and every third cycle thereafter. Treatment will continue as long as the participant experiences clinical benefit or until unacceptable toxicity, withdrawal of consent, or the end of Part II of the study (expected 18 months).
Intervention: Bevacizumab
Outcomes
Primary Outcomes
Percentage of Participants With Adverse Events (AEs)
Time Frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
From D1 of C1 until treatment discontinuation and approximately 45 days after last dose (cycle length=28 days)
Part II: Percentage of Participants With Disease Control per RECIST v1.1 Criteria
Time Frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Tumor assessments at Screening and on D1 of C3, C5, C7; and every 12 weeks thereafter until disease progression (cycle length=28 days)
MTD of Selicrelumab in Combination With Vanucizumab
Time Frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
From D1 until D28 of C1 (cycle length=28 days)
Recommended Phase II Dose of Selicrelumab in Combination With Vanucizumab
Time Frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
From D1 until D28 of C1 (cycle length=28 days)
Part II: Percentage of Participants With Best Overall Response per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Criteria
Time Frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Tumor assessments at Screening and on D1 of C3, C5, C7; and every 12 weeks thereafter until disease progression (cycle length=28 days)
Percentage of Participants With Dose-Limiting Toxicities (DLTs)
Time Frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
From Day (D) 1 until D28 of Cycle (C)1 (cycle length=28 days)
Part II: Duration of Objective Response per RECIST v1.1 Criteria
Time Frame: TBaseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Tumor assessments at Screening and on D1 of C3, C5, C7; and every 12 weeks thereafter until disease progression (cycle length=28 days)
Part II: Clinical Activity of SC Selicrelumab in Combination with Bevacizumab as Assessed by Response Evaluation in Solid Tumors, Version 1.1 (RECIST v1.1)
Time Frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
From D1 of C1 through safety follow up visit (45 days post final dose; Cycle = 28 days)
Part II: Progression-free Survival (PFS) per RECIST v1.1 Criteria
Time Frame: Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months)
Tumor assessments at Screening and on D1 of C3, C5, C7; and every 12 weeks thereafter until disease progression (cycle length=28 days)
Secondary Outcomes
- Percentage of Participants with ADAs to Vanucizumab(Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months))
- Area Under the Concentration-Time Curve From Time 0 to Last Measureable Concentration (AUClast) of Selicrelumab Following Subcutaneous (SC) Administration(Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months))
- Time to Maximum Concentration (Tmax) of Selicrelumab Following SC Administration(Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months))
- Apparent Clearance (CL/F) of Selicrelumab Following SC Administration(Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months))
- Apparent Terminal Half-Life (t1/2) of Selicrelumab Following SC Administration(Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months))
- Percentage of Participants With Anti-Drug Antibodies (ADAs) to Selicrelumab(Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months))
- Area Under the Concentration-Time Curve From Time 0 to Infinity (AUCinf) of Selicrelumab Following SC Administration(Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months))
- Maximum Concentration (Cmax) of Selicrelumab Following SC Administration(Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months))
- Part I: Clinical Activity of SC Selicrelumab in Combination with Bevacizumab as Assessed by Response Evaluation in Solid Tumors, Version 1.1 (RECIST v1.1)(Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months))
- Part I: AUCinf of Vanucizumab(Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months))
- Percentage of Participants With Disease Control per irRC(Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months))
- Apparent Volume of Distribution (Vd/F) of Selicrelumab Following SC Administration(Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months))
- Part I: AUClast of Vanucizumab(Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months))
- Part I: Percentage of Participants With Disease Control per RECIST v1.1 Criteria(Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months))
- Duration of Objective Response per irRC(Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months))
- Part I: Concentration at the End of Infusion (Cend) of Vanucizumab(Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months))
- Part I: CL of Vanucizumab(Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months))
- Part I: Vss of Vanucizumab(Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months))
- Part I: Percentage of Participants With Best Overall Response per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Criteria(Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months))
- Part I: Duration of Objective Response per RECIST v1.1 Criteria(Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months))
- Part I: t1/2 of Vanucizumab(Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months))
- Part I: Progression-free Survival (PFS) per RECIST v1.1 Criteria(Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months))
- Change in Blood and Tumor Tissue Immune Cell Subpopulations(Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months))
- Change in Peripheral Blood Level of Cytokines(Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months))
- Change in Blood Soluble Proteins(Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months))
- Percentage of Participants With Best overall Response Immune-Related Response Criteria (irRC)(Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months))
- PFS per irRC(Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months))
- Clinical Activity of SC Selicrelumab in Combination with Bevacizumab as Assessed by Unidimensional Immune-Related Response Criteria (irRC)(Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months))
- Overall Survival (OS)(Baseline until Participant's discontinuation or death, whichever occurs first (up to approximately 42 months))
- Concentration at the end of Infusion (Cend) of Bevacizumab(Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months))
- Minimum Concentration (Cmin) of Bevacizumab after Infusion(Baseline until Participant's discontinuation or death, whichever occurs first, as per schedule in the description (up to approximately 42 months))