Neoplasms
Conditions
Brief summary
This first-in-human study consists of three parts. The primary purpose of Part 1 is to characterize the safety and tolerability of RO6874813 in participants with locally advanced and/or metastatic solid tumors whose disease has progressed despite standard therapy or for whom no standard therapy exists. In addition, the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) will be determined. In Part 2 the safety and tolerability of RO6874813 will continue to be characterized in participants with locally advanced and/or metastatic solid tumors known to be fibroblast activation protein-alpha positive (FAP+). In addition, treatment-induced efficacy of RO6874813 will be assessed by functional imaging and paired tumor biopsies. The primary purpose of Part 3 is to demonstrate anti-tumor activity of RO6874813 in participants with recurrent or metastatic FAP+ sarcomas.
Interventions
BIOLOGICALRO6874813
RO6874813 will be administered at a single low dose of 0.5 mg/kg via IV infusion in a 7- day PK run-in period (Cycle 0). Dose level for RO6874813 will be escalated to determine MTD and RP2D for RO6874813.
Sponsors
Hoffmann-La Roche
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Part 1: Participants with histologically/cytologically confirmed locally advanced or metastatic, non-resectable solid tumors whose disease has progressed despite standard therapy or for whom no standard therapy exists * Part 2: Participants with histologically/ cytologically confirmed locally advanced or metastatic, non-resectable solid tumors known to be FAP+ whose disease has progressed despite standard therapy or for whom no standard therapy exists * Part 3: Participants with histologically confirmed recurrent or metastatic, non-resectable confirmed FAP+ sarcoma with two or fewer prior regimens for advanced disease * All participants must have tumor tissue that can be imaged for pharmacodynamic assessments and from which a pre- and on-treatment biopsy can be safely obtained * An archival tumor sample must be available for retrospective FAP expression analysis * Measurable disease as determined by RECIST v1.1 * World Health Organization (WHO)/ Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0-1 * Recovery from all reversible AEs of previous anti-cancer therapies to baseline or Common Terminology Criteria for Adverse Events (CTCAE) Grade 1, except for alopecia (any grade) and Grade \<=2 sensory peripheral neuropathy * Negative pregnancy test
Exclusion criteria
* Primary central nervous (CNS) tumors or CNS tumor involvement * Major surgery or any other prior anti-cancer treatment within 4 weeks prior to study Day 1. * Received wide-field radiotherapy \<= 4 weeks or limited-field radiotherapy \<=2 weeks prior to starting study drug * Known hypersensitivity to any of the components of RO6874813 or to the contrast agents used in the study * Another invasive malignancy in the last 2 years except for those with a minimal risk of metastasis or death * Any other conditions or diseases that would contraindicate participation in the clinical study because of safety concerns or compliance with clinical study procedures
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Percentage of Participants With Dose-Limiting Toxicity (DLT) | 28 days | — |
| Part 1: Maximum Tolerated Dose (MTD) of RO6874813 | 28 days | — |
| Part 1: Recommended Phase 2 Dose (RP2D) of RO6874813 | 28 days | — |
| Parts 1 and 2: Percentage of Participants With Adverse Events (AEs) | Baseline up to approximately 24 months | — |
| Parts 1 and 2: Percentage of Participants With Anti-Drug Antibodies (ADAs) | Predose (Hour [Hr] 0) on Day 1 up to approximately 12 months; please see outcome measure description for detailed time frame | Q2W (1 cycle=14 days): Predose (Hr 0) on Day 1 of Run-in period (Part 1 only), Cycles 1, 3, 5, then every 2 cycles (up to approximately 12 months); QW (1 cycle=7 days): Predose on Day 1 of Run-in period (Part 1 only), Cycles 1, 2, 5, then every 2 cycles (up to approximately 12 months) |
| Part 3: Percentage of Participants With Objective Response as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Baseline until disease progression (up to approximately 12 months) | — |
| Part 3: Percentage of Participants With Disease Control as Determined by the Investigator Using RECIST v1.1 | Baseline up to approximately 12 months | — |
| Part 3: Duration of Response (DoR) as Determined by the Investigator Using RECIST v1.1 | Baseline up to approximately 12 months | — |
| Part 3: Median Progression-Free Survival (PFS) as Determined by the Investigator Using RECIST v1.1 | Baseline up to approximately 12 months | — |
| Part 3: Percentage of Participants Who are Progression-Free at Months 3 as Determined by the Investigator Using RECIST v1.1 | Month 3 | — |
| Part 3: Percentage of Participants Who are Progression-Free at Month 6 as Determined by the Investigator Using RECIST v1.1 | Month 6 | — |
| Part 3: Median Overall Survival (OS) | Baseline until death (up to approximately 24 months) | — |
| Part 3: Percentage of Participants Who are Alive at Month 12 | Month 12 | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 1 and 2: DOR as Determined by the Investigator Using RECIST v1.1 | Baseline up to approximately 12 months | — |
| Part 1 and 2: Median PFS as Determined by the Investigator Using RECIST v1.1 | Baseline up to approximately 12 months | — |
| Part 1 and 2: Percentage of Participants With Objective Response as Determined by the Investigator Using RECIST v1.1 | Baseline up to approximately 12 months | — |
| Part 3: Percentage of Participants With AEs | Baseline up to approximately 24 months | — |
| Part 3: Percentage of Participants With ADAs | Predose (Hr 0) on Day 1 up to approximately 12 months; please see outcome measure description for detailed time frame | Q2W (1 cycle=14 days): Predose (Hr 0) on Day 1 of Run-in period (Part 1 only), Cycles 1, 3, 5, then every 2 cycles (up to approximately 12 months); QW (1 cycle=7 days): Predose on Day 1 of Run-in period (Part 1 only), Cycles 1, 2, 5, then every 2 cycles (up to approximately 12 months) |
| Part 1 and 2: Percentage of Participants Who are Progression-Free at Month 6 as Determined by the Investigator Using RECIST v1.1 | Month 6 | — |
| Parts 1, 2, and 3: Maximum Observed Serum Concentration (Cmax) of RO6874813 | Predose (Hr 0) up to approximately 12 months; please see outcome measure description for detailed time frame | Run-in Period (Part 1 only): Predose (Hr 0), End of Infusion (EoI) (infusion length less than or equal to \[\<=\] 1.5 hrs), 24, 48, 72 (only for QW), and 96 hrs after EoI. Q2W (1 cycle=14 days): Predose, EoI, 2, 6, 24, 72, 96, 168, and 240 hrs after EoI in Cycles 1 and 4; Predose, EoI, and 2 hrs after EoI in Cycles 2 and 6; Predose and EoI in Cycles 3, 5, 7, and every 2 cycles thereafter (up to approximately 12 months). QW (1 cycle=7 days): Predose, EoI, 2, 6, 24, 48, 72, and 96 hrs after EoI in Cycles 1 and 4; Predose, EoI, and 2 hrs after EoI in Cycles 2 and 6; Predose, EoI in Cycles 3, 5, 7, and every 2 cycles thereafter (up to approximately 12 months) |
| Parts 1, 2, and 3: Minimum Observed Serum Concentration (Cmin) of RO6874813 | QW or Q2W: Predose (Hr 0) on Day 1 in Cycles 0, 1, 2, 3, 4, 5, 6, 7, and every 2 cycles thereafter (up to approximately 12 months) | — |
| Parts 1, 2, and 3: Observed Steady-State Concentration at the End of a Dosing Interval (Ctrough) of RO6874813 | Predose (Hr 0) up to approximately 12 months; please see outcome measure description for detailed time frame | Q2W (1 cycle=14 days): Predose, EoI, 2, 6, 24, 72, 96, 168, and 240 hrs after EoI in Cycle 1. QW (1 cycle=7 days): Predose, EoI, 2, 6, 24, 48, 72, and 96 hrs after EoI in Cycle 1 |
| Parts 1, 2, and 3: Time to Reach Cmax (Tmax) of RO6874813 | Predose (Hr 0) up to approximately 12 months; please see outcome measure description for detailed time frame | Run-in Period (Part 1 only): Predose (Hr 0), EoI (infusion length \<=1.5 hrs), 24, 48, 72 (only for QW), and 96 hrs after EoI. Q2W (1 cycle=14 days): Predose, EoI, 2, 6, 24, 72, 96, 168, and 240 hrs after EoI in Cycles 1 and 4; Predose, EoI, and 2 hrs after EoI in Cycles 2 and 6; Predose and EoI in Cycles 3, 5, 7, and every 2 cycles thereafter (up to approximately 12 months). QW (1 cycle=7 days): Predose, EoI, 2, 6, 24, 48, 72, and 96 hrs after EoI in Cycles 1 and 4; Predose, EoI, and 2 hrs after EoI in Cycles 2 and 6; Predose, EoI in Cycles 3, 5, 7, and every 2 cycles thereafter (up to approximately 12 months) |
| Parts 1, 2, and 3: Half-Life (t1/2) of RO6874813 | Predose (Hr 0) up to approximately 12 months; please see outcome measure description for detailed time frame | Run-in Period (Part 1 only): Predose (Hr 0), EoI (infusion length \<=1.5 hrs), 24, 48, 72 (only for QW), and 96 hrs after EoI. Q2W (1 cycle=14 days): Predose, EoI, 2, 6, 24, 72, 96, 168, and 240 hrs after EoI in Cycles 1 and 4; Predose, EoI, and 2 hrs after EoI in Cycles 2 and 6; Predose and EoI in Cycles 3, 5, 7, and every 2 cycles thereafter (up to approximately 12 months). QW (1 cycle=7 days): Predose, EoI, 2, 6, 24, 48, 72, and 96 hrs after EoI in Cycles 1 and 4; Predose, EoI, and 2 hrs after EoI in Cycles 2 and 6; Predose, EoI in Cycles 3, 5, 7, and every 2 cycles thereafter (up to approximately 12 months) |
| Parts 1, 2, and 3: Area Under the Concentration-Time Curve (AUC) of RO6874813 | Predose (Hr 0) up to approximately 12 months; please see outcome measure description for detailed time frame | Run-in Period (Part 1 only): Predose (Hr 0), EoI (infusion length \<=1.5 hrs), 24, 48, 72 (only for QW), and 96 hrs after EoI. Q2W (1 cycle=14 days): Predose, EoI, 2, 6, 24, 72, 96, 168, and 240 hrs after EoI in Cycles 1 and 4; Predose, EoI, and 2 hrs after EoI in Cycles 2 and 6; Predose and EoI in Cycles 3, 5, 7, and every 2 cycles thereafter (up to approximately 12 months). QW (1 cycle=7 days): Predose, EoI, 2, 6, 24, 48, 72, and 96 hrs after EoI in Cycles 1 and 4; Predose, EoI, and 2 hrs after EoI in Cycles 2 and 6; Predose, EoI in Cycles 3, 5, 7, and every 2 cycles thereafter (up to approximately 12 months) |
| Parts 1, 2, and 3: Clearance (CL) of RO6874813 | Predose (Hr 0) up to approximately 12 months; please see outcome measure description for detailed time frame | Run-in Period (Part 1 only): Predose (Hr 0), EoI (infusion length \<=1.5 hrs), 24, 48, 72 (only for QW), and 96 hrs after EoI. Q2W (1 cycle=14 days): Predose, EoI, 2, 6, 24, 72, 96, 168, and 240 hrs after EoI in Cycles 1 and 4; Predose, EoI, and 2 hrs after EoI in Cycles 2 and 6; Predose and EoI in Cycles 3, 5, 7, and every 2 cycles thereafter (up to approximately 12 months). QW (1 cycle=7 days): Predose, EoI, 2, 6, 24, 48, 72, and 96 hrs after EoI in Cycles 1 and 4; Predose, EoI, and 2 hrs after EoI in Cycles 2 and 6; Predose, EoI in Cycles 3, 5, 7, and every 2 cycles thereafter (up to approximately 12 months) |
| Parts 1, 2, and 3: AUC During One Dose Interval (AUCtau) of RO6874813 | Q2W (1 cycle=14 days): Predose, EoI, 2, 6, 24, 72, 96, 168, and 240 hrs after EoI in Cycle 1 and QW (1 cycle=7 days): Predose, EoI, 2, 6, 24, 48, 72, and 96 hrs after EoI in Cycle 1 | — |
| Parts 1, 2, and 3: Volume at Steady State (Vss) of RO6874813 | Predose (Hr 0) up to approximately 12 months; please see outcome measure description for detailed time frame | Run-in Period (Part 1 only): Predose (Hr 0), EoI (infusion length \<=1.5 hrs), 24, 48, 72 (only for QW), and 96 hrs after EoI. Q2W (1 cycle=14 days): Predose, EoI, 2, 6, 24, 72, 96, 168, and 240 hrs after EoI in Cycles 1 and 4; Predose, EoI, and 2 hrs after EoI in Cycles 2 and 6; Predose and EoI in Cycles 3, 5, 7, and every 2 cycles thereafter (up to approximately 12 months). QW (1 cycle=7 days): Predose, EoI, 2, 6, 24, 48, 72, and 96 hrs after EoI in Cycles 1 and 4; Predose, EoI, and 2 hrs after EoI in Cycles 2 and 6; Predose, EoI in Cycles 3, 5, 7, and every 2 cycles thereafter (up to approximately 12 months) |
| Parts 1, 2, and 3: Accumulation Ratio (RA) of RO6874813 | Predose (Hr 0) up to approximately 12 months; please see outcome measure description for detailed time frame | Run-in Period (Part 1 only): Predose (Hr 0), EoI (infusion length \<=1.5 hrs), 24, 48, 72 (only for QW), and 96 hrs after EoI. Q2W (1 cycle=14 days): Predose, EoI, 2, 6, 24, 72, 96, 168, and 240 hrs after EoI in Cycles 1 and 4; Predose, EoI, and 2 hrs after EoI in Cycles 2 and 6; Predose and EoI in Cycles 3, 5, 7, and every 2 cycles thereafter (up to approximately 12 months). QW (1 cycle=7 days): Predose, EoI, 2, 6, 24, 48, 72, and 96 hrs after EoI in Cycles 1 and 4; Predose, EoI, and 2 hrs after EoI in Cycles 2 and 6; Predose, EoI in Cycles 3, 5, 7, and every 2 cycles thereafter (up to approximately 12 months) |
| Parts 1, 2, and 3: Change from Baseline in Body Weight Corrected Maximum Standardized Uptake Volume (SUVmax) as Measured by 2-[18F]Fluoro-2-Deoxyglucose Positron Emission Tomography ([18F]-FDG PET) | Baseline and 12 months | — |
| Part 1 and 2: Percentage of Participants With Disease Control as Determined by the Investigator Using RECIST v1.1 | Baseline up to approximately 12 months | — |
Countries
France, Spain, United States
Outcome results
None listed