Antibody DS-8273a Administered in Combination With Nivolumab in Subjects With Advanced Colorectal Cancer
|ClinicalTrials.gov Identifier: NCT02991196|
Recruitment Status : Terminated (Business Decision)
First Posted : December 13, 2016
Last Update Posted : February 12, 2019
This trial is being performed in two parts: Dose Escalation and Dose Expansion.
The primary objective for the Dose Escalation part is to determine the safety and tolerability at different doses of DS-8273a administered in combination with nivolumab and to identify the dose combination for the Dose Expansion cohort in subjects with mismatch repair (MMR)-proficient advanced colorectal cancer.
The primary objectives for the Dose Expansion part are:
- To further evaluate the safety and tolerability of DS-8273a administered at the selected dose in combination with nivolumab in subjects with MMR-proficient advanced colorectal cancer
- To evaluate preliminary anti-tumor activity of DS-8273a plus nivolumab administered at the selected dose in subjects with MMR-proficient advanced colorectal cancer
|Condition or disease||Intervention/treatment||Phase|
|Colorectal Neoplasm||Drug: DS-8273a + nivolumab||Phase 1|
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||4 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Primary Purpose:||Basic Science|
|Official Title:||A Phase 1 Study of TRAIL-R2 (DR5) Antibody DS-8273a Administered in Combination With Nivolumab in Subjects With Advanced Colorectal Cancer|
|Actual Study Start Date :||December 1, 2016|
|Actual Primary Completion Date :||September 22, 2017|
|Actual Study Completion Date :||September 22, 2017|
Experimental: DS-8273a + nivolumab
Participants will receive their treatment dose until discontinuation for any reason, or trial completion, within two years
Drug: DS-8273a + nivolumab
Nivolumab will be administered at 240 mg intravenously (IV) once every two weeks (Q2W) over 30 (± 5) minutes (on Days 1 and 15 of each cycle of 28 days). DS-8273a will be administered [90 (± 15) minutes on Day 1 of Cycle 1, and 60 (± 15) minutes in subsequent infusions] after the end of the nivolumab infusion in ascending doses up to 1200 mg IV Q2W. The regimen is adjusted based on injection site reactions or adverse events. Additional dose combinations may be considered based on the assessment of safety, primary pharmacodynamic (PDy) effects, and preliminary anti-tumor activities.
- Dose Escalation Part: Number of Participants with Dose-Limiting Toxicities (DLT) [ Time Frame: During the first treatment cycle (28 days) ]A DLT is defined as a study drug-related ≥ Grade 3 Adverse Event (AE) occurring during the first cycle (28 days) of treatment, with specific exceptions for hematologic events, elevations in hepatic function enzymes, and adverse events that are pre-identified as not being DLTs.
- Dose Escalation and Dose Expansion Parts: Number of Participants with Clinically Significant Safety Parameters [ Time Frame: 2 years ]Safety parameters will include adverse events that are serious (SAEs), treatment emergent (TEAEs), dose-limiting toxicities (DLTs), physical examination findings (including Eastern Cooperative Oncology Group [ECOG] Performance Status), vital sign measurements, clinical laboratory parameters (serum chemistry, hematology, and urinalysis), immune-related (ir) adverse events (irAEs), anti-drug antibody (ADA), and electrocardiogram (ECG) parameters.
- Dose Escalation Part: Maximum Tolerated Dose (MTD) [ Time Frame: 2 years ]The MTD is defined as the highest dose of DS-8273a in combination with the tested dose of nivolumab that results in a DLT in less than one-third of the subjects enrolled at that dose level of at least 6 evaluable subjects. However, AEs that meet the definition of DLT appearing at later cycles will also be considered for the determination of MTD and selection of the Dose Expansion dose. If the MTD is not reached at 1200 mg of DS-8273a IV Q2W, this highest tested dose may be selected as the maximum administered dose (MAD).
- Dose Expansion Part: Overall Objective Response Rate (per Response Evaluation Criteria in Solid Tumors [RECIST] Version 1.1) [ Time Frame: 2 years ]The overall objective response rate (ORR) is defined as the number of subjects whose Best Overall Response is either a Complete Response (CR) or Partial Response (PR), divided by the total number of treated subjects with at least one post-baseline tumor assessment.
- Dose Expansion Part: Number of Participants in each Category of Best Overall Response (per Response Evaluation Criteria in Solid Tumors [RECIST] Version 1.1) [ Time Frame: 2 years ]Categories: CR, PR, Stable Disease (SD), Progressive Disease (PD)
- Dose Expansion Part: Disease Control Rate (DCR) for 6 Months [ Time Frame: 6 months ]DCR for 6 months defined as the number of subjects with CR, PR, or SD for 6 months divided by the total number of treated subjects with at least 1 post-baseline tumor assessment
- Dose Expansion Part: Number of Participants with Progression-Free Survival (PFS) [ Time Frame: 2 years ]PFS is defined as survival without disease progression
- Dose Expansion Part: Time to Progression (TTP) [ Time Frame: within 2 years ]Mean TTP within 2 years
- Dose Expansion Part: Duration of Response [ Time Frame: within 2 years ]Duration of response for those subjects with a Best Overall Response of CR or PR
- Dose Escalation Part: Number of Participants with Immune-related Response (per Criteria Modified from RECIST Version 1.1 [irRECIST]) [ Time Frame: 2 years ]
- Immune-related (ir) Best Overall Response with response categories of irCR, irPR, irSD, irPD
- Immune-related ORR (irORR) defined as the number of subjects whose Best Overall Response is either an irCR or irPR divided by the total number of treated subjects with at least 1 post-baseline tumor assessment
- Duration of immune-related-response for those subjects with immune-related Best Overall Response of irCR or irPR
- Immune-related DCR (irDCR) for 6 months defined as the number of subjects with irCR, irPR, or irSD for 6 months divided by the total number of treated subjects with at least 1 post-baseline tumor assessment
- Immune-related PFS
- Immune-related TTP
- Plasma Concentrations of DS-8273a [ Time Frame: Before and at the end of the first 3 infusions (Cycle 1 Days 1 and 15, and Cycle 2 Day 1), a single time point on Cycle 1 Day 8, then every 16 weeks on the same days as ADA sample analysis, and at the last Visit (if not collected within prior 16 weeks) ]The plasma concentrations of DS-8273a may be used to assess the exposure levels and for population pharmacokinetic (PK) analysis, if feasible, but no PK parameters will be calculated from the concentrations collected from this study due to sparse sampling time points.
- Number of Participants with Primary Pharmacodynamic (PDy) Effects of the Combination Regimen on Myeloid-Derived Suppressor Cells (MDSCs) and their Subsets in Peripheral Blood [ Time Frame: 2 years ]Subset Categories: Polymorphonuclear (PMN)-type and Monocytic-MDSCs (M-MDSCs)
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02991196
|United States, District of Columbia|
|Georgetown University Medical Center|
|Washington, District of Columbia, United States, 20007|
|United States, Michigan|
|South Texas Accelerated Research Therapeutics (START) Midwest|
|Grand Rapids, Michigan, United States, 49503|
|United States, Texas|
|MD Anderson Cancer Center|
|Houston, Texas, United States, 77030-4009|
|South Texas Accelerated Research Therapeutics, LLC (START)|
|San Antonio, Texas, United States, 78229|
|Study Director:||Study Director||Daiichi Sankyo, Inc.|