A Study of DS-6000a in Subjects With Advanced Renal Cell Carcinoma and Ovarian Tumors

Study Overview
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Brief Summary
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This clinical trial will evaluate raludotatug deruxtecan (R-DXd; DS-6000a) in participants with advanced renal cell carcinoma (RCC) and ovarian cancer (OVC). The main goals of this study will be to investigate the recommended dose of R-DXd that can be given safely to participants, assess the side effects of R-DXd, and evaluate the effectiveness of R-DXd.

Detailed Description
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R-DXd is an antibody drug conjugate that specifically binds to CDH6 on the cell surface of target cells, which leads to the internalization of R-DXd into the cells. MAAA-1181a that is released from R-DXd in the target cells inhibits cell replication and induces cell apoptosis. This study will evaluate R-DXd given as a single agent once every 21 days. The dose escalation phase will enroll participants with OVC and RCC, and is designed to assess the safety and tolerability of R-DXd and to determine the maximum tolerated dose (MTD)/recommended dose for expansion (RDE). Following the selection of the RDE, the dose expansion phase will be initiated to evaluate clinical activity of R-DXd.

Official Title
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Phase I, Two-Part, Multi-Center, First-in-Human Study of DS-6000a in Subjects With Advanced Renal Cell Carcinoma and Ovarian Tumors

Conditions
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Renal Cell Carcinoma, Ovarian Tumor

Intervention / Treatment
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* Drug: DS-6000a
* Drug: DS-6000a


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent At least 18 years of age Eastern Cooperative Oncology Group Performance Status score of 0 or 1 Availability of archived tumor tissue samples Has a left ventricular ejection fraction (LVEF) ≥50% by either an echocardiogram (ECHO) or multigated acquisition scan (MUGA) within 28 days before start of study treatment Has adequate organ function within 7 days before the start of study treatment Has an adequate treatment washout period prior to start of study treatment Male participants with female partners of childbearing potential and female participants of child-bearing potential must agree to use a highly effective form of contraception or avoid intercourse during and upon completion of the study and for at least 4 months (for males) and for at least 7 months (for females) after the last dose of study drug. Exclusion Criteria: Has had prior treatment with other CDH6-targeted agents Has had prior treatment with an ADC that consists of an exatecan derivative that is a topoisomerase I inhibitor (e.g., trastuzumab deruxtecan, DS-1062a, DS-7300a) Has history or current presence of CNS metastases except for participants who have completed radiotherapy or surgery ≥2 weeks before the start of study treatment and have no evidence of disease progression in the CNS and no requirement for chronic corticosteroid therapy within 2 weeks before the start of study treatment Has multiple primary malignancies, except adequately resected non-melanoma skin cancer, curatively treated in situ disease, or other solid tumors curatively treated, with no evidence of disease for ≥3 years) Has a history of myocardial infarction or unstable angina within 6 months before start of study treatment Has a medical history of symptomatic congestive heart failure (New York Heart Association classes II-IV) or a serious cardiac arrhythmia requiring treatment Lung-specific intercurrent clinically significant illnesses Has an uncontrolled infection requiring systemic therapy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation<br>Participants with ovarian cancer (OVC) or renal cell carcinoma (RCC) will receive an intravenous infusion of R-DXd (starting dose 1.6 mg/kg). | Drug: DS-6000a<br>* Intravenous administration at doses starting at 1.6 mg/kg on Day 1 of Cycle 1<br>* Other names: R-DXd;|
| Experimental: Dose Expansion: Cohort B-1<br>Participants with RCC will receive an intravenous infusion of R-DXd at the RDE. | Drug: DS-6000a<br>* Intravenous administration at RDE on Day 1 of Cycle 1<br>* Other names: R-DXd;|
| Experimental: Dose Expansion: Cohort B-2<br>Participants with OVC will receive an intravenous infusion of R-DXd at the RDE. | Drug: DS-6000a<br>* Intravenous administration at RDE on Day 1 of Cycle 1<br>* Other names: R-DXd;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose-limiting toxicities (DLTs) |  | Day 1 to Day 21 in Cycle 1 (each cycle is 21 days) | 
| Number of Participants Reporting Treatment-emergent Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest |  | From start of treatment up to 40 days after last dose, up to approximately 24 months | 
| Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) (Dose Expansion) | ORR is defined as the proportion of participants with best overall response (BOR) of complete response (CR) or partial response (PR). | From start of treatment (Cycle 1, Day 1) up to disease progression, up to approximately 24 months (each cycle is 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic Analysis Area Under the Plasma Concentration-Time Curve from Time Zero to 21 Days (AUC 21d) for R-DXd and its Metabolites |  | Cycles 1 and 3, Day 1: Predose, 3 hours, 5 hours, 8 hours postdose, end of infusion (EOI); Cycles 1 and 3, Day 2; Cycles 1 and 3, Days 4, 8, and 15; Cycle 2, Day 1: predose and EOI; Cycle 4, Day 1 and every then 2 cycles: predose (each cycle is 21 days) | 
| Pharmacokinetic Analysis Area Under the Plasma Concentration-Time Curve Up to the Last Quantifiable Time (AUClast) for R-DXd and its Metabolites |  | Cycles 1 and 3, Day 1: Predose, 3 hours, 5 hours, 8 hours postdose, end of infusion (EOI); Cycles 1 and 3, Day 2; Cycles 1 and 3, Days 4, 8, and 15; Cycle 2, Day 1: predose and EOI; Cycle 4, Day 1 and every then 2 cycles: predose (each cycle is 21 days) | 
| Pharmacokinetic Analysis Maximum Plasma Concentration (Cmax) for R-DXd and its Metabolites |  | Cycles 1 and 3, Day 1: Predose, 3 hours, 5 hours, 8 hours postdose, end of infusion (EOI); Cycles 1 and 3, Day 2; Cycles 1 and 3, Days 4, 8, and 15; Cycle 2, Day 1: predose and EOI; Cycle 4, Day 1 and then every 2 cycles: predose (each cycle is 21 days) | 
| Pharmacokinetic Analysis Lowest Plasma Concentration (Ctrough) for R-DXd and its Metabolites |  | Cycles 1 and 3, Day 1: Predose, 3 hours, 5 hours, 8 hours postdose, end of infusion (EOI); Cycles 1 and 3, Day 2; Cycles 1 and 3, Days 4, 8, and 15; Cycle 2, Day 1: predose and EOI; Cycle 4, Day 1 and then every 2 cycles: predose (each cycle is 21 days) | 
| Pharmacokinetic Analysis Time to Maximum Plasma Concentration (Tmax) for R-DXd and its Metabolites |  | Cycles 1 and 3, Day 1: Predose, 3 hours, 5 hours, 8 hours postdose, end of infusion (EOI); Cycles 1 and 3, Day 2; Cycles 1 and 3, Days 4, 8, and 15; Cycle 2, Day 1: predose and EOI; Cycle 4, Day 1 and then every 2 cycles: predose (each cycle is 21 days) | 
| Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) (Dose Escalation) | ORR is defined as the proportion of participants with best overall response (BOR) of complete response (CR) or partial response (PR). | From start of treatment (Cycle 1, Day 1) up to disease progression, up to approximately 24 months (each cycle is 21 days) | 
| Duration of Response (DoR) Based on RECIST v1.1 | DoR is defined as the duration from the first documented response to the date of progression or death due to any cause. | From date of first documented response to date of progression or death due to any cause (whichever occurs first), up to approximately 24 months | 
| Disease Control Rate (DCR) Based on RECIST v1.1 | DCR is defined as the proportion of participants with BOR of CR, PR, or SD. | From start of treatment up to first documented response (CR, PR, or SD), disease progression, or death (due to any cause), up to approximately 24 months | 
| Clinical Benefit Rate (CBR) Based on RECIST v1.1 | CBR is defined as the proportion of participants with BOR of CR or PR, or participants with stable disease (SD) lasting at least 180 days. | From date of first documented response (CR, PR) whichever occurs first or SD lasting at least 180 days to disease progression or death (due to any cause), up to approximately 24 months | 
| Percentage of Participants Who Are Anti-Drug Antibody (ADA)-Positive (Baseline and Post-Baseline) and Percentage of Participants Who Have Treatment-emergent ADA |  | Cycle 1 Day 1, Cycle 1 Day 15, and pre-dose on Day 1 of Cycle 2 through Cycle 4; then every 2 cycles from Cycle 4 through the end of treatment visit (each cycle is 21 days), and 40-day safety follow up visit, up to approximately 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Renal Cell Carcinoma, Ovarian Tumor, Raludotatug deruxtecan (R-DXd; DS-6000a)