DS-3201b in Participants With Lymphomas

Study Overview
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Brief Summary
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DS-3201b is an experimental drug. It is not approved for regular use. It can only be used in clinical research. Adults with non-Hodgkin lymphoma (NHL) might be able to join this study if their disease: has come back after remission is not responding to current treatment This study has three parts: Dose Escalation is to find the safe dose of DS-3201b that adults with advanced NHL can tolerate. Dose Expansion is to: find out how effective DS-3201b is for rare types of NHL collect additional safety data Drug-Drug Interaction (DDI) Cohort (US Only) is to evaluate the effect of DS-3201b on the pharmacokinetics (PK) midazolam and digoxin when co-administered to patients with NHL

Official Title
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A Phase 1 Multiple Ascending Dose Study of DS-3201b in Subjects With Lymphomas

Conditions
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Lymphoma, Malignant, Non-hodgkin Lymphoma

Intervention / Treatment
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* Drug: DS-3201b


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has hematocytological or pathological diagnosis of non- Hodgkin's lymphoma (NHL) Has relapsed from or is refractory to standard treatment or no standard treatment is available Is the age of majority in their country (18 in the US and 20 in Japan) at the time of informed consent Has Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 Has at least one evaluable lesion site (not applicable for the DDI cohort) Has preserved organ function based on baseline laboratory data at screening tests If of reproductive potential, agrees to avoid harvesting ova or sperm, and to use a protocol-defined form of contraception or avoid intercourse, during and upon completion of the study, and for at least 3 months after the last dose of study drug Tumor biopsy collections: willing to provide archived or fresh tumor tissue samples that are sufficient for comprehensive genomic and/or proteomic analyses at baseline [US only] willing to provide fresh on-treatment tumor biopsy if deemed acceptable risk by the investigator [Japan only] fresh on-treatment tumor biopsy should be performed if deemed acceptable risk by the investigator willing to provide optional fresh end-of-treatment biopsy For ATL subjects: Has a positive test result for human T-lymphotropic virus type I antibody Has ATL subtype classified as acute, lymphomatous, or chronic with poor prognostic factor Has diagnosis of relapse (including relapse after partial remission [PR]) or treatment-resistant ATL at the time of informed consent after prior treatment with at least 1 anti-cancer medication regimen Exclusion Criteria: Has been diagnosed with protocol-defined cutaneous T-cell lymphoma or T-cell leukemia. For DDI cohort, CTCL is not exclusionary. Has a history or presence of central nervous system (CNS) involvement Has a medical history, complication or other malignancy considered inappropriate for participation in the study, or a serious physical or psychiatric disease, the risk of which may be increased by participation in the study Has received drugs or other treatments not allowed by the protocol History of treatment with other enhancer of zeste (EZH) inhibitors Has had allogeneic hematopoietic stem cell transplantation (HTCP) within 90 days before scheduled dosing on Cycle 1 Day 1 Is pregnant or breastfeeding Is otherwise deemed ineligible to participate by the investigator or sub-investigator DDI Cohort Only: Has received following medications within 14 days prior to study drug administration Any CYP3A inhibitors/inducers including weak CYP3A inhibitors/inducers, and P-gp inhibitors, midazolam as well as digoxin

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DS-3201b<br> | Drug: DS-3201b<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Escalation Period: Number of participants with dose-limiting toxicities (DLTs) | Number of DLT-evaluable participants with protocol-defined DLTs | within 28 days after the initial dose of the study drug | 
| Dose Escalation Period: Maximum concentration (Cmax) of DS-3201 | Categories: Cycle 1 Day 1, Cycle 1 Day 15 | within the first 28-day cycle | 
| Dose Escalation Period: Time of maximum concentration (Tmax) of DS-3201 | Categories: Cycle 1 Day 1, Cycle 1 Day 15 | within the first 28-day cycle | 
| Dose Escalation Period: Area under the plasma concentration time curve up to the last quantifiable time (AUClast) for DS-3201 |  | Day 1 of the first 28-day cycle | 
| Dose Escalation Period: Area under the plasma concentration time curve during the dosing interval (AUCtau) for DS-3201 |  | Day 1 of the first 28-day cycle | 
| Dose Escalation Period: Trough (minimum) plasma concentration (Ctrough) |  | Day 15 of the first 28-day cycle | 
| Dose Escalation Period: Average plasma concentration (Cavg) |  | Day 15 of the first 28-day cycle | 
| DDI cohort only: Maximum concentration (Cmax) of DS-3201, midazolam, digoxin | Categories: Day -4, Cycle 1 Day 1, Cycle 1 Day 15 | within the first 28-day cycle | 
| DDI cohort only: Time of maximum concentration (Tmax) of DS-3201, midazolam, digoxin | Categories: Day -4, Day 0 (for alternate schedule), Cycle 1 Day 1, Cycle 1 Day 15 | within the first 28-day cycle | 
| DDI cohort only: Area under the plasma concentration time curve up to the last quantifiable time (AUClast) for DS-3201,midazolam,digoxin | Categories: Day -4, Day 0 (for alternate schedule), Cycle 1 Day 1, Cycle 1 Day 15 | within the first 28-day cycle | 
| DDI cohort only: Area under the plasma concentration time curve during the dosing interval (AUCtau) for DS-3201, midazolam, digoxin | Cycle 1 Day 1, Cycle 1 Day 15 | within the first 28-day cycle | 
| Number of participants with treatment-emergent adverse events (TEAEs) | TEAEs are systematically collected from lab values, physical exams, and other investigations | through the end of the study (within approximately 5 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best overall response, based on international consensus criteria | Best overall response is defined as the percentage of participants who achieved each category as the best response, considering all overall responses assessed at all time points after the start of study treatment. Categories: CR, CRu, PR, SD, RD/PD, UA Categories: Malignant lymphoma, ATL, CTCL | from the start of study treatment to the end of follow-up visit (within 5 years) | 
| Objective response rate (ORR) | ORR is defined as the percentage of participants who were assessed for best overall response, who achieved CR, UCR, or PR | within 5 years | 
| Disease control rate (DCR) | DCR is defined as the percentage of participants who were assessed for best overall response, who achieved a best response of CR, UCR, PR, or SD | within 5 years | 
| Duration of response (DOR) | DOR is defined as the time from the date at which criteria are first met for CR or PR (including CRu for ATL) until the first date that progressive disease is objectively documented. | within 5 years | 
| Progression-free survival (PFS) | PFS is defined as the time from the date of the first dose to the earlier of the dates of the first objective documentation of disease progression or death due to any cause. | witihn 5 years | 
| Number of participants with malignant lymphoma who achieved each level of therapeutic response per international consensus standards | Categories: Complete remission (CR), Partial remission (PR), Stable disease (SD), Relapsed disease or progressive disease (RD/PD) | through the end of the study (within approximately 5 years) | 
| Number of participants with ATL who achieved each level of therapeutic response per international consensus standards | Categories: CR, Uncertified complete remission (CRu), PR, SD, RD/PD, Unassessable (UA) | through the end of the study (within approximately 5 years) | 
| Number of participants with CTCL who achieved response per 2011 CTCL criteria | Categories: CR,PR,SD,PD,Relapse | through the end of the study (within approximately 5 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adult T-cell leukemia-lymphoma (ATL), Peripheral T-cell lymphoma (PTCL), Cutaneous T-cell lymphoma (CTCL), B-cell lymphoma