Clinical trial NCT06244485: A Study of Valemetostat Tosylate in Combination With DXd ADCs in Subjects With Solid Tumors
Official title: A Phase 1b, Multicenter, Open-Label Study of Valemetostat Tosylate in Combination With DXd ADCs in Subjects With Solid Tumors
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Advanced Solid Tumor
Keywords: Advanced Solid Tumor
Valemetostat tosylate
DXD Antibody-drug Conjugates
Lead sponsor: Daiichi Sankyo
Sponsor class: INDUSTRY
First posted: 2024-02-06
Enrollment: 210
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This study will evaluate the safety, tolerability, and efficacy of valemetostat tosylate in combination with DXd ADC in patients with advanced solid tumors.

Detailed description: This is a 2-part study of valemetostat in combination with DXd ADCs in patients with HER2-positive gastric cancer, non-squamous NSCLC, or unresectable or metastatic HER2 low breast cancer. The study will begin with a Part 1 Dose-escalation Phase and will continue until the recommended dose for expansion "RDE" of valemetostat is determined and will then be followed by a Part 2 Dose-expansion Phase to further evaluate the safety and tolerability of the combination.

Eligibility criteria: Key Inclusion Criteria

All participants must meet all of the following criteria, as well as all criteria from the relevant sub-protocol to be eligible for enrollment:

* At least 18 years or the minimum legal adult age (whichever is greater) at the time the ICF is signed.
* Has at least 1 measurable lesion based on investigator imaging assessment (computed tomography or magnetic resonance imaging) using RECIST v 1.1 at Screening.
* Is willing to provide an adequate tumor sample.
* Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 at Screening.

Additional Key Inclusion for Sub-Protocol A:

* Diagnosed with pathologically documented breast cancer that:

  1. Is unresectable or metastatic.
  2. Has progressed on and would no longer benefit from endocrine therapy in hormone receptor-positive subjects in the opinion of the investigator.
  3. Has been treated with at least 1 and at most 2 prior lines of chemotherapy in the recurrent or metastatic setting.
  4. Has a history of low HER2 expression, defined as IHC 2+ /ISH-negative or IHC 1+ (ISH-negative or untested). ), as classified by the American Society of Clinical Oncology/College of American Pathologists 2018 HER2 testing guidelines.
  5. Was never previously HER2-positive (IHC 3+ or IHC 2+/ISH+) on prior pathology testing (per American Society of Clinical Oncology/College of American Pathologists guidelines

     Additional Key Inclusion for Sub-Protocol B:

     • Gastric or GEJ adenocarcinoma that is (a) unresectable or metastatic or (b) has progressed on trastuzumab or approved trastuzumab biosimilar-containing regimen.

     Additional Key Inclusion for Sub-Protocol C:
* Pathologically documented Stage IIIB, IIIC, or IV non-squamous NSCLC with or without AGA at the time of enrollment.
* Must meet prior therapy requirements:

  * Participants without AGA: (a) received platinum-based chemotherapy in combination with α-PD-1/α -PD-L1 mAb as a prior line of therapy or (b) received platinum-based chemotherapy and α -PD-1/ α -PD-L1 mAb (in either order) sequentially as 2 prior lines of therapy.
  * Participants with AGA: (a) has been treated with at least 1 or 2 prior lines of applicable targeted therapy that is locally approved for participant's genomic alteration at the time of Screening, (b) participants who have received platinum-based chemotherapy as a prior line of cytotoxic therapy, (c) may have received α -PD-1/α -PD-L1 mAb alone or in combination with a cytotoxic agent

Key Exclusion Criteria

* Has previously been treated with any enhancer of zeste homolog inhibitors.
* Uncontrolled or significant cardiovascular disease.
* Has spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms.
* Has leptomeningeal carcinomatosis or metastasis.
* Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses.
* Current use of moderate or strong cytochrome P450 (CYP)3A inducers.
* Systemic treatment with corticosteroids (\>10 mg daily prednisone equivalents).
* History of severe hypersensitivity reactions to other monoclonal antibodies (mAbs).
* Evidence of ongoing uncontrolled systemic bacterial, fungal, or viral infection requiring treatment with intravenous (IV) antibiotics, antivirals, or antifungals.
* Female who is pregnant or breastfeeding or intends to become pregnant during the study.
* Psychological, social, familial, or geographical factors that would prevent regular follow-up.

Additional Key Exclusion for Sub-Protocol A:

* Has previously received any anti-HER2 therapy in the metastatic setting.
* Has received prior treatment with an antibody-drug conjugate that consists of an exatecan derivative that is a topoisomerase I inhibitor, including either as part of prior treatment history or within prior participation in a clinical study.

Additional Key Exclusion for Sub-Protocol B:

\* Participants who have received an antibody-drug conjugate consisting of an exatecan derivative that is a topoisomerase I inhibitor.

Additional Key Exclusion for Sub-Protocol C:

\* Has received any agent, including an ADC, containing a chemotherapeutic agent targeting topoisomerase I or TROP2-targeted therapy including Dato-DXD

Primary outcomes:
measure: Number of Participants Reporting Dose-limiting Toxicities (Part 1 Dose Escalation)
timeFrame: Cycle 1 Day 1 up to Day 21 (each cycle is 21 days)
measure: Number of Participants Reporting Treatment-emergent Adverse Events (Part 1 Dose Escalation)
timeFrame: Screening up to 40 days after last dose
measure: Objective Response Rate Based on Investigator Assessment (Part 2 Dose Expansion)
timeFrame: Baseline (Screening), at every 6 weeks from Cycle 1 Day 1 in the first year, and every 12 weeks thereafter until disease progression or until the start of a new anticancer treatment, up to approximately 5 years
Secondary outcomes:
measure: Overall Survival
timeFrame: Date of enrollment up to date of death due to any cause, up to approximately 5 years
measure: Progression-free Survival
timeFrame: Date of enrollment up to date of radiographic disease progression or death due to any cause (whichever occurs first), up to approximately 5 years
measure: Duration of Response (DoR)
timeFrame: Date of first documentation of objective tumor response (CR or PR) that is subsequently confirmed to the first documentation of objective tumor progression or to death due to any cause (whichever occurs first), up to approximately 5 years
measure: Objective Response Rate Based on Investigator Assessment (Part 1 Dose Escalation)
timeFrame: Baseline (Screening), at every 6 weeks from Cycle 1 Day 1 in the first year, and every 12 weeks thereafter until disease progression or until the start of a new anticancer treatment, up to approximately 5 years
measure: Number of Participants Reporting Treatment-emergent Adverse Events (Part 2 Dose Expansion)
timeFrame: Screening up to 40 days after last dose
measure: Total and Unbound Plasma Concentration of Valemetostat
timeFrame: Cycle 1, Day 1: Predose, 1 hour (hr), 2 hr, 4 hr, and 5 hr postdose; Cycle 1, Day 8 and Day 15: Predose; Cycles 2, 3, 4, Day 1: Predose (each cycle is 21 days)
measure: Plasma Concentration of DXd Antibody-Drug Conjugates
timeFrame: Cycle 1, Day 1: Predose, 1 hour (hr), 2 hr, 4 hr, and 5 hr postdose; Cycle 1, Day 8 and Day 15: Predose; Cycles 2, 3, 4, Day 1: Predose (each cycle is 21 days)
Other outcomes:
Locations:
city: Irvine
country: United States
facility: City of Hope At Orange County Lennar Foundation Cancer Center
state: California
city: Los Angeles
country: United States
facility: Valkyrie Clinical Trials
state: California
city: San Diego
country: United States
facility: Sharp Memorial Hospital
state: California
city: Plantation
country: United States
facility: Brcr Medical Center, Inc Dba Boca Raton Clinical Research
state: Florida
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center and Research Institute, Inc
state: Florida
city: Honolulu
country: United States
facility: University of Hawaii At Manoa
state: Hawaii
city: Chicago
country: United States
facility: University of Chicago Medical Center
state: Illinois
city: Boston
country: United States
facility: Dana-Farber Cancer Institute - Parent.
state: Massachusetts
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center (Mskcc) - New York
state: New York
city: Westbury
country: United States
facility: Clinical Research Alliance
state: New York
city: Chapel Hill
country: United States
facility: Unc Hospitals
state: North Carolina
city: Cleveland
country: United States
facility: The Cleveland Clinic Foundation
state: Ohio
city: Portland
country: United States
facility: Providence Portland Medical Center
state: Oregon
city: Dallas
country: United States
facility: Mary Crowley Cancer Research Centers
state: Texas
city: Dallas
country: United States
facility: Ut Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: University of Texas M. D. Anderson Cancer Center
state: Texas
city: Fairfax
country: United States
facility: Inova Schar Cancer Institute
state: Virginia
city: Fairfax
country: United States
facility: Next Virginia
state: Virginia
city: Seattle
country: United States
facility: Fred Hutch
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Guangzhou
country: China
facility: Sun Yat-Sen University, Cancer Center
city: Chuo-ku
country: Japan
facility: National Cancer Center Hospital
city: Fukuoka
country: Japan
facility: National Hospital Org-Kyushu Cancer Center
city: Kashiwa
country: Japan
facility: National Cancer Center Hospital East
city: Koto-ku
country: Japan
facility: The Cancer Institute Hospital of Jfcr
city: Nagoya
country: Japan
facility: Aichi Cancer Center Hospital
city: Osaka-Fu
country: Japan
facility: Kindai University Hospital
city: Osaka-Sayama
country: Japan
facility: Kindai University Hospital
city: Osaka
country: Japan
facility: Osaka International Cancer Institute
city: Shizuoka
country: Japan
facility: Shizuoka Cancer Center
city: Suita
country: Japan
facility: Osaka University Hospital
city: Yokohama
country: Japan
facility: Kanagawa Cancer Center
Study officials:
affiliation: Daiichi Sankyo
name: Global Clinical Leader
role: STUDY_DIRECTOR
References: