A Phase Ib, Multicenter, Open-Label Study of Valemetostat Tosylate in Combination With DXd ADCs in Subjects With Solid Tumors

Study Identifier:
DS3201-324
CT.gov Identifier:
NCT06244485
EudraCT Identifier:
202452000000
EU Trial (CTIS) Number:
2024-516916-93-00
Study Contact Information:
N/A
Recruiting

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Study Summary

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

To evaluate the clinical activity and safety of valemetostat in combination with T-DXd in patients with GC or GEJ adenocarcinoma, as part of a Master Protocol trial evaluating valemetostat in combination with ADCs in solid tumors.

The dose-escalation (Part 1) will determine the recommended dose for expansion (RDE), combining valemetostat 50–200 mg PO QD with T-DXd 5.4 or 6.4 mg/kg IV Q3W. The dose-expansion (Part 2) will assess the efficacy of valemetostat + T-DXd at the RDE.

A preliminary dose-escalation part will assess escalating valemetostat doses of 50-200 mg PO QD with fixed-dose Dato-DXd 6.0 mg/kg IV Q3W, to determine the valemetostat recommended dose for expansion (RDE). A subsequent dose-expansion part will evaluate the efficacy of valemetostat (at the RDE) + Dato-DXd.

An interim futility analysis will be performed when 20 patients are enrolled with ≥ 6 months of follow-up.

The dose escalation phase of Part 1 of each sub-scheme will evaluate the safety of valemetostat tosylate combined with T-DXd treatment and valemetostat tosylate combined with Dato-DXd treatment until the recommended dose of valemetostat tosylate combined with DXd ADC in the expansion phase is determined. For the dose expansion phase of Part 2 of each sub-scheme, the safety and efficacy of valemetostat tosylate combined with DXd ADC treatment in selected solid tumors will be further evaluated.

Medical Condition
The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.
  • Solid Tumor
    • Phase
    The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
    I
    Sex
    Female & Male
    Age
    18+ years
    Study Drug
  • Drug: Experimental: Part 1: Dose Escalation Phase (Sub-protocol B) Participants with previously treated, advanced, or metastatic HER2-positive gastric or gastro-esophageal junction (GEJ) adenocarcinoma will receive valemetostat in combination with T-DXd. Drug: Valemetostat tosylate Administered orally once daily Drug: T-DXd One IV infusion Q3W on Day 1 of each 21-day cycle Experimental: Part 1: Dose Escalation Phase (Sub-protocol C) Participants with previously treated, locally advanced, unresectable, or metastatic non-squamous non-small cell lung cancer (NSCLC) with or without actionable genomic alteration(s) will receive valemetostat in combination with datopotamab deruxtecan (Dato-DXd). Drug: Valemetostat tosylate Administered orally once daily Drug: Dato-DXd One IV infusion Q3W on Day 1 of each 21-day cycle. Experimental: Part 1: Dose Escalation (Sub-protocol A) Participants with unresectable or metastatic HER2-low IHC]1+ or IHC 2+/ISH-negative breast cancer will receive valemetostat in combination with T-DXd. Drug: Valemetostat tosylate Administered orally once daily Drug: T-DXd One IV infusion Q3W on Day 1 of each 21-day cycle Experimental: Part 2: Dose Expansion (Sub-protocol B) Participants with previously treated, advanced, or metastatic HER2-positive gastric or gastro-esophageal junction (GEJ) adenocarcinoma will receive valemetostat at the RDE in combination with T-DXd at RDE. Drug: Valemetostat tosylate Administered orally once daily Drug: T-DXd One IV infusion Q3W on Day 1 of each 21-day cycle Experimental: Part 2: Dose Expansion (Sub-protocol C) Participants with previously treated, locally advanced, unresectable, or metastatic non-squamous non-small cell lung cancer (NSCLC) with or without actionable genomic alteration(s) will receive valemetostat at the RDE in combination with datopotamab deruxtecan (Dato-DXd). Drug: Valemetostat tosylate Administered orally once daily Drug: Dato-DXd One IV infusion Q3W on Day 1 of each 21-day cycle. Experimental: Part 2: Dose Expansion (Sub-protocol A) Participants with unresectable or metastatic HER2-low IHC]1+ or IHC 2+/ISH-negative breast cancer will receive valemetostat at the RDE in combination with T-DXd at RDE. Drug: Valemetostat tosylate Administered orally once daily Drug: T-DXd One IV infusion Q3W on Day 1 of each 21-day cycle ASCO 2024: Part 1 will determine the valemetostat recommended dose for expansion (RDE), combining escalating doses of valemetostat 50-200 mg PO QD with T-DXd at 5.4 mg/kg or 6.4 mg/kg (dose after first escalation) IV Q3W (GC protocol), or with fixed dose Dato-DXd 6.0 mg/kg IV Q3W (NSCLC protocol). Part 2 will evaluate the efficacy of valemetostat QD + Dato-DXd or T-DXd at the RDE. SABCS 2024: In Part 1, patients will receive valemetostat doses of 50-200 mg PO QD (continuous) and fixed-dose T-DXd 5.4 mg/kg IV Q3W until disease progression. The dose-limiting toxicity evaluation period will be the first treatment cycle (21 days). In Part 2, patients will receive valemetostat and T-DXd at the recommended dose for expansion identified in Part 1. Investigational drug Valemetostat Tosylate Valemetostat Tosylate Dosage form: tablet Specification: 25mg Dosage: oral once a day Medication duration: a cycle of 21 consecutive days Dosage form: tablet Specification: 50mg Dosage: oral once a day Medication duration: 21 consecutive days for a cycle Dosage form: tablet Specification: 100mg Dosage: oral once a day Medication course: a cycle of 21 consecutive days DS-8201a DS-8201a for Injection DS-8201a Dosage form: lyophilized powder Specification: 100 mg Dosage: Intravenous infusion once on day 1 of each 21-day cycle, Q3W Dosage course: IV infusion every 21 days DS-1062a DS-1062a for Injection DS-1062a Dosage form: lyophilized powder Specification: 100mg Dosage: Intravenous infusion once on day 1 of each 21-day cycle, Q3W Dosage course: IV infusion every 21 days
    • Study Status
    Indicates the current recruitment status or the expanded access status
    Recruiting

    Requirements information
    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:
    • Is unresectable or metastatic.
    • Has progressed on and would no longer benefit from endocrine therapy in hormone receptor-positive subjects in the opinion of the investigator.
    • Has been treated with at least 1 and at most 2 prior lines of chemotherapy in the recurrent or metastatic setting.
    • 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.
    • 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
    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

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    Study Locations

    Location
    Investigator
    Status
    Condition(s) Treated at Site
    Location
    START Barcelona
    Barcelona, Spain, 08023
    Investigator
    Tatiana Hernandez Guerrero
    Status
    Recruitment on Hold
    Condition(s) Treated at Site
    Solid Tumor
    Location
    START Madrid, Spain (FJD)
    Madrid, Spain, 28040
    Investigator
    Bernard Doger de Speville
    Status
    Recruitment on Hold
    Condition(s) Treated at Site
    Solid Tumor