A Phase 1b, Multicenter, Open-Label Study of Valemetostat Tosylate in Combination With DXd ADCs in Subjects With Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 210
- 试验地点
- 63
- 主要终点
- Objective Response Rate Based on Investigator Assessment (Part 2 Dose Expansion)
研究概览
简要总结
This study will evaluate the safety, tolerability, and efficacy of valemetostat tosylate in combination with DXd antibody-drug conjugates (ADC) in participants with advanced solid tumors.
详细描述
This is a 2-part study of valemetostat in combination with DXd ADCs in participants with human epidermal growth factor 2 (HER2)-positive gastric cancer, non-squamous non-small cell lung cancer (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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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 informed consent form (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 immunohistochemistry (IHC) 2+ /in situ hybridization (ISH)-negative or IHC 1+ (ISH-negative or untested), as classified by the American Society of Clinical Oncology/College of American Pathologists 2023 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 gastro-esophageal junction (GEJ) adenocarcinoma that is (a) unresectable or metastatic (b) has progressed on HER2-directed monoclonal antibody (mAb) containing therapy, such as 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 actionable genomic alterations (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 the only prior line of therapy or (b) received platinum-based chemotherapy and α -PD-1/ α -PD-L1 mAb (in either order) sequentially as the only 2 prior lines of therapy.
- •Participants with AGA: (a) has been treated with 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 the only prior line of cytotoxic therapy, (c) may have received α -PD-1/α -PD-L1 mAb alone or in combination with a cytotoxic agent
排除标准
- •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
研究组 & 干预措施
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.
干预措施: Valemetostat tosylate (Drug)
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.
干预措施: T-DXd (Drug)
Part 2: Dose Expansion (Sub-protocol C)
Participants with previously treated, locally advanced, unresectable, or metastatic non-squamous NSCLC with or without actionable genomic alteration(s) will receive valemetostat at the RDE in combination with Dato-DXd.
干预措施: Dato-DXd (Drug)
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.
干预措施: Valemetostat tosylate (Drug)
Part 2: Dose Expansion (Sub-protocol B)
Participants with previously treated, advanced, or metastatic HER2-positive gastric or GEJ adenocarcinoma will receive valemetostat at the RDE in combination with T-DXd at RDE.
干预措施: T-DXd (Drug)
Part 1: Dose Escalation Phase (Sub-protocol C)
Participants with previously treated, locally advanced, unresectable, or metastatic non-squamous NSCLC with or without actionable genomic alteration(s) will receive valemetostat in combination with datopotamab deruxtecan (Dato-DXd).
干预措施: Dato-DXd (Drug)
Part 2: Dose Expansion (Sub-protocol B)
Participants with previously treated, advanced, or metastatic HER2-positive gastric or GEJ adenocarcinoma will receive valemetostat at the RDE in combination with T-DXd at RDE.
干预措施: Valemetostat tosylate (Drug)
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.
干预措施: T-DXd (Drug)
Part 2: Dose Expansion (Sub-protocol C)
Participants with previously treated, locally advanced, unresectable, or metastatic non-squamous NSCLC with or without actionable genomic alteration(s) will receive valemetostat at the RDE in combination with Dato-DXd.
干预措施: Valemetostat tosylate (Drug)
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.
干预措施: T-DXd (Drug)
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.
干预措施: Valemetostat tosylate (Drug)
Part 1: Dose Escalation Phase (Sub-protocol C)
Participants with previously treated, locally advanced, unresectable, or metastatic non-squamous NSCLC with or without actionable genomic alteration(s) will receive valemetostat in combination with datopotamab deruxtecan (Dato-DXd).
干预措施: Valemetostat tosylate (Drug)
结局指标
主要结局
Objective Response Rate Based on Investigator Assessment (Part 2 Dose Expansion)
时间窗: 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
Number of Participants Reporting Treatment-emergent Adverse Events (Part 1 Dose Escalation)
时间窗: Screening up to 40 days after last dose, up to approximately 5 years
Number of Participants Reporting Dose-limiting Toxicities (Part 1 Dose Escalation)
时间窗: Cycle 1 Day 1 up to Day 21 (each cycle is 21 days)
Number of Participants Reporting Treatment-emergent Adverse Events (Part 1 Dose Escalation)
时间窗: Screening up to 40 days after last dose
次要结局
- Duration of Response (DoR)(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)
- Overall Survival(Date of first dose up to date of death due to any cause, up to approximately 5 years)
- Progression-free Survival(Date of first dose up to date of radiographic disease progression or death due to any cause (whichever occurs first), up to approximately 5 years)
- Objective Response Rate Per Investigator Assessment Based on RECIST v1.1 (Part 1 Dose Escalation)(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)
- Number of Participants Reporting Treatment-emergent Adverse Events (Part 2 Dose Expansion)(Screening up to 40 days after last dose, up to approximately 5 years)
- Total and Unbound Plasma Concentration of Valemetostat(Cycle 1, Day 1 up to approximately 5 years (cycle length=21 days))
- Plasma Concentration of DXd Antibody-Drug Conjugates(Cycle 1, Day 1 up to approximately 5 years (cycle length=21 days))
- Overall Survival(Date of enrollment up to date of death due to any cause, up to approximately 5 years)
- Progression-free Survival(Date of enrollment up to date of radiographic disease progression or death due to any cause (whichever occurs first), up to approximately 5 years)
- Objective Response Rate Based on Investigator Assessment (Part 1 Dose Escalation)(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)
- Number of Participants Reporting Treatment-emergent Adverse Events (Part 2 Dose Expansion)(Screening up to 40 days after last dose)
- Total and Unbound Plasma Concentration of Valemetostat(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))
- Plasma Concentration of DXd Antibody-Drug Conjugates(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))