An open label phase II platform modular study exploring the efficacy and safety of the Valemetostat (EZH1/2 inhibitor) in patients with selected solid tumors (EZHiSWITCH)

Trial ID: 2024-519788-16-00
Protocol: 2024/3993 EZHiSWITCH
Sponsor: Institut Gustave Roussy

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Diseases & Conditions

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Objectives

The primary objective is to evaluate the antitumor activity of valemetostat in patients with selected advanced solid tumors as measured by the Overall Response Rate according to RECIST v1.1, mRECIST, PCWG3, or CHOI criteria depending on the specific pathology. This assessment is clinically relevant for determining the therapeutic efficacy of valemetostat, a dual EZH1/2 inhibitor, in tumors harboring chromatin remodeling deficiencies in genes such as SMARCB1, SMARCA4, SMARCA2, SMARCC1, SMARCC2, ARID1A, ARID1B, PBRM1, BAP1, and other SWI/SNF subunits, as well as in molecularly wildtype and phenotypically-selected clear cell endometrial or ovarian carcinoma.

The secondary objectives include: describing secondary efficacy endpoints; describing the ability of valemetostat to influence tumor growth; evaluating Overall Survival; evaluating the safety and tolerability of valemetostat; exploring the relationship between tumor chromatin remodeling defects and measures of efficacy; exploring molecular profiling related to clinical response; evaluating the relationship between the tumor epigenetic landscape and its treatment-induced modifications with efficacy measures; exploring the relationship between immune-related biomarkers and chromatin remodeling-related biomarkers; assessing whether identified biomarkers are tumor type-specific or shared across histologies; evaluating Quality of Life; evaluating safety through patient-reported outcomes based on selected PRO-CTCAE; evaluating anxiety and depression; evaluating patient experience through qualitative interviews; and evaluating biometric physiological parameters including mobility, heart rate, SpO2, and sleep cycle through wearable devices.

Participants

The sponsor did not provide information regarding the total number of participants for this clinical trial. The study population consists of **adult patients** aged 18 years and older with **histologically** or **cytologically confirmed** progressive **metastatic** or **recurrent solid tumors**. Both **male** and **female** subjects are eligible for enrollment. Participants must have documented **bi-allelic deletion** of specific **chromatin remodeling genes** including **SMARCB1**, **SMARCA4**, **SMARCA2**, **ARID1A**, **ARID1B**, **PBRM1**, **BAP1**, or other **SWI/SNF subunits**, with confirmed loss of expression in tumor cells, or have molecularly wild-type and phenotypically-selected **clear cell endometrial** or **ovarian carcinoma**. The trial population is selected based on specific molecular deficiencies and includes patients who have exhausted standard-of-care therapeutic options. Participants must have an **Eastern Cooperative Oncology Group performance status** of 0 or 1, an estimated life expectancy greater than 12 weeks, and adequate **hematologic** and **organ function** including appropriate **absolute neutrophil count**, **platelet count**, **hemoglobin**, **liver function tests**, and **renal function**. The number of prior treatment lines varies by cohort, ranging from a maximum of 1 to 3 prior treatment lines depending on the specific genetic deficiency. Women of childbearing potential and sexually active male participants must agree to use highly effective contraception methods during the study and for 3 months following the last dose of study treatment.

Plans and Procedures

This is an open-label, phase II platform modular study designed to evaluate the efficacy and safety of **valemetostat tosylate**, a dual inhibitor of **enhancer of zeste homolog (EZH) 1 and EZH2**, in adult patients with selected advanced **solid tumors**. The study follows a non-randomized, uncontrolled design with multiple cohorts based on specific **chromatin remodeling deficiencies**. Eligible patients must have **histologically** or **cytologically** confirmed progressive **metastatic** or **recurrent solid tumor** with documented bi-allelic deletion in genes including **SMARCB1**, **SMARCA4**, **SMARCA2**, **ARID1A**, **ARID1B**, **PBRM1**, **BAP1**, or other **SWI/SNF** subunits, confirmed by loss of expression through centralized **immunohistochemistry (IHC)**. A separate cohort includes patients with molecularly wild-type and phenotypically-selected **clear cell endometrial** or **ovarian carcinoma**. The investigational medicinal product is administered as a **film-coated tablet** via **oral use** at a maximum daily dose of 200 mg, with a maximum total dose of 5600 mg over a treatment period of up to 24 weeks.

The primary objective is to evaluate antitumor activity as measured by **Overall Response Rate (ORR)** at 24 weeks according to **RECIST v1.1** criteria, with modifications including **mRECIST** for **pleural mesothelioma**, **PCWG3** for **prostate cancer**, and **Choi Criteria** for **sarcoma**. Secondary endpoints include **Disease Control Rate** at 24 weeks, **Duration of Response**, **Best Overall Response Rate**, percentage change from baseline in tumor size at 24 weeks, **Tumor Growth Rate**, **PFS ratio**, and **Overall Survival (OS)**. Safety assessments comprise the incidence and severity of **adverse events (AEs)**, including **serious adverse events (SAEs)** and **adverse events of special interest (AESIs)**, graded according to **NCI CTCAE v5.0**, as well as changes in clinical laboratory parameters, dose interruptions, modifications, and discontinuations. Exploratory objectives include correlation between SWI/SNF defects and clinical outcomes, molecular profiling, modifications of the epigenetic landscape, and immune-related biomarkers in tumor and liquid biopsies. Patient-reported outcomes are assessed using the **EORTC-QLQ30** quality of life questionnaire, **PRO CTCAE** composite scores, and the **Hospital Anxiety and Depression Scale (HADS)**, along with physiological parameters captured by wearable devices.

The study comprises multiple cohorts with varying maximum prior treatment lines: Cohort 1.A (SMARCB1-defective, maximum 1 prior line), Cohort 1.B (SMARCA4, maximum 3 prior lines), Cohort 1.C (ARID1A, maximum 2 prior lines, subdivided into 1.Ca for clear cell endometrial and ovarian cancers and 1.Cb for other ARID1A-defective tumors), Cohort 1.D (PBRM1, maximum 3 prior lines), Cohort 1.E (BAP1, maximum 2 prior lines), Cohort 1.F (SMARCA2 or other SWI/SNF subunits, maximum 2 prior lines), and Cohort 1.G (clear cell endometrial or ovarian carcinoma SWI/SNF wild-type, maximum 2 prior lines). Patients must have exhausted all standard-of-care therapeutic options expected to be more effective than valemetostat. Key inclusion criteria include at least one measurable lesion according to RECIST v1.1 that has not been previously irradiated, estimated life expectancy greater than 12 weeks, **Eastern Cooperative Oncology Group (ECOG) performance status** of 0 or 1, and adequate hematologic and organ function. Archival tissue samples with sufficient tumor material for IHC confirmation are required, and if unavailable, a new biopsy must be performed. Tissue used for assessing SWI/SNF or BAP1 status must be less than 3 years old.

The screening visit includes verification of informed consent, assessment of eligibility criteria, collection of demographic data, medical history, physical examination, **ECOG performance status** evaluation, vital signs, laboratory assessments including hematology, biochemistry, coagulation parameters, and pregnancy testing for women of childbearing potential. Baseline tumor assessment is performed using **computed tomography (CT)** or **magnetic resonance imaging (MRI)** within a specified timeframe prior to treatment initiation. During the treatment period, patients attend regular study visits on Day 1 and Day 15 of each 28-day cycle for safety assessments, laboratory monitoring, and evaluation of adverse events. Tumor assessments are conducted at 8-week intervals according to RECIST v1.1 or applicable criteria for specific tumor types. Follow-up visits continue until disease progression, unacceptable toxicity, withdrawal of consent, or other protocol-defined reasons for discontinuation. The end-of-study visit includes final safety assessments, tumor evaluation, and collection of survival data. Patients who discontinue treatment for reasons other than disease progression enter a post-treatment follow-up phase for survival monitoring.

The estimated duration of participant involvement extends from the screening period through the treatment phase of up to 24 weeks, with subsequent follow-up for survival and long-term safety monitoring. The overall trial duration is estimated from February 2026 to February 2032, encompassing recruitment, treatment, and follow-up phases. Conditions leading to early termination from the study include disease progression as defined by applicable response criteria, unacceptable toxicity or adverse events requiring permanent discontinuation, withdrawal of informed consent, investigator decision based on patient safety concerns, significant protocol violations, pregnancy during the study period, or administrative reasons such as sponsor decision to terminate the trial. Dose interruptions, modifications, and discontinuations are managed according to predefined guidelines based on the severity and type of adverse events. Women of childbearing potential must use highly effective contraception supplemented by a barrier method during the study and for 3 months following the last dose, with negative pregnancy tests required at screening and prior to treatment initiation. Male patients with partners of childbearing potential must also use highly effective contraception during the same period. Participants must agree not to donate blood, sperm, or ova during the study and for 3 months after the last dose of study treatment.

Treatment

The experimental treatment under investigation is **Valemetostat Tosylate** (sponsor product code DS-3201b), a dual inhibitor of **enhancer of zeste homolog (EZH) 1 and EZH2**. The **active substance** is valemetostat tosilate, which is of chemical origin. The investigational medicinal product is formulated as a **film-coated tablet** for **oral use**. The maximum daily dose is **200 mg**, with a maximum total dose of **5600 mg** administered over a maximum treatment period of **24 weeks**. The dosing schedule and frequency of administration are designed to evaluate the **antitumor activity** of valemetostat in patients with selected advanced solid tumors.

This is an **open-label phase II platform modular study** investigating the **efficacy and safety** of valemetostat in patients with selected solid tumors. The study design does not include a **placebo** or active comparator treatment, as all participants receive the experimental medication. Tumor response is assessed according to **RECIST v1.1**, modified RECIST, **PCWG3**, or **CHOI criteria**, depending on the specific tumor pathology being evaluated. The primary endpoint is the **Overall Response Rate** in patients with advanced solid tumors treated with valemetostat.

Efficacy

The primary efficacy endpoint is the Overall Response Rate at 24 weeks, defined as the proportion of patients with a confirmed best overall response of either complete response or partial response. The assessment will be conducted according to RECIST v1.1 for most patients, mRECIST v1.1 for mesothelioma, RECIST 1.1/PCWG3 for prostate cancer, and Choi Criteria for sarcoma at 24 weeks.

Secondary efficacy endpoints include Disease Control Rate at 24 weeks, Duration of Response, Best Overall Response Rate, percentage of change from baseline in tumor size at 24 weeks, and Tumor Growth Rate (G-score). Additional secondary endpoints comprise the PFS ratio on valemetostat (PFS pre-treatment/PFS on-treatment at 24 weeks and 12 months) and Overall Survival. Exploratory endpoints evaluate correlations between SWI/SNF defect and primary and/or secondary endpoints, correlations between molecular profiling and/or endpoints, and correlations between modifications of epigenetic landscape on treatment and primary and/or secondary endpoints. Correlations between SWI/SNF defects and immune-related biomarkers on tumor and liquid biopsies at baseline and on treatment will also be assessed, with comparison of these correlations according to histotype.

Patient-reported outcomes will be measured using the EORTC-QLQ30 quality of life questionnaire, PRO CTCAE composite score of selected events, and the Hospital Anxiety and Depression Scale (HADS) to assess patient-reported anxiety and depression. Qualitative evaluation of patient experience regarding themes around the care journey, expectations, and uncertainty whilst undergoing therapy will be conducted through in-person or virtual qualitative interviews before disease re-evaluation. Physiological parameters including heartbeat, mobility, SpO2, and sleep cycle will be captured by wearable device.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Patient should understand, sign, and date the written informed consent form prior to any protocol-specific procedures performed
Female subjects must not donate, or retrieve for their own use, ova from the time of screening and throughout the study treatment period, and for at least 3 months after the final study drug administration.
Ability to comply with the protocol.
Patient should be able and willing to comply with study visits and procedures as per protocol.
Patients must be affiliated to a social security system or beneficiary of an equivalent system.
Age ≥ 18 years.
Patients must have histologically or cytologically confirmed progressive metastatic or recurrent solid tumor (as defined below for each tumor type). Diagnosis must be stated in a pathology report and confirmed by the investigator.
Evidence of disease progression prior to trial entry.
Have an archival tissue sample available with sufficient tumor tissue for IHC confirmation of loss expression (20 slides required). If patients do not have sufficient archival material, a new biopsy should be scheduled.
Have documented bi-allelic (homozygous) deletion of SMARCB1, SMARCA4/2, ARID1A/B, PBRM1, BAP1, SMARCC1/2 or other SWI/SNF in a tumor detected by a validated NGS test (solid or liquid) and confirmed loss of expression in tumour cells by centralized IHC. Cohort 1.A – SMARCB1-defective (maximum of 1 prior treatment line) Cohort 1.B – SMARCA4 (maximum of 3 prior treatment lines) Cohort 1.C – ARID1A (maximum of 2 prior treatment lines) Cohort 1Ca: Endometrial and ovarian clear cell only Cohort 1Cb: Other ARID1A-defective tumors Cohort 1.D – PBRM1 (with a minimum of 6 clear cell renal cell carcinoma during stage 1; maximum of 3 prior treatment lines) Cohort 1.E – BAP1 (with a maximum of 5 mesothelioma during stage 1; maximum of 2 prior treatment lines) Cohort 1.F – SMARCA2 or other SWI/SNF subunits (maximum of 2 prior treatment lines) Cohort 1.G – Clear cell Endometrial or Ovarian carcinoma SWI/SNF wild-type (maximum of 2 prior treatment lines) Tissue used for assessing SWI/SNF or BAP1 status must be < 3 years old; otherwise, a new fresh biopsy should be performed.
At least one lesion, not previously irradiated, measurable according to RECIST v1.1 (PCWG3/RECIST1.1 for prostate cancer and mRECIST for pleural mesothelioma) as ≥10 mm in the longest diameter (except lymph nodes which must have short axis ≥ 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) and suitable for repeated assessment.
Estimated life expectancy of greater than 12 weeks.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 with no deterioration at the time of enrollment.
Adequate hematologic and organ function, defined by the following laboratory results obtained within 3 days prior to the first study treatment (Cycle 1 Day 1): a. Absolute neutrophil count (ANC) ≥ 1500 cells/μL (without granulocyte colony-stimulating factor support within 14 days prior to the screening assessment). b. Lymphocyte count ≥ 500/μL. c. Platelet count ≥ 100.000/μL (platelet transfusion is not allowed within 14 days prior to the screening assessment). d. Hemoglobin ≥ 9g/dL (packed red blood cell transfusion is not allowed within 14 days prior to the screening assessment). e. Total bilirubin ≤ 1.5 ULN (subjects with documented/suspected Gilbert’s disease can have total bilirubin ≤3x ULN and direct bilirubin ≤1.5x ULN or subjects with liver metastases at baseline can have total bilirubin ≤ 3 × ULN). f. Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) ≤ 3.0x upper normal limit (ULN) or ≤ 5 × ULN in case of liver metastases. g. Albumin ≥ 2.5g/dL. h. Creatinine clearance ≥ 40 mL/min (according to Cockroft and Gault formula). i. International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN. This applies only to patients who do not receive therapeutic anticoagulation; patients receiving therapeutic anticoagulation (such as low-molecular weight heparin or warfarin) should be on stable dose and must have PT-INR within therapeutic range as deemed appropriate by the Investigator.
Women of childbearing potential must have at least one negative serum β-HCG pregnancy test during the screening assessment. Prior to the administration of the first study treatment, there must be a negative serum β-HCG pregnancy test within 72 hours prior or a negative urine pregnancy test within 24 hours prior. Women of childbearing potential must have a negative serum pregnancy test at Screening and must be willing to use highly effective birth control, as detailed in Table 3, upon enrollment, during the Treatment Period, and for 3 months, following the last dose of study drug administration.
Sexually active women of childbearing potential must agree to use a highly effective method of contraception << supplemented by a barrier method >>, or to abstain from sexual activity during the study and for at least 3 months after the last dose of study treatment.
Participant must agree to not breastfeed during the study or for 3 months after the last dose of study treatment.
Sexually active male’s patients with partner of childbearing potential, the subject must be surgically sterile or willing to use highly effective birth control (see Table 3) upon enrollment, during the Treatment Period, and for 3 months following the last dose of study drug.
Participant must agree to not donate blood during the study or for 3 months days after the last dose of study treatment.
Male subjects must not freeze or donate sperm starting at Screening and throughout the study period, and for at least 3 months after the final study drug administration.
Have exhausted all other standard-of-care therapeutic options which have shown efficacy in their disease and are expected to be more effective than valemetostat based on current evidence for standard-of-care and EZH1/2 inhibitors

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Exclusion Criteria

Participation in another clinical study with an investigational product during the last 4 weeks (excepting observational or non-interventional clinical studies).
Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, other investigational agent) 21 days prior to the first dose of study drug, or five half-lives of the previous agent, whichever is the longer.
Participant has had radiation therapy encompassing >20% of the bone marrow within 2 weeks prior to Cycle 1 Day 1; or curative radiation therapy or major surgery within 4 weeks or palliative radiation therapy within 2 weeks prior to Cycle 1 Day 1
History of another primary malignancy within 5 years prior to Cycle 1 Day 1 except for: a. Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of study drug and of low potential risk for recurrence. b. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. c. Adequately treated carcinoma in situ without evidence of disease (eg, carcinoma in situ of the cervix, ductal carcinoma in situ treated surgically with curative intent).
Treatment with systemic (>10 mg daily prednisone equivalents). or other immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and antitumor necrosis factor agents) within 2 weeks prior to Cycle 1 Day 1, or anticipated requirements for systemic immunosuppressive medications during the trial
Acute toxicities from previous therapies that have not resolved to Grade ≤ 1, with the exception of alopecia.
History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins. Known or suspected hypersensitivity to valemetostat tosylate or any of the excipients.
Uncontrolled or significant cardiovascular disease, including the following: a. Evidence of prolongation of QT/QTc interval (eg, repeated episodes of QT corrected for heart rate using Fridericia’s method [QTcF] >470 ms) (average of triplicate determinations) refer to APPENDIX 9. b. Myocardial infarction within 6 months prior to Screening. c. Uncontrolled angina pectoris within 6 months prior to Screening. d. New York Heart Association (NYHA) Class 3 or 4 congestive heart failure. e. Uncontrolled hypertension (resting systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg). f. Patients with known left ventricular ejection fraction (LVEF) < 40%; patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or LVEF < 50% must be on a stable cardiologic treatment.
Known positive test for HIV or known acquired immunodeficiency syndrome
Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection within 28 days prior to the first dose of study drug (hepatitis B surface antigen positive or have detectable HBV DNA or detectable HCV RNA).
Active tuberculosis.
Evidence of ongoing uncontrolled systemic bacterial, fungal, or viral infection requiring treatment with intravenous antibiotics, antivirals, or antifungals. Note: Subjects with localized fungal infections of skin or nails are eligible.
Any active uncontrolled systemic diseases or other medical conditions considered to be poorly controlled by the investigator, including, but not limited to, bleeding diatheses
Current use of moderate or strong cytochrome P450 (CYP)3A inducers
Administration of attenuated or live vaccine within 4 weeks prior to Cycle 1 Day 1 or anticipation that such a live attenuated vaccine will be required during the study (except anti-COVID-19 vaccines).
Major surgical procedure within 20 days prior ty Cycle 1 Day 1 or anticipation of need for a major surgical procedure during the course of the study.
Uncontrolled tumor-related pain: patients requiring pain medication must be on a stable regimen at study entry and symptomatic lesions amenable to palliative radiotherapy should be treated prior to enrolment.
Uncontrolled effusion (pleural, pericardial or ascites) requiring recurrent drainage procedures (once a month or more frequently); patients with indwelling catheters (e.g. PleurX) are allowed.
Uncontrolled hypercalcemia (>1.5mmol/L ionized calcium or Ca > 12mg/dL or corrected serum calcium >ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab.
History of leptomeningeal disease
Symptomatic Central Nervous System (CNS) metastasis or uncontrolled CNS metastasis, requiring increasing doses of steroids or stable dose of steroids > 10mg prednisone QD.
Spinal cord compression without evidence that disease has been clinically stable for ≥ 2 weeks prior to Cycle 1 Day 1.
Female subjects who are pregnant, breast-feeding or male / female patients of reproductive potential who are not employing an effective method of birth control.
Previous treatment with EZH2 (or EZH1/2) inhibitors, except for cohort 1A where EZH2 inhibitors are approved
Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study result.
Patient under guardianship or deprived of his liberty by a judicial or administrative decision or incapable of giving its consent.