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.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut Gustave Roussy

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

5 Mar 2026 → ongoing

Decision date (initial)

2025-12-09

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

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. ; m RECISIT; PCWG3 or CHOI depending on the pathologies

Secondary objectives 14

1. To describe the secondary efficacy endpoints
2. To describe the ability of valemetostat to influence tumor growth
3. To evaluate the Overall Survival (OS)
4. To evaluate the safety and tolerability of valemetostat
5. To explore the relationship between the tumor chromatin remodeling defect and measures of efficacy
6. To explore molecular profiling related with clinical response
7. To evaluate the relationship between the tumor epigenetic landscape and its modifications on treatment, and measures of efficacy
8. To explore the relationship between immune-related biomarkers and chromatin remodeling-related biomarkers
9. To assess whether the identified biomarkers of interest are private to each tumor type or shared across histologies.
10. To evaluate Quality of Life
11. To evaluate safety evaluated by patient’s reported outcomes based on selected PRO-CTCAE of valemetostat
12. To evaluate anxiety and depression of valemetostat
13. To evaluate patient experience through qualitative interviews
14. To evaluate biometric physiological parameters (mobility, heart rate, SpO2 and sleep cycle) through wearable devices

Conditions and MedDRA coding

Adult patients with histologically/cytologically confirmed progressive metastatic or recurrent solid tumor, who have selected chromatin remodeling deficiency in at least one of the following genes: SMARCB1, SMARCA4, SMARCA2, SMARCC1, SMARCC2, ARID1A, ARID1B, PBRM1, BAP1and other SWI/SNF sub-units; or molecularly (Wildtype) and phenotypically-selected Clear cell endometrial or ovarian carcinoma cancers.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 21

1. Patient should understand, sign, and date the written informed consent form prior to any protocol-specific procedures performed
2. 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.
3. Ability to comply with the protocol.
4. Patient should be able and willing to comply with study visits and procedures as per protocol.
5. Patients must be affiliated to a social security system or beneficiary of an equivalent system.
6. Age ≥ 18 years.
7. 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.
8. Evidence of disease progression prior to trial entry.
9. 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.
10. 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.
11. 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.
12. Estimated life expectancy of greater than 12 weeks.
13. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 with no deterioration at the time of enrollment.
14. 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.
15. 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.
16. 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.
17. Participant must agree to not breastfeed during the study or for 3 months after the last dose of study treatment.
18. 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.
19. Participant must agree to not donate blood during the study or for 3 months days after the last dose of study treatment.
20. 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.
21. 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

Exclusion criteria 26

1. Participation in another clinical study with an investigational product during the last 4 weeks (excepting observational or non-interventional clinical studies).
2. 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.
3. 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
4. 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).
5. 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
6. Acute toxicities from previous therapies that have not resolved to Grade ≤ 1, with the exception of alopecia.
7. 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.
8. 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.
9. Known positive test for HIV or known acquired immunodeficiency syndrome
10. 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).
11. Active tuberculosis.
12. 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.
13. Any active uncontrolled systemic diseases or other medical conditions considered to be poorly controlled by the investigator, including, but not limited to, bleeding diatheses
14. Current use of moderate or strong cytochrome P450 (CYP)3A inducers
15. 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).
16. 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.
17. 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.
18. 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.
19. 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.
20. History of leptomeningeal disease
21. Symptomatic Central Nervous System (CNS) metastasis or uncontrolled CNS metastasis, requiring increasing doses of steroids or stable dose of steroids > 10mg prednisone QD.
22. Spinal cord compression without evidence that disease has been clinically stable for ≥ 2 weeks prior to Cycle 1 Day 1.
23. Female subjects who are pregnant, breast-feeding or male / female patients of reproductive potential who are not employing an effective method of birth control.
24. Previous treatment with EZH2 (or EZH1/2) inhibitors, except for cohort 1A where EZH2 inhibitors are approved
25. Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study result.
26. Patient under guardianship or deprived of his liberty by a judicial or administrative decision or incapable of giving its consent.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Overall Response Rate at 24 weeks, defined as the proportion of patients with a confirmed best overall response of either CR or PR according to RECISTv1.1 (for all patients, except prostate), mRECIST v1.1 (mesothelioma), RECIST1.1/PCWG3 (prostate) and Choi Criteria (sarcoma) at 24 weeks

Secondary endpoints 21

1. Disease Control Rate at 24 weeks
2. Duration Of Response
3. Best Overall Response Rate
4. Percentage of change from baseline in tumor size at 24 weeks
5. Tumor Growth Rate (G-score)
6. PFS ratio on valemetostat (PFS pre-treatment / PFS on-treatment at 24W and 12 months)
7. Overall survival (OS)
8. Incidence and severity of AEs (including SAE and AESIs) according to the NCI CTCAE v5.0
9. Changes in clinical laboratory parameters, when clinically significant
10. Incidence of dose interruptions, dose modifications and discontinuations to AEs
11. Dose-intensity, incidence of SAEs and AESIs per cycle
12. Correlation between SWI/SNF defect and primary and/or secondary endpoints
13. Correlation between molecular profiling and/or endpoints
14. Correlation between modifications of epigenetic landscape on treatment and primary and/or secondary endpoints
15. Correlation between SWI/SNF defects and immune-related biomarkers on tumor and liquid biopsies o At baseline o On treatment
16. Comparison of the correlations defined above according to the histotype
17. EORTC-QLQ30 QoL questionnaire and Patients Reported Outcomes
18. PRO CTCAE composite score of selected events
19. Patient reported Anxiety and Depression as measured by the Hospital Anxiety and Depression Scale (HADS).
20. Qualitative evaluation of patient experience regarding themes around the care journey, expectations and uncertainty whilst undergoing therapy through in-person or virtual qualitative interviews conducted before disease re-evaluation
21. Physiological parameters (Heartbeat, mobility, SpO2, and sleep cycle) captured by wearable device

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut Gustave Roussy

Sponsor organisation

Institut Gustave Roussy

Address

114 Rue Edouard Vaillant

City

Villejuif

Postcode

94800

Country

France

Scientific contact point

Organisation

Institut Gustave Roussy

Contact name

Regulatory affairs officer

Public contact point

Organisation

Institut Gustave Roussy

Contact name

Regulatory affairs officer

Locations

1 EU/EEA country · 4 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 11 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications