Informations générales (source: ClinicalTrials.gov)
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
Interventional
Phase 2
Gustave Roussy, Cancer Campus, Grand Paris (Voir sur ClinicalTrials)
mars 2026
février 2032
18 mai 2026
Rational, objective and design: Some cancer-protecting genes are inactivated when the
EZH2 enzyme is too active or the SWI/SNF complex is less active. The EZH1/2 enzymes and
the SWI/SNFs complex play opposing roles in gene expression: we hypothesize that
valemetostat, an inhibitor of the EZH1/2 enzymes, will stop/slow down the growth of
cancer cells by reactivating these genes. Numerous clinical trials are currently underway
worldwide to optimize the development of valemetostat tosylate and potentially offer a
new targeted therapeutic option for patients suffering from various cancer pathologies.
The aim of this research is to evaluate the efficacy of valemetostat on solid tumors,
which have an alteration in certain genes: SMARC (B1/A4/A2/C1/C2), ARID (1A/1B), PBRM1,
BAP1 and other SWI/SNF sub-units. The research will be conducted in two phases: 1)
Pre-selection of patients with the desired alterations. 2) Treatment with valemetostat,
200mg/day, for a maximum of 2 years, with examinations every 28 days.
This is a multicenter, international, phase II open-label, multicenter modular study
exploring the efficacy and safety of valemetostat. Module 1 will be the SWI/SNF basket
monotherapy study describe below. Such design will allow the study to evolve considering
signals for further monotherapy and/or combination modules.
The Primary endpoint of the study is Overall Response Rate at 24 weeks, defined as the
proportion of patients with a confirmed best overall response.
Trial population: 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. Patients
must be using an effective method of contraception and have signed the consent form. They
must not participate in another clinical study with an investigational product during the
last 3 weeks, during the study treatment and not have a contraindication to the study
treatment (…) Intervention: After confirmation by IHC of the loss of expression in tumors
cells of SMARCB1, SMARCA4, SMARCA2, SMARCC1, SMARCC2, ARID1A, ARID1B, PBRM1, BAP1and
other SWI/SNF sub-units and validation of inclusion/exclusion criteria patients will
included in different cohorts (refer to investigation scheme). All patients will receive
Valemetostat (200 mg per day), divided into 28-day periods called treatment cycles, for a
maximum of two years. The main interventions scheduled are blood samples (to evaluate
biological parameters and for translational research), electrocardiogram,
echocardiography and CTscan. For patients who have consented, sequential biopsies will be
performed as follow: at baseline, on treatment and at progression.
Ethical consideration: This research will make it possible to collectively evaluate the
interest of EZH1/2 inhibitor in solids tumors with SWI/SNF defect. Individually, by
participating in this research, patients could benefit from these treatments based on
cell-based results and in the treatment of relapsed/refractory peripheral T-cell
lymphomas, with an improvement in symptoms and quality of life. As with any research, the
investigational drug and other procedures that take place may involve risks, some of
which are already known and others not yet described. The main risks (described in the
consent form) are side effects of the valemetostat. If they agree, patients will also be
monitored more closely with their safety assessed through patient-reported outcomes
(PRO), the evaluation of their experience through qualitative interviews & assessment of
quality of care and the evaluation of their biometric physiological via a wearable
device.
Etablissements
| Les établissements d'Île-de-France ayant mis à jour leurs données Origine et niveau de fiabilité des données | |||||
|---|---|---|---|---|---|
| CLCC INSTITUT GUSTAVE ROUSSY | Sophie POSTEL-VINAY | 11/06/2026 09:15:06 | Contacter | ||
| Les établissements d'Île-de-France dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
| CLCC INSTITUT CURIE | Clément BONNET, MD | Contact (sur clinicalTrials) | |||
| Les établissements hors Île-de-France dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
| Centre Léon Berard - 69373 - Lyon - France | DUFRESNE Armelle, MD | Contact (sur clinicalTrials) | |||
| Les établissements sans correspondance certaine dans le répertoire FINESS dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
| Institut Bergonié - 33076 - Bordeaux - France | douard AUCLIN, MD | Contact (sur clinicalTrials) | |||
Critères
Tous
1. Patient should understand, sign, and date the written informed consent form prior to
any protocol-specific procedures performed.
2. Ability to comply with the protocol.
3. Age ≥ 18 years.
4. 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.
5. Evidence of disease progression prior to trial entry.
6. 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
7. 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.
8. 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.
9. 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.
10. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 with no
deterioration at the time of enrollment.
11. Estimated life expectancy of greater than 12 weeks.
12. 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):
1. Absolute neutrophil count (ANC) ≥ 1500 cells/μL (without granulocyte
colony-stimulating factor support within 14 days prior to the screening
assessment).
2. Lymphocyte count ≥ 500/μL.
3. Platelet count ≥ 100.000/μL (platelet transfusion is not allowed within 14 days
prior to the screening assessment).
4. Hemoglobin ≥ 9g/dL (packed red blood cell transfusion is not allowed within 14
days prior to the screening assessment).
5. 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).
6. Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) ≤ 3.0x upper
normal limit (ULN) or ≤ 5 × ULN in case of liver metastases.
7. Albumin ≥ 2.5g/dL.
8. Creatinine clearance ≥ 40 mL/min (according to Cockroft and Gault formula).
9. 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.
13. 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, upon enrollment, during the
Treatment Period, and for 3 months, following the last dose of study drug
administration.
A woman is considered of childbearing potential following menarche and until
becoming post-menopausal (≥ 12 months of non-therapy-induced amenorrhea) unless
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral
oophorectomy and bilateral salpingectomy with surgery at least 1 month before the
first dose of study drug or confirmed by follicle stimulating hormone (FSH) test >40
mIU/mL and estradiol <40 pg/mL (<140 pmol/L).
14. 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.
15. Participant must agree to not breastfeed during the study or for 3 months after the
last dose of study treatment.
16. Sexually active male's patients with partner of childbearing potential, the subject
must be surgically sterile or willing to use highly effective birth control upon
enrollment, during the Treatment Period, and for 3 months following the last dose of
study drug.
17. Participant must agree to not donate blood during the study or for 3 months days
after the last dose of study treatment.
18. 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.
19. 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.
20. Patient should be able and willing to comply with study visits and procedures as per
protocol.
21. Patients must be affiliated to a social security system or beneficiary of an
equivalent system.
Exclusion Criteria:
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:
1. 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.
2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease.
3. 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:
The use of inhaled corticosteroids for chronic obstructive pulmonary disease,
mineralocorticoids for patients with orthostatic hypotension, low-dose supplemental
corticosteroids for adrenocortical insufficiency and topical steroids for cutaneous
diseases are allowed.
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:
1. 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.
2. Myocardial infarction within 6 months prior to Screening.
3. Uncontrolled angina pectoris within 6 months prior to Screening.
4. New York Heart Association (NYHA) Class 3 or 4 congestive heart failure.
5. Uncontrolled hypertension (resting systolic blood pressure >160 mmHg or
diastolic blood pressure >100 mmHg).
6. 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 (Table 8)
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 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.