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
- Phase
- Phase 2
- Status
- Recruiting
- Enrollment
- 900
- Locations
- 8
- Primary Endpoint
- Evaluate the antitumor activity of valemetostat
Overview
Brief Summary
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.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Patient should understand, sign, and date the written informed consent form prior to any protocol-specific procedures performed.
- •Ability to comply with the protocol.
- •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 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
- •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.
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
- •History of another primary malignancy within 5 years prior to Cycle 1 Day 1 except for:
- •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.
- •Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
- •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:
- •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.
- •Acute toxicities from previous therapies that have not resolved to Grade ≤ 1, with the exception of alopecia.
Arms & Interventions
Valemetostat treatment
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 patients will included in different cohorts depending of gene with loss of expression. They will be all treated by Valemetostat
Intervention: Valemetostat Tosylate (Drug)
Outcomes
Primary Outcomes
Evaluate the antitumor activity of valemetostat
Time Frame: From enrollment to visit at week 24
Overall Response Rate 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)
Secondary Outcomes
- Disease Control Rate(From enrollment to visit at week 24 + Until the end of the study, an average of 1 year)
- Duration Of Response(From enrollment to visit at week 24 + Until the end of the study, an average of 1 year)
- Ability of valemetostat to influence tumor growth(From enrollment to visit at week 24 and 12 months)
- Severity of AEs(Through study completion, an average of 1 year)
- Overall Survival(Through study completion, an average of 1 year)
- Incidence of AEs(Through study completion, an average of 1 year)
- Change in tumor size(From enrollment to visit at week 24 + Until the end of the study, an average of 1 year)
- Best Overall Response Rate(From enrollment to visit at week 24 + Until the end of the study, an average of 1 year)
- Progression-free survival(From enrollment to visit at week 24 and 12 months)