Valemetostat in Combination with Lenalidomide and Rituximab for the Treatment of Grade 1-3a Relapsed or Refractory Follicular Lymphoma
This phase I/II trial evaluates the safety, best dose, and effectiveness of valemetostat tosylate (valemetostat) in combination with lenalidomide plus rituximab for the treatment of patients with grade 1-3a follicular lymphoma that has come back (relapsed) or that does not respond to treatment (refractory). Valemetostat is an enzyme inhibitor that can reduce proliferation of cancer cells by preventing the expression of genes that are associated with certain cancer pathways. Lenalidomide is a drug that alters the immune system, inhibits the growth of blood vessels that cancer cells use to grow, and promotes death of cancer cells. Rituximab is a monoclonal antibody. It binds to a protein called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. The combination of lenalidomide and rituximab is a Food and Drug Administration-approved treatment for follicular lymphoma. Adding valemetostat to lenalidomide and rituximab may be more effective at treating patients with grade 1-3a relapsed or refractory follicular lymphoma than lenalidomide and rituximab alone.
Inclusion Criteria
- Subjects >= 18 years of age at the time the informed consent form (ICF) is signed
- Have histologically confirmed FL, grades 1-3A
- Must have been previously treated with at least 1 prior systemic therapy followed by relapsed, refractory or progressive disease * Systemic therapy includes: ** Anti-CD20 monoclonal antibody in combination with chemotherapy ** Anti-CD20 monoclonal antibody monotherapy ** Anti-CD20 monoclonal antibody in combination with lenalidomide ** Anti-CD20 monoclonal antibody plus investigational agent on protocol
- Requiring systemic therapy as assessed by investigator based on tumor size, location, and/or Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria
- Bi-dimensionally measurable disease, with at least one mass lesion >= 2 cm in longest diameter by CT, PET/CT, and/or MRI which was not previously irradiated
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- Adequate renal function defined as calculated creatinine clearance per the Cockcroft and Gault formula * In phase 1, creatinine clearance must be > 60 mL/minute * In phase 2, creatinine clearance must be >= 30 mL/minute
- Absolute neutrophil count (ANC) >= 1,000/mm^3 (>= 1.0 x 10^9/L) if no lymphoma infiltration of bone marrow OR ANC >= 750/mm^3 (>= 0.75 x 10^9/L) with bone marrow infiltration, without growth factor support (filgrastim or pegfilgrastim) for at least 14 days
- Platelet >= 75,000/mm^3 (>= 75 x 10^9/L). Evaluated at least 7 days after platelet transfusion
- Hemoglobin > 8.0 g/dL. Evaluated at least 7 days after red blood cell (RBC) transfusion
- Total bilirubin =< 1.5 x the upper limit of normal (ULN) except for unconjugated hyperbilirubinemia of Gilbert’s syndrome (eg, a gene mutation in UGT1A1), who can have total bilirubin < 3.0 mg/dL
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN
- International normalized ratio (INR) =< 1.5 x ULN and activated partial thromboplastin time (aPTT) =< 1.5 x ULN (unless on warfarin, then INR =< 3.0)
- If the subject is a female of childbearing potential, she must have a negative serum pregnancy test at screening and must be willing to use 1 highly effective method and 1 additional effective birth control method upon enrollment, during the treatment period, and for 3 months, following the last dose of study drug. A female is considered of childbearing potential following menarche and until becoming postmenopausal (no menstrual period for a minimum of 12 months) unless permanently sterile (undergone a hysterectomy, bilateral salpingectomy or bilateral oophorectomy) 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)
- If the subject is a male, the subject must be surgically sterile or willing to use a highly effective birth control upon enrollment, during the treatment period, and for 3 months following the last dose of study drug. 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
- 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. Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Revlimid Risk Evaluation and Mitigation Strategy (REMS [registered trademark]) program
- All study participants must be registered into the mandatory Revlimid REMS (registered trademark) program, and be willing and able to comply with the requirements of the REMS (registered trademark) program
- Able and willing to provide written informed consent and to comply with the study protocol
Exclusion Criteria
- Transformation to diffuse large B-cell lymphoma (DLBCL) at study entry
- Grade 3B FL
- Prior systemic therapy (eg, chemotherapy, immunomodulatory therapy, or monoclonal antibody therapy) within 3 weeks prior to the first dose of study drug
- Having progressive disease while on prior lenalidomide, discontinuing lenalidomide due to unacceptable toxicity, or prior lenalidomide therapy within the past 12 months prior to the first dose of study drug
- Had curative radiation therapy or major surgery within 4 weeks or palliative radiation therapy within 2 weeks prior to the first dose of study drug
- Systemic treatment with corticosteroids (> 10 mg daily prednisone equivalents) * Note: Short-course systemic corticosteroids (eg, prevention/treatment for transfusion reaction) or use for a non-cancer indication (eg, adrenal replacement) is permissible
- History of autologous stem cell transplant within 60 days prior to first dose of study drug
- History of allogeneic stem cell transplant within 90 days prior to the first dose of study drug, and clinically significant graft-versus-host disease (GVHD) or GVHD requiring systemic immunosuppressive prophylaxis or treatment
- Prior malignancy active within the previous 2 years except for locally curable cancer that is currently considered as cured, such as cutaneous basal or squamous cell carcinoma, superficial bladder cancer, or cervical carcinoma in situ, or an incidental histological finding of prostate cancer
- Presence or history of central nervous system (CNS) involvement of lymphoma
- Prior EZH inhibitor therapy
- Current use of moderate or strong cytochrome P450 (CYP)3A inducers or inhibitors, or prior use of moderate or strong CYP3A within the past 2 weeks
- Current use of P-gp inducers and on narrow therapeutic index, sensitive P-gp substrates
- Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator’s opinion, could compromise the subject’s safety, interfere with the absorption or metabolism of lenalidomide capsules, or put the study outcomes at undue risk
- Human immunodeficiency virus (HIV), active hepatitis C virus, active hepatitis B virus infection, or any active systemic infection. Patients with inactive hepatitis B infection must adhere to hepatitis B reactivation prophylaxis unless contraindicated
- Clinically significant cardiovascular disease such asymptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any class 3 (moderate) or class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification
- Significant screening electrocardiogram (ECG) abnormalities including left bundle branch block, 2nd degree atrioventricular (AV) block, type II AV block, or 3rd degree block. QT prolongation is not a significant ECG abnormality that would warrant exclusion
- Lactating or pregnant subjects
Additional locations may be listed on ClinicalTrials.gov for NCT05683171.
Locations matching your search criteria
United States
Texas
Houston
PRIMARY OBJECTIVES:
I. Evaluate the safety and tolerability of valemetostat tosylate (valemetostat) in combination with rituximab plus lenalidomide (R^2) in subjects with relapsed and/or refractory (R/R) follicular lymphoma (FL) and determine the recommended phase 2 dose (RP2D) for evaluation in phase 2. (Phase 1)
II. Evaluate the efficacy of valemetostat in combination with R^2 in R/R FL. (Phase 2)
SECONDARY OBJECTIVES:
I. Evaluate the efficacy of valemetostat in combination with R^2 in R/R FL. (Phase 1)
II. Evaluate the pharmacokinetics (PK) of valemetostat in combination with R^2. (Phase 1)
III. Evaluate the objective/overall response rate (ORR). (Phase 2)
IV. Evaluate the duration of response (DOR). (Phase 2)
V. Evaluate the time to next anti-lymphoma treatment (TTNT). (Phase 2)
VI. Evaluate the safety and tolerability. (Phase 2)
VII. Evaluate the PK of valemetostat in combination with R^2. (Phase 2)
EXPLORATORY OBJECTIVES:
I. Evaluate pharmacodynamic profile of valemetostat. (Phase 1)
II. Evaluate the progression free survival (PFS) of valemetostat in combination with R^2 in R/R FL. (Phase 2)
III. Evaluate overall survival (OS). (Phase 2)
IV. Evaluate the effect of valemetostat in combination with R^2 in R/R FL on epigenetic remodeling and gene expression. (Phase 2)
V. Evaluate the role of tumor genetic mutation status on the effect of valemetostat + R^2 therapy. (Phase 2)
VI. Evaluate changes in tumor/immune microenvironment. (Phase 2)
VII. Evaluate pharmacodynamic profile of valemetostat. (Phase 2)
OUTLINE: This is a phase I, dose-escalation study of valemetostat and lenalidomide followed by a phase II study.
Patients receive valemetostat tosylate orally (PO) once daily (QD) on days 1-21 of cycle 1, and days 1-28 of subsequent cycles, rituximab intravenously (IV) on days 1, 8, 15, and 22 of cycle 2 and on day 1 of subsequent cycles, and lenalidomide PO on days 1-21. Cycle 1 is 21 days, and subsequent cycles are 28 days. Treatment of valemetostat repeats every 28 days for up to 13 cycles, lenalidomide repeats every 28 days for up to 12 cycles, and cycles of rituximab repeat every 28 days for up to 5 cycles. Patients undergo bone marrow aspiration and bone marrow biopsy during screening and undergo collection of blood samples on study. Patients also undergo computed tomography (CT), positron emission tomography (PET)/CT and/or magnetic resonance imaging (MRI) during screening and on study. Patients may also undergo optional blood sample collection during screening and on study.
After completion of the study treatment, patients are followed up every 24 weeks for 1 year, then annually for up to 2 years.
Trial PhasePhase I/II
Trial Typetreatment
Lead OrganizationM D Anderson Cancer Center
Principal InvestigatorChijioke Nze
- Primary ID2022-0551
- Secondary IDsNCI-2023-00072
- ClinicalTrials.gov IDNCT05683171