IRB Study Number 25-422
Status Recruiting
Phase Phase 3
Location Cleveland Clinic Weston Hospital
Institute Taussig Cancer Institute
Description
Primary Objective
To demonstrate superiority of sonrotoclax plus zanubrutinib over placebo plus zanubrutinib as measured by progression-free survival (PFS) determined by a blinded independent review committee (BIRC)
Secondary Objectives
To compare the efficacy of sonrotoclax plus zanubrutinib with that of placebo plus zanubrutinib as measured by overall survival (OS
• To evaluate efficacy, as measured by the following
o PFS determined by investigator
o Overall response rate (ORR), as determined by BIRC and by investigator assessment (INV), per Lugano 2014 criteria
Complete response rate (CRR), as determined by BIRC and by investigator
Duration of response (DOR), as determined by BIRC and by investigator
Time to first response, as determined by BIRC and by investigator
• To evaluate patient-reported disease and treatment symptoms
To evaluate safety and tolerability
Inclusion Criteria
Histologically confirmed diagnosis of MCL based on the World Health Organization 2022 classification of Haematolymphoid Tumors (WHO-HAEM5) (Alaggio et al 2022), or based on International Consensus Classification (ICC) (Campo et al 2022)
Received 1 to 5 prior lines of systemic therapy including an anti-CD20 mAb-based immunotherapy or chemoimmunotherapy and requiring treatment in the opinion of the investigator. Note: A line of therapy is considered ≥ 2 consecutive cycles of a systemic anticancer regimen. Patients should have received ≥ 2 consecutive cycles of anti-CD20 mAb unless a ≥ Grade 3 anaphylactic reaction to the first dose of anti-CD20 mAb occurs. Examples of therapy: R-CHOP and platinum containing regimen will be considered as appropriate for patients who can tolerate intensive therapy, and BR or rituximab combined with BTKi will be considered as appropriate for patients who require less intensive therapy. Radiation alone, single-agent anti-CD20 mAb or BTKi for maintenance, and consolidation therapies such as ASCT after response to induction/salvage treatment are not considered separate lines of therapy.
Relapsed or refractory disease after the last line of therapy.
Age ≥ 18 years.
Measurable disease defined as ≥ 1 nodal lesion that is > 1.5 cm in longest diameter, or ≥ 1 extranodal lesion that is > 1 cm in longest diameter.
ECOG Performance Status of 0 to 2.
Adequate organ function defined as:
a. Absolute neutrophil count ≥ 1000/mm3 (or ≥ 750/mm3 for patients with bone marrow involvement by lymphoma); without growth factor support within 7 days of randomization
b. Platelets ≥ 75,000/mm3 (or ≥ 50,000/mm3 for patients with bone marrow involvement by lymphoma); without growth factor support or transfusion within 7 days of randomization
c. AST/serum glutamic oxaloacetic transaminase, and ALT/serum glutamic pyruvic transaminase ≤ 3.0 x ULN
d. Total bilirubin ≤ 2.0 x ULN (unless documented Gilbert’s syndrome)
e. Adequate renal function defined by a value ≥ 50 mL/min determined via estimated GFR (eGFR) using the CKD-EPI equation (Inker et al 2021; Appendix 6).
Adequate blood clotting function as defined by International normalized ratio ≤ 1.5 x ULN and activated partial thromboplastin time ≤ 1.5 x ULN.
Meet the following drug washout times for prior medications before the first dose of the study drug:
a. ≥ 28 days (or 5 half-lives, whichever is shorter) before the first dose of the study drug for any biologic and/or immunologic-based anticancer therapy(ies) including experimental therapy(ies) (including, but not limited to, mAb therapy such as rituximab and/or cancer vaccine therapies)
b. ≥ 14 days (or 5 half-lives, whichever is shorter) before the first dose of the study drug for systemic chemotherapy or radiation therapy.
c. ≥ 7 days before the first dose of the study drug for corticosteroid given with antineoplastic intent (symptom control will not be considered as antineoplastic intent)
d. ≥ 7 days (or 5 half-lives, whichever is shorter) before the first dose of the study drug for targeted small molecules given with antineoplastic intent, such as BTKis or tyrosine kinase inhibitors.
Women of childbearing potential must have a negative serum pregnancy test result ≤ 72 hours before the first dose of study drug(s). Female patients of childbearing potential must practice highly effective methods of contraception and refrain from egg donation. Contraception must be initiated prior to the first dose of the study drug and practiced for the duration of the study and for ≥ 90 days after the last dose of sonrotoclax/matched placebo or ≥ 30 days after the last dose of zanubrutinib, whichever occurs later. See Appendix 1 for a list of highly effective methods of birth control.
Nonsterile male patients must be willing to use a highly effective method of birth control and refrain from sperm donation for the duration of the study and for ≥ 90 days after the last dose of sonrotoclax/matched placebo or ≥ 30 days after the last dose of Zanubrutinib (whichever occurs last). See Appendix 1 for the definition of sterile.
Ability to provide written informed consent and ability to understand and comply with the requirements of the study.
For France only: Patients must be registered with the French social security (“affiliation à la Sécurité Sociale”).
Life expectancy of ≥ 6 months.
Exclusion Criteria
Prior therapy with BCL2i
Prior therapy with covalent or non-covalent BTKi unless was intolerant of non-zanubrutinib covalent or non-covalent BTKi, with treatment intolerance defined as an unacceptable toxicity where, in the opinion of the investigator, treatment should be discontinued despite dose modification and optimal supportive care because of one of the following:
a. One or more Grade 3 or two or more Grade 2 non-hematologic toxicities or
b. One or more Grade 3 neutropenia with infection or fever or
c. One or more Grade 4 hematologic toxicity
Prior ASCT or chimeric antigen receptor T-cell therapy within 3 months before the first dose of study drug
Prior allogeneic stem cell transplant within 6 months of the first dose of the study treatment Note: Patients who have previously received allogeneic stem cell transplant must not be receiving immunosuppressive therapy or have signs or symptoms of active graft versus host disease.
Known central nervous system involvement by lymphoma.
Clinically significant cardiovascular disease including the following:
a. Myocardial infarction within 6 months before screening
b. Unstable angina within 6 months before screening
c. New York Heart Association Class III or IV congestive heart failure (Appendix 7)
d. History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, Torsades de pointes)
e. QTcF > 480 msec based on Fridericia’s formula.
f. History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place
g. Uncontrolled atrial fibrillation
h. Uncontrolled hypertension as indicated by a minimum of 2 consecutive blood pressure measurements showing systolic blood pressure ≥ 160 mm Hg and diastolic blood pressure ≥ 100 mm Hg at screening
History of stroke or intracranial hemorrhage within 6 months before first dose of study drug
Active fungal, bacterial and/or viral infection requiring systemic therapy (including both oral and parenteral anti-microbial therapy for treatment purpose). Note: Only oral anti-microbial therapies are allowed for prophylaxis purpose.
Infection with HIV, or active infection with HBV or HCV as follows:
a. Presence of HBsAg or HBcAb. Patients with presence of HBcAb but absence of HBsAg are eligible if HBV DNA is undetectable (< 20 IU/mL) and if they are willing to undergo monitoring for HBV reactivation.
b. Presence of HCV antibody. Patients with presence of HCV antibody are eligible if HCV RNA is undetectable (< 15 IU/mL) and if they are willing to undergo monitoring for HCV reactivation.
Receiving treatment with any moderate or strong CYP3A4 inhibitor or moderate or strong CYP3A4 inducer ≤ 14 days or 5 half-lives (whichever is shorter) before the first dose of study drug, or requiring ongoing treatment with a moderate or strong CYP3A inhibitor or a moderate or strong CYP3A inducer.
Vaccination with a live vaccine within 4 weeks prior to the first dose of study drug. Note: Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. Intranasal vaccines are live vaccines and are not allowed. A non-live COVID-19 vaccine may be administered if recommended per local practice.
Pregnant or lactating women.
History of hypersensitivity to excipient(s) of the sonrotoclax and Zanubrutinib formulations
Patients with concurrent participation in another therapeutic clinical study. Note: Concurrent participation in observational or noninterventional studies is allowed. In addition, patients who have completed active treatment in a clinical study and are in the follow-up period can be enrolled in this study.
Underlying medical conditions that, in the investigator’s opinion, will render the administration of the study drug(s) hazardous or obscure the interpretation of safety or efficacy results.
Unable to swallow capsules or tablets or diseases significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction.
Major surgery ≤ 4 weeks before the first dose of study treatment
History of a severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood transfusion or other medical intervention
Prior malignancy (other than the disease under study) within the past 2 years, except in situ malignancies that have been curatively resected, localized breast cancer treated with curative intent with no evidence of active disease for > 3 years and receiving adjuvant hormonal therapy, localized Gleason score ≤ 6 prostate cancer undergoing observation or treatment with androgen deprivation, or any other cancer treated with curative intent, not on adjuvant treatment, and in the opinion of the investigator is unlikely to recur.
Ongoing alcohol or drug addiction.
