Status and phase
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About
This study aims to evaluate the efficacy and safety of an induction regimen combining Bendamustine, Rituximab, Cytarabine (AraC), and Zanubrutinib (BRAZAN), followed by maintenance therapy with Zanubrutinib and Rituximab with or without Sonrotoclax in participants with Mantle Cell Lymphoma (MCL).
The names of the study drugs involved in this study are:
Full description
This Phase 2, multi-center, randomized study is to evaluate the efficacy and safety of an induction regimen combining Bendamustine, Rituximab, Cytarabine (AraC), and Zanubrutinib (BRAZAN), followed by maintenance therapy with Zanubrutinib and Rituximab with or without Sonrotoclax in participants with MCL. These specific maintenance therapy combinations are investigational and are being evaluated to see if the therapies may lengthen the time before MCL returns after initial therapy.
After completing induction therapy, participants will be randomized into one of two groups: Arm A: zanubrutinib + rituximab or Arm B: zanubrutinib + rituximab + sonrotoclax. Randomization means a participant is placed into a study group by chance.
The U.S. Food and Drug Administration (FDA) has approved bendamustine, cytarabine, rituximab, and zanubrutinib for the treatment of other lymphomas and/or blood cancers.
The FDA has approved rituximab as a treatment option for Mantle Cell Lymphoma (MCL).
The FDA has also approved zanubrutinib for mantle cell lymphoma, but only after trying other therapies first.
The FDA has not approved sonrotoclax as a treatment for Mantle Cell Lymphoma (MCL). However sonrotoclax works similarly to a drug called venetoclax, which is also sometimes used to treat mantle cell lymphoma. The U.S. Food and Drug Administration (FDA) has approved venetoclax for the treatment of other blood cancers.
The research study procedures include screening for eligibility, in-clinic treatment visits, electrocardiograms (ECGs), Positron Emission Tomography (PET) scans, Computerized Tomography CT) scans, blood tests, urine tests, lymph node biopsies, and bone marrow biopsies.
It is expected that about 60 people will take part in this research study.
The induction therapy will be 6 "cycles", or rounds of treatment, which will last for up to a little over 5 months. The maintenance therapy will last for up to 2 years.
Induction phase:
Maintenance phase - either:
BeiGene, Ltd., a pharmaceutical company, is also supporting this research study by providing the drugs zanubrutinib and sonrotoclax and other funding support.
Enrollment
Sex
Ages
Volunteers
Inclusion criteria
Histologically confirmed diagnosis of mantle cell lymphoma, with review of the diagnostic pathology specimen at one of the participating institutions. Whenever possible, the Ki67 fraction should be reported or evaluated, cytogenetics should be performed, and TP53 status should be assessed (preferably by next-generation sequencing; immunohistochemical staining would be next-preferred).
No prior anti-lymphoma therapy, with the following exceptions:
Measurable disease, defined as ≥1 measurable nodal lesion (long axis >1.5 cm or short axis >1.0 cm) or ≥1 measurable extra-nodal lesion (long axis >1.0 cm) on PET, CT, or magnetic resonance imaging (MRI). Disease should be FDG-avid based on PET.
Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. (Appendix A)
Age ≥18 years and considered a candidate for high-dose cytarabine by the treating physician.
Adequate hematologic and organ function defined as:
Patients with known infection with human immunodeficiency virus (HIV) are eligible, provided all 3 of the following are true: 1) presence of controlled disease, defined as CD4 count ≥ 200/uL and an undetectable viral load, 2) disease control has been stable on anti-retroviral therapy for at least 6 months prior to study enrollment, and 3) there are no prohibitive drug-drug interactions between study drugs and the necessary anti- retroviral therapies.
Willingness to provide a pre-treatment tumor sample by core needle or excisional surgical biopsy. A fresh biopsy is strongly encouraged, but an archival sample is acceptable if it is collected within 90 days and without intervening treatment and the following provisions are met: 1) availability of a tumor-containing formalin-fixed, paraffin-embedded (FFPE) tissue block, 2) if the tumor containing FFPE tissue block cannot be provided in total, sections from this block should be provided that are freshly cut and mounted on positively-charged glass slides. Preferably, 25 slides should be provided; if not possible, a minimum of 15 slides is required. Exceptions to this criterion may be made with approval of the Sponsor-Investigator.
Willingness to remain abstinent or to use two effective contraceptive methods that result in a failure rate of <1% per year from screening until at least:
6 months after the last dose of bendamustine,
6 months after the last dose of cytarabine,
90 days after the last dose of zanubrutinib,
90 days after the last dose of sonrotoclax, and/or
12 months after the last dose of rituximab, whichever of the above is longest. Examples of contraceptive methods with a failure rate of <1% per year include:
Ability to understand and the willingness to sign a written informed consent document.
Exclusion criteria
Known central nervous system involvement.
Known active infection requiring systemic antimicrobial therapy at trial enrollment.
Patients, who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia).
Participants who require warfarin or other vitamin K antagonists for anticoagulation. Other anticoagulants including direct oral anticoagulants (i.e. apixaban, rivaroxaban) and low-molecular weight heparin are allowed.
History of severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood transfusions or other medical interventions.
History of stroke or intracranial hemorrhage within 6 months of first dose of zanubrutinib.
History of significant or life-threatening hemorrhage within 3 months of first dose of zanubrutinib.
History of uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia, unless these conditions are related to the underlying malignancy.
Active hepatitis C infection. Patients with presence of HCV antibody are eligible if HCV RNA is undetectable (NOTE: the limit of detection for HCV RNA must have a sensitivity of < 15 IU/mL). Subjects who received treatment for HCV that was intended to eradicate the virus and who have an undetectable HCV RNA may participate without serial HCV RNA screening. Other patients may participate if they are willing to undergo every 3- month monitoring for HCV reactivation.
Active hepatitis B infection. Patients with positive hepatitis B serologies with undetectable HBV DNA (NOTE: the limit of detection for HBV DNA must have a sensitivity of < 20 IU/mL) are permitted in the trial but should receive prophylactic antiviral therapy (i.e. entecavir) and undergo every 3 month HBV DNA monitoring.
Prior history of another malignancy unless treated with curative intent and disease-free for at least 3 years at time of screening with expected low risk of recurrence during expected timeframe of study participation. Such patients should first be discussed with the Sponsor-Investigator. Additional exceptions: non-melanoma skin cancer, in situ cervical or breast cancer, or Gleason 6 prostate cancer managed with observation.
Patients with the following cardiac conditions will be excluded:
Screening 12-lead EKG showing a baseline QTcF (Fridericia's correction) > 480 msec.
Unable to swallow capsules or disease significantly affecting gastrointestinal function, such as malabsorption syndrome.
Participants receiving any medications or substances that are strong CYP3A inducers.
Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the participant will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the participant is considering a new over-the-counter medicine or herbal product.
Primary purpose
Allocation
Interventional model
Masking
60 participants in 4 patient groups
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Central trial contact
Clare Phinney; Dana-Farber Cancer Institute Clinical Trials
Data sourced from clinicaltrials.gov
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