GATE1: A Multicenter Phase II Study of Pirtobrutinib, Rituximab and Venetoclax Combination Therapy for Patients With Previously Untreated Mantle Cell Lymphoma
GATE1: A Multicenter Phase II Study of Pirtobrutinib, Rituximab and Venetoclax Combination Therapy for Patients With Previously Untreated Mantle Cell Lymphoma
Primary Objectives:
To estimate the percent of participants who achieve a best response of complete response by the end of the PRV combination therapy in the induction therapy phase in patients with previously untreated MCL.
Secondary Objectives:
Inclusion Criteria:
Age ≥ 18 years old.
Confirmed pathology diagnosis of MCL with t(11;14)(q13;q32) translocation and/or cyclin D1 overexpression (e.g., positive immunohistochemistry staining).
MCL cells are CD20 positive (e.g., positive staining on immunohistochemistry or flow cytometry).
No prior MCL-directed systemic treatment (such as chemotherapy, immunotherapy, targeted therapy, and cellular therapy) or radiotherapy.
NOTE: A short course of corticosteroids (e.g., ≤ 1 week of intravenous or ≤ 2 weeks of oral) given for acute MCL-related symptoms or impending severe organ dysfunction is allowed, but a washout period of 3 days is required before registration.
Have a clinical indication to treat (e.g., B symptoms, or symptomatic or progressive lymphadenopathy or hepatosplenomegaly, or cytopenia caused by MCL, etc.).
ECOG performance status (PS) 0-2 (Appendix I).
Evaluable disease, i.e., ANY of the following:
Meet ALL following criteria in lab values obtained ≤ 14 days prior to registration:
Left ventricular ejection fraction by ECHO or MUGA ≥ 50% (must be within 12 months prior to registration).
Able to understand and voluntarily sign an IRB-approved informed consent form.
Willing to provide mandatory research blood, bone marrow, lymphoma biopsy tissue, and saliva specimens for correlative research.
Willing to return to enrolling institution for follow-up.
Negative serum pregnancy test done ≤ 7 days prior to registration, for persons of childbearing potential, defined as post menarche and not postmenopausal (i.e., ≥ 2 years of non-therapy-induced amenorrhea) or surgically sterile (e.g., post-hysterectomy, bilateral salpingectomy, or oophorectomy).
Persons of reproductive potential and their partners must agree to use highly effective birth control methods for the duration of study treatment and for 1 month (30 days) following the last dose of pirtobrutinib and/or venetoclax and for 12 months following the last dose of rituximab (Appendix III).
Males must agree to not donate sperms for the duration of study treatment and for 3 months following the last dose of any study drug.
Exclusion Criteria:
CNS involvement by MCL (e.g., any parenchymal, leptomeningeal, CSF, cranial nerve, or spinal cord or nerve root involvement).
Pregnant or plan to become pregnant during study treatment or within 1 month following the last dose of pirtobrutinib and/or venetoclax or within 12 months following the last dose of rituximab; or breast-feeding or plan to breastfeed during study treatment or within 1 week following the last dose of pirtobrutinib and/or venetoclax or within 6 months following the last dose of rituximab.
Malabsorption syndrome or other condition that precludes enteral route of administration.
Any of the following medication requirement or recent use:
Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
History of a bleeding disorder (e.g., hemophilia, von Willebrand disease, etc.) or active bleeding.
Active or recent infections, including but not limited to:
Uncontrolled cardiovascular disease including but not limited to:
Uncontrolled hypertension (SBP > 160 mmHg or DBP > 110 mmHg despite of 3 different classes of full dose anti-hypertensives medications) History of myocardial infarction ≤ 3 months prior to registration Unstable angina or acute coronary syndrome ≤ 2 months prior to registration New York Heart Association (NYHA) Class III or IV or symptomatic congestive heart failure or dilated cardiomyopathy Uncontrolled or symptomatic arrhythmias NOTE: Patients with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias while using the pacemaker
Prolongation of QT interval corrected for heart rate (QTcF, calculated using Fridericia's Formula: QTcF=QT/∛RR) > 470 msec.
NOTE: Correction for widened QRS complex (e.g., with pacing, or underlying bundle branch block, etc) allowed (e.g., "Adjusted QTcF" = measured QTcF - [measured QRS - 90 ms]). Correction of suspected drug induced QTcF prolongation can be attempted at the investigator's discretion and only if clinically safe to do so with either discontinuation of the offending drug or switch to another drug not known to be associated with QTcF prolongation.
History of cerebral vascular accident ≤ 6 months prior to registration.
Oxygen dependent lung disease (such as interstitial lung disease or COPD).
Ongoing inflammatory bowel disease (such as ulcerative colitis) requiring active treatment.
Psychiatric illness/social situations that would limit compliance with study requirements.
Major surgery ≤ 28 days prior to registration.
Vaccination with a live vaccine ≤ 28 days prior to registration.
Another primary malignancy (other than localized non-melanotic skin cancer or carcinoma in situ of the cervix or breast) that is not in remission or requires ongoing treatment (except for adjuvant hormonal therapy for adequately treated nonmetastatic breast or prostate cancer), or limits expected survival to ≤ 3 years.