PRIMARY OBJECTIVE:
I. To evaluate the end of induction (EOI) complete response rate (CR) for treatment with the
regimen of rituximab and hyaluronidase human + polatuzumab vedotin + venetoclax (RSC + Pola +
Ven) in relapsed/refractory mantle cell lymphoma (MCL).
SECONDARY OBJECTIVES:
I. To evaluate the EOI overall response rate (ORR) for the combination of RSC + Pola + Ven in
relapsed/refractory MCL.
II. To evaluate the best response (CR, partial response [PR]) in patients who continue on to
maintenance therapy and evaluate the improvement in the depth of response.
III. To evaluate the progression free survival (PFS) and overall survival (OS) for the
combination of RSC + Pola + Ven) in relapsed/ refractory MCL.
IV. To compare the ORR, CR, PFS, and OS in ibrutinib refractory compared to ibrutinib naive
patients.
V. To evaluate regimen-related toxicity for patients treated with RSC + Pola + Ven.
CORRELATIVE RESEARCH OBJECTIVES:
I. To evaluate changes in minimal residual disease (MRD) status in both responding and
non-responding patients at EOI and end of maintenance and compared to baseline as well as
correlate MRD status with PFS and OS.
II. To evaluate changes in systemic immune profiles and T cell activation induced by
treatment with RituxSC (RSC) + Pola + Ven.
III. To evaluate the prognostic importance of high risk cytogenetic alterations, and other
risk stratification scores in patients with relapsed/refractory MCL receiving RituxSC + Pola
+ Ven.
OUTLINE:
INDUCTION: Patients receive rituximab intravenously (IV) on day 1 of cycle 1 and rituximab
and hyaluronidase human subcutaneously (SC) over 5 minutes on day 1 of cycles 2-6. Patients
also receive polatuzumab vedotin IV over 30-90 minutes on day 1 and venetoclax orally (PO)
daily on days 1-21. Treatment repeats every 21 days for up to 6 cycles in the absence of
disease progression or unacceptable toxicity.
MAINTENANCE: Patients receive venetoclax PO daily and rituximab and hyaluronidase human SC
over 5 minutes every 60 days for up to 1 year in the absence of disease progression or
unacceptable toxicity.
After completion of study treatment, patients are followed up every 90 days for up to 5
years.
Inclusion Criteria:
- Pathologically confirmed relapsed or primary refractory mantle cell lymphoma with
concurrent or prior tissue sample immunohistochemistry (IHC) positive for cyclin D1 or
that is positive for fluorescence in situ hybridization (FISH) or cytogenetics for
t(11;14)
- NOTE: Safety Portion only: MCL or indolent B cell non-Hodgkin lymphoma (NHL)
(follicular lymphoma [FL] [grades I-IIIa] marginal zone lymphoma [MZL]), or,
small lymphocytic lymphoma (SLL) stratified as low risk for tumor lysis syndrome
(TLS), relapsed or progressed after at least two lines of therapy (or one BTK
inhibitor containing line of therapy). No limit to prior lines of therapy
- NOTE: Expansion Portion only: MCL relapsed or progressed after at least two lines
of therapy or one BTK inhibitor line of therapy. Prior autologous stem cell
transplant (AutoSCT) is allowed. No limit to number of prior therapies. May have
received prior BTK inhibitor therapy
- Measurable disease as defined with at least one lesion measuring >= 1 x 1.5 cm
- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
- Absolute neutrophil count (ANC) >= 1000/mm^3 (obtained =< 14 days prior to
registration)
- Platelet count >= 75,000/mm^3 (obtained =< 14 days prior to registration)
- Hemoglobin >= 9.0 g/dL (obtained =< 14 days prior to registration)
- International normalized ratio =< 1.5 x upper limit of normal (ULN) for patients not
receiving therapeutic anticoagulation (obtained =< 14 days prior to registration)
- Partial thromboplastin time (PTT) or activated PTT (aPTT) =< 1.5 x ULN (obtained =< 14
days prior to registration)
- Calculated creatinine (Cr) clearance >= 45 ml/min using the modified Cockcroft-Gault
formula (obtained =< 14 days prior to registration)
- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 2.5 x ULN
(obtained =< 14 days prior to registration)
- Total bilirubin < 1.5 x ULN (or =< 3 x ULN for patients with documented Gilbert
syndrome) (obtained =< 14 days prior to registration)
- Negative serum pregnancy test done =< 7 days prior to registration, for women of
childbearing potential only
- Able to provide informed written consent, and ability to comply with study related
procedures
- Willing to return to enrolling institution for follow-up (during the Active Monitoring
Phase of the study)
- Willing to provide tissue samples for mandatory correlative research
- For women of childbearing potential: agreement to remain abstinent (refrain from
heterosexual intercourse) or use a contraceptive method with a failure rate of < 1%
per year during the treatment period and for at least 30 days after the last dose of
venetoclax or 18 months after the last dose of rituximab and hyaluronidase human,
whichever is longer. For men: agreement to remain abstinent (refrain from heterosexual
intercourse) or use contraceptive measures, and agreement to refrain from donating
sperm, as defined below:
- With female partners of childbearing potential, men must remain abstinent or use
a condom plus an additional contraceptive method that together result in a
failure rate of < 1% per year during the treatment period and for at least 6
months after the last dose. Men must refrain from donating sperm during this same
period.
- With pregnant female partners, men must remain abstinent or use a condom during
the treatment period and for at least 6 months after the last dose to avoid
exposing the embryo
Exclusion Criteria:
- Any of the following because this study involves an investigational agent whose
genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are
unknown:
- Pregnant women
- Nursing women
- Men or women of childbearing potential who are unwilling to employ adequate
contraception
- 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
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements
- Receiving any other investigational or chemotherapeutic agent which would be
considered as a treatment for the primary neoplasm
- Known CD20-negative status at relapse or progression
- Prior allogeneic SCT
- Completion of autologous SCT =< 100 days prior to registration
- Radioimmunoconjugate =< 12 weeks prior to registration
- Monoclonal antibody or antibody-drug conjugate (ADC) therapy within 5 half-lives or 4
weeks prior to registration, whichever is longer
- Radiotherapy, chemotherapy, hormonal therapy, or targeted small-molecule therapy
within 2 weeks prior to registration (with the exception of ibrutinib to prevent tumor
flare, patients taking ibrutinib who are progressing must discontinue ibrutinib 2
half-lives or 2 days prior to initiating protocol therapy)
- Clinically significant toxicity (other than alopecia) from prior therapy that has not
resolved to grade =< 2 (per National Cancer Institute [NCI] Common Terminology
Criteria for Adverse Events [CTCAE] version [v]5.0) prior to registration
- Current grade > 1 peripheral neuropathy
- Any history of central nervous system (CNS) lymphoma or leptomeningeal infiltration
- Treatment with systemic corticosteroids > 20 mg/day prednisone or equivalent Patients
who are receiving corticosteroids =< 20 mg/day, prednisone or equivalent, for
non-lymphoma treatment reasons must be documented to be on a stable dose for at >= 4
weeks prior to registration. If corticosteroid treatment is urgently required for
lymphoma symptom control prior to the start of study treatment, up to 100 mg/day of
prednisone or equivalent can be given for a maximum of 5 days, but all tumor
assessments must be completed prior to start of corticosteroid treatment
- History of severe allergic or anaphylactic reaction or known sensitivity to humanized
or murine monoclonal antibodies rituximab, polatuzumab vedotin, and venetoclax
- Active bacterial, viral, fungal, or other infection
- Requirement for warfarin treatment (because of potential drug-drug interactions [DDIs]
that may increase the exposure of warfarin)
- Treatment with the following agents =< 7 days prior to registration
- Strong and moderate CYP3A inhibitors such as fluconazole, ketoconazole, and
clarithromycin
- Strong and moderate CYP3A inducers such as rifampin and carbamazepine. If taking
proton pump inhibitors willing to avoid co-administration and stagger venetoclax
dosing
- Consumption of grapefruit, grapefruit products, Seville oranges (including marmalade
that contains Seville oranges), or star fruit =< 3 days prior to registration
- Clinically significant history of liver disease, including viral or other hepatitis,
current alcohol abuse, or cirrhosis
- Active hepatitis B or hepatitis C infection. Patients who have been successfully
treated and cleared their virus as evidenced a negative hepatitis (Hep) B or Hep C
polymerase chain reaction (PCR) are eligible
- Known history of human immunodeficiency virus (HIV) positive status or known infection
with human T-cell leukemia virus 1. For patients with unknown HIV status, HIV testing
will be performed at screening if required by local regulations
- History of PML (progressive multifocal leukoencephalopathy)
- Vaccination with a live virus vaccine =< 28 days prior to registration
- History of other malignancy that could affect compliance with the protocol or
interpretation of results, with the exception of the following: curatively treated
carcinoma in situ of the cervix, good-prognosis ductal carcinoma in situ of the
breast, basal- or squamous-cell skin cancer, stage I melanoma, or low-grade,
early-stage localized prostate cancer
- Any previously treated malignancy that has been in remission without treatment for =<
3 years prior to registration
- Evidence of any significant, uncontrolled concomitant disease that could affect
compliance with the protocol or interpretation of results, including significant
cardiovascular disease (such as New York Heart Association class III or IV cardiac
disease, myocardial infarction within the previous 6 months, unstable arrhythmia, or
unstable angina) or significant pulmonary disease (such as obstructive pulmonary
disease or history of bronchospasm)
- Major surgical procedure other than for diagnosis =< 28 days prior to day 1 of cycle
1, or anticipation of a major surgical procedure during the course of the study
- Inability or unwillingness to swallow pills
- History of malabsorption syndrome or other condition that would interfere with enteral
absorption
- History of inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis) or
active bowel inflammation (e.g., diverticulitis)
