A Phase 3 Randomized, Open-Label, Multicenter Study Comparing Zanubrutinib (BGB-3111) plus Rituximab Versus Bendamustine plus Rituximab in Patients with Previously Untreated Mantle Cell Lymphoma Who Are Ineligible for Stem Cell Transplantation

Mantle cell lymphoma (MCL) is diagnosed in 0.51-0.55/100,000 persons per year
in the United States of America, making up 6% of all non-Hodgkin lymphoma
(NHL), with a similar incidence rate worldwide (Smedby and Hjalgrim, 2011; Wang
et al, 2015). MCL is a cancer of older persons with a median age at diagnosis
of approximately 70 years (Sharman et al, 2017, Dreyling et al, 2017) and a
male preponderance of roughly 2.5:1 (Barista et al, 2001; Smedby and Hjalgrim,
2011). Patients usually present with advanced disease; 70% are diagnosed in
stage IV. Most commonly, there is generalized lymphadenopathy and organomegaly.
Approximately 10-20% of patients present with bone marrow involvement, and B
symptoms (fever, night sweats, and weight loss) are present in approximately
40% of patients. Extranodal involvement of the gastrointestinal tract,
particularly the colon, is common, but central nervous system involvement is
uncommon (Skarbnik and Goy, 2015).The diagnosis is based on
pathological assessment with typical immunophenotype of CD5+, CD20+, CD43+,
CD23-/+,cyclin D1+, and CD10-/+ (NCCN Guideline, 2018).
In addition to the classic MCL immunophenotype of CD20+, the pathognomonic
feature of MCL is overexpression of cyclin D1, which is a consequence of
juxtaposition of the proto-oncogene CCND1 on chromosome 11q13 to the
immunoglobulin (Ig) heavy chain gene at chromosome 14q32. Cyclin D1 can be
confirmed by immunohistochemistry in almost 100% of specimens. The molecular
consequence of cyclin D1 overexpression is deregulation of cell cycle control
by overcoming the suppressor effect of the retinoblastoma 1 (RB1) and the cell
cycle inhibitor p27. Frequent companion anomalies include secondary chromosomal
and molecular alterations targeting proteins that regulate the cell cycle and
senescence (B lymphoma Mo-MLV insertion region 1 homolog [BMI1], inhibitor of
kinase 4a [INK4a], alternate reading frame [ARF], cyclin D-dependent kinase
[CDK]4, and RB1), and interfere with the cellular response to deoxyribonucleic
acid (DNA) damage (ataxia telangiectasia mutated [ATM]), checkpoint kinase 2
[CHK2] and p53) (Rickert, 2013). Concomitantly, β2 microglobulin and lactate
dehydrogenase (LDH) are increased in 56% and 45% of patients, respectively;
these markers should be monitored for disease activity and are also prognostic.
The Mantle Cell Lymphoma International Prognostic Index (MIPI) is composed of
the parameters of the Eastern Cooperative Oncology Group (ECOG) performance
status, age, leukocyte count, and LDH, and classifies patients into low,
intermediate, and high-risk groups, with corresponding median overall survival
(OS) time of 72 months, 51 months, and 29 months, respectively (Vose, 2013).
The histological pattern of MCL is also prognostic, with complete response (CR)
rates of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for
mantle-zone/nodular/diffuse patterns of 73%, 25%, and 19%, respectively, and 3
year survival rates of 100%, 50%, and 55%, respectively (Barista, 2001).
Another prognostic factor is the expression of the proliferation-associated
antigen Ki-67; 60% of patients have over 10% of their tumors staining positive
for Ki-67, with highly proliferative cases showing a much poorer outcome than
tumors with low proliferation.
Management of MCL has been with chemo-immunotherapeutic combinations, most
commonly rituximab-CHOP (R-CHOP) or bendamustine plus rituximab (BR)
combinations that result in high response rates; however, patients invariably
relapse (Rummel et al, 2013; Kluin-Nelemans et al, 2012). Younger, fit
patients have the option of high intensity chemotherapy, such as
hyper-fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone
(hyper- CVAD), or induction chemotherapy followed by stem cell transplantation,
with many patients achieving prolonged remissions (Dreyling et al, 2005;
Romaguera et al, 2005). Among the available therapies, the BR combination has
demonstrated better tolerability with lower rates of hematological toxicities,
infections, peripheral neuropathy, alopecia, and stomatitis when compared with
R-CHOP. Furthermore, the BR combination also showed better efficacy in that
median progression-free survival of BR is significantly longer than R-CHOP
(69.5 months versus 31.2 months; p < 0.0001) in treatment-naive MCL patients
(Rummel et al, 2013; Flinn et al, 2014). Combination therapy with bendamustine
and rituximab has become one of the most used first-line regimens for MCL,
given the recent evidence showing longer progression-free survival with this
combination than with R-CHOP (35.4 versus. 22.1 months); and a better safety
profile (Martin et al, 2021). However, elderly patients and those with
comorbidities that preclude treatment with standard chemoimmunotherapy regimens
and stem cell transplantation have few options, and treatment is largely
palliative. No standard approach to treatment has been defined for these
patients (Dreyling et al, 2017).
Additionally, there is as yet no conclusive evidence that rituximab maintenance
therapy following a combination of rituximab and bendamustine treatment
provides a benefit in MCL. In an ongoing study of 120 patients with previously
untreated stage II (with bulky disease > 7 cm), III or IV MCL treated with up
to 6 cycles of rituximab and bendamustine followed by 1:1 randomization to
either rituximab maintenance (375 mg/m2 every 2 months for a total of 2 years)
or observation only arms, after a median time of observation of 4.5 years, no
significant difference in progression-free survival (PFS) could be observed
between the 2 arms (p=0.130, 47 events, hazard ratio [HR] 0.64, 95% CI:
0.73-1.14). The median for rituximab maintenance was not yet reached, whereas
for the observation arm the median was 54.7 months (95% CI: 40.1. - not yet
reached). There was no difference in OS between arms (p = 0.271, 27 events, HR
1.53, 95% CI 0.73 - 3.32) with a median of 69.6 months for rituximab
maintenance versus a median not yet reached in the observation arm (Rummel et
al, 2016). National Comprehensive Cancer Network (NCCN) guidelines currently
recommend against rituximab maintenance following bendamustine-based therapy
for mantle cell lymphoma (NCCN v5.2018).

This study has been transitioned to CTIS with ID 2023-509908-15-00 check the CTIS register for the current data.

All primary and secondary objectives will compare zanubrutinib (also known as
BGB-3111) plus rituximab followed by zanubrutinib monotherapy versus
bendamustine plus rituximab followed by observation only.
Primary:
• To compare efficacy, as measured by progression-free survival (PFS)
determined by independent central review

Secondary:
• To evaluate efficacy, as measured by the following:
- Progression-free survival determined by investigator assessment
- Overall response rate (ORR), as determined by independent central review and
by investigator assessment
- Duration of response (DOR), as determined by independent central review and
by investigator assessment
- Overall survival (OS)
- Rate of complete response (CR) or complete metabolic response determined by
independent central review and by investigator assessment
- Time to response, as determined by independent central review and by
investigator assessment
- Patient reported outcomes
- To evaluate safety and tolerability

Exploratory:
- To evaluate the pharmacokinetics (PK) of zanubrutinib (zanubrutinib plus
rituximab arm only) when co administered with rituximab
- To evaluate the correlation of certain pathologic features (eg, Ki-67) and
molecular characteristics (including but not limited to mutations in genes and
pathways of the cell cycle and senescence, DNA damage response, and cell
survival) with rate of CR or complete metabolic response, ORR, DOR, and PFS
- To evaluate the mechanisms of resistance to zanubrutinib

This is an international, multicenter, Phase 3, open-label, randomized,
active-controlled study of zanubrutinib plus rituximab followed by zanubrutinib
monotherapy versus bendamustine plus rituximab followed by observation in
approximately 500 patients with previously untreated mantle cell lymphoma (MCL)
who are ineligible for stem cell transplantation due to age or comorbidities.
The primary efficacy endpoint is PFS as determined by independent central
review. Disease response will be assessed per the Lugano Classification for
Non-Hodgkin Lymphoma (NHL) (Cheson et al, 2014), hereafter referred to as
Lugano Classification for NHL.
Central randomization (1:1) will be used to assign patients to one of the
following study drug treatments:
• Arm A: zanubrutinib plus rituximab for 6 cycles, followed by zanubrutinib
monotherapy
• Arm B: bendamustine plus rituximab for 6 cycles, followed by observation
Randomization will be stratified by MCL International Prognostic Index (MIPI)
score (low vs. intermediate or high), age (>= 70 years vs. < 70 years), and
geographic region (North America/Europe and Asia-Pacific region).

Study treatment must commence within 5*days after randomization. Each cycle of
zanubrutinib and rituximab or bendamustine and rituximab consists of 28 days.
Study drug treatments will be administered as follows, depending on treatment
assignment:
In Arm A, zanubrutinib will be administered as two 80-mg capsules orally twice
a day (160 mg twice a day) with or without food. Rituximab will be
administered intravenously at a dose of 375 mg/m2 on Day 1 of Cycles 1 to 6
only. Zanubrutinib will be administered prior to the start of rituximab
infusion. For patients considered by the investigator to be at high risk for
infusion reaction, rituximab may be administered by split dosing over more than
one day for the first and/or subsequent cycles as per institutional guidelines.
(NOTE: Rituximab split dosing is not available in Japan based on local
labeling). Following completion of Cycle 6, patients in Arm A will continue on
zanubrutinib monotherapy until disease progression, withdrawal of consent,
death, lost to follow-up, or end of study, whichever occurs first. Following
disease progression, subjects will be followed further for survival and
subsequent MCL therapies.

In Arm B, bendamustine will be administered intravenously at a dose of 90
mg/m2/day on Days 1 and 2 of Cycles 1 to 6, and rituximab will be administered
intravenously at a dose of 375 mg/m2 on Day 1 of Cycles 1 to 6. Following
completion of Cycle 6, patients in Arm B will receive no further treatment but
will continue to be observed (including assessments for safety and efficacy)
until disease progression, withdrawal of consent, death, lost to follow up, or
end of study, whichever occurs first. Following disease progression, subjects
will be followed further for survival and subsequent MCL therapies.

• Arm A: zanubrutinib plus rituximab for 6 cycles, followed by zanubrutinib
monotherapy
• Arm B: bendamustine plus rituximab for 6 cycles, followed by observation

Rituximab is given by intravenous (IV) infusion

Zanubrutinib is an experimental agent and therefore it is not known if
zanubrutinib will have any direct benefit to the patient. Taking part in this
medical scientific research may or may not improve the patient's health. Even
if there is no direct benefit others may benefit from what is learned from this
study.

Disadvantages of participation in the study may be:
- possible side effects/complications of the intervention;
- possible adverse effects/discomforts of the measurements in the study.

Participation in the study also means:
- additional time;
- an additional or an extended hospitalization;
- additional testing;
- that the patient has appointments to attend;