Pilot Study of Glofitamab and Lenalidomide in Patients with Relapsed or Refractory Mantle Cell Lymphoma Previously Treated with a BTK Inhibitor

The purpose of this study is to find out whether the combination of glofitamab and
lenalidomide is an effective treatment for relapsed or refractory Mantle Cell Lymphoma

Inclusion Criteria:

- Age ≥18 years at the time of signing Informed Consent

- ECOG 0-2

- Histologic diagnosis confirmed as relapsed/refractory mantle cell lymphoma according
to WHO guidelines.

- Evidence of CD20 expression on neoplastic cells according to institutional pathology
department guidelines

- Previously treated with at least one prior line of systemic therapy for mantle cell
lymphoma. Prior BTKi failure is required. BTKi failure is defined as progression of
disease during BTKi therapy or patients must have progressed or relapsed after
completing BTK inhibitor therapy, or failed to achieve a PR following 12 weeks of
BTK inhibitor therapy.

- Presence of evaluable disease

- Adequate bone marrow and organ function:

- Absolute neutrophil count (ANC) ≥1,000 cells/mcL, unless felt to be secondary
to underlying MCL (minimum ANC 500 cells/mcL)

- Hgb ≥ 8 g/dL, unless felt to be secondary to underlying MCL (minimum Hgb 7.0
g/dL)

- Platelet count ≥50,000 cells/mcL, unless felt to be secondary to underlying MCL
(minimum platelet count 25,000 cells/mcL)

- Renal function assessed by calculated Cockcroft-Gault creatinine clearance
(CrCl; see Appendix A) ≥ 50 ml/min. See lenalidomide Treatment Plan, (Table
10-1), for lenalidomide dose adjustment for CrCl ≥ 30 mL/min and < 60 mL/min

- Adequate hepatic function as determined by:

- Total bilirubin ≤1.5X upper limit of normal (ULN) unless secondary to Gilbert's
syndrome or documented liver involvement by lymphoma. Patients with Gilbert's
syndrome or documented liver involvement by lymphoma may be included if their total
bilirubin is ≤ 5 x ULN

- Aspartate aminotransferase (AST, SGOT) and alanine aminotransferase (ALT, SGPT) ≤ 3
x ULN or ≤ 5 x ULN in cases of documented liver involvement.

- Willingness to receive adequate prophylaxis and/or therapy for thromboembolic
events, unless contraindicated in the opinion of the investigator.

- Willingness to undergo confirmatory procedures for assessment of disease status and
experimental studies as required by protocol, including bone marrow (BM)
aspiration/biopsy and gastrointestinal endoscopy/colonoscopy with biopsy, and/or
biopsy of other tissue when appropriate and medically feasible.

- Each patient must sign an informed consent form indicating that he or she
understands the purpose of and procedures required for the study and are willing to
participate.Patients with impaired decision-making capacity (IDMC) who have a
legally authorized representative (LAR) or caregiver and/or family member available
will also be eligible.

- Willingness of patients who can become pregnant, according to Revlimid/lenalidomide
Risk Evaluation and Mitigation Strategy (REMS) criteria, to undergo pregnancy
testing in accordance with REMS requirements

- Willingness of all patients to complete surveys and adhere to contraception
requirements mandated by the Revlimid/lenalidomide REMS

- For women of childbearing potential: Agreement to remain abstinent (refrain from
heterosexual intercourse) or use two adequate methods of contraception, including at
least one method with a failure rate of <1% per year, for at least 28 days prior to
Day 1 of Cycle 1, during the treatment period (including periods of treatment
interruption), and for at least 2 months after the final dose of glofitamab, 28 days
after the last dose of lenalidomide, 18 months after the last dose of obinutuzumab.

- 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 or pregnant female partners,
men must remain abstinent or use a condom during the treatment period and for at
least 2 months after the final dose of glofitamab, 28 days after last dose of
lenalidomide, 6 months after the last dose of obinutuzumab. Men must refrain from
donating sperm during this same period.

- Life expectancy ≥ 12 weeks as determined by patient's primary clinician

Exclusion Criteria:

- Investigational agent or anticancer therapy within 5 half-lives prior to start of
study therapy except therapeutic monoclonal antibody treatment must be discontinued
a minimum of 4 weeks prior to study therapy. An exception is BTKi therapy, which can
be continued to prevent disease flare up until 1 day prior to start of study
therapy.

- Major surgery within 4 weeks prior to planned start of study therapy.

- Radiotherapy within 7 days of the start of study therapy.

- CART infusion within 30 days prior to Day 1 of Cycle 1

- Active hepatitis B or C, as defined below:

- HBV surface antigen positive

- HBV surface antigen negative, HBV core antibody positive and detectable HBV
viral DNA. Note: subjects who are HBV core antibody positive and viral DNA
negative are eligible.

- HCV antibody positive and HCV RNA positive.

- History of human immunodeficiency virus (HIV) unless all of the following criteria
are met:

- CD4+ T cell count ≥ 250 cells/mcL

- No acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections
within 1 year prior to signing Informed Consent Form

- Stable (no change in regimen for ≥ 4 weeks) and effective antiretroviral
regimen, and HIV viral load < 400 copies/mL within 4 weeks prior to signing
Informed Consent form

- Active concurrent malignancy requiring active therapy within the last 3 years with
the exception of basal cell carcinoma limited to the skin, squamous cell carcinoma
limited to the skin, carcinoma in situ of the cervix or breast, adequately treated
lentigo maligna melanoma, or localized prostate cancer. Adjuvant or maintenance
therapy to reduce the risk of recurrence of other malignancy previously treated for
curative intent is permitted.

- Pregnant or lactating, intending to become pregnant, or unable/unwilling to comply
with pregnancy testing and birth control measures and REMS enrollment, as described
in inclusion criteria.

- Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection
(excluding fungal infections of nail beds) at study enrollment, or any major episode
of infection requiring treatment with IV antibiotics or hospitalization (relating to
the completion of the course of antibiotics) within 4 weeks prior to cycle 1, day 1.

- Clinically significant history of liver disease, including active viral or other
hepatitis or current uncontrolled alcohol use disorder that would compromise
patient's ability to safely participate in the trial, per clinician's judgment

- Active central nervous system (CNS) involvement with lymphoma, either parenchymal or
leptomeningeal

- Presence of ≥Grade 2 toxicity (CTCAE v5.0) due to prior cancer therapy

- History of severe allergic or anaphylactic reactions to monoclonal antibody therapy
(or recombinant antibody-related fusion proteins)

- Patient with history of confirmed progressive multifocal leukoencephalopathy (PML)

- History of hypersensitivity to compounds of similar biological or chemical
composition to IMiDs® and/or the excipients contained in the study drug formulations

- Previous treatment with bispecific antibody therapy directed against CD20 and CD3

- Previous treatment with lenalidomide or other IMiDs® within 12 months of treatment
initiation on this study.

- Documented refractoriness to lenalidomide, defined as no response (PR or CR) within
6 months of therapy

- Autologous stem cell transplantation (ASCT) within the period ≤3 months prior to the
signing of the informed consent form. Patients with a more distant history of ASCT
must exhibit full hematologic recovery before enrollment into the study

- Allogenic stem cell transplantation within the period of ≤3 months prior to signing
of the Informed Consent form, evidence of graft-versus-host-disease (GVHD), or
receiving active immunosuppression for GVHD.

- A history of deep venous thrombosis/embolism, threatening thromboembolism or known
thrombophilia or are at a high risk for a thromboembolic event in the opinion of the
investigator and who are not willing/able to take venous thromboembolic event
prophylaxis during the entire treatment period

- Concurrently use other anticancer or experimental treatments

- Administration of a live vaccine within 28 days prior to the start of study
treatment (Cycle 1 Day 1).

- Prior treatment with systemic immunosuppressive medications (including, but not
limited to, cyclophosphamide, azathioprine, methotrexate, thalidomide, and
anti-tumor necrosis factor agents), within 2 weeks or five half-lives (whichever is
shorter) prior to first dose of study treatment

- Corticosteroid therapy within 2 weeks prior to first dose of study treatment, with
the following exceptions:

- Short course systemic corticosteroids (total daily dose equivalent of
prednisone 100mg or dexamethasone 20 mg) is permissible for disease control,
improvement of performance status, or non-cancer indication if administered for
≤ 5 days, and must be discontinued prior to study initiation of study
treatment. When clinically indicatedfeasible, tumor assessments such as imaging
and biopsies should be performed prior to steroid administration, though this
is not required for enrollment.

- Chronic corticosteroid use of ≤20 mg prednisone equivalent per day, on a stable
dose for ≥4 weeks prior to registration.

- Any life-threatening illness, medical condition, or organ system dysfunction that,
in the opinion of the investigator, could compromise the subject's safety, or affect
compliance with the protocol or interpretation of results.

- 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 or
Objective Assessment Class C or D cardiac disease, myocardial infarction ≤ 6 months
from registration, symptomatic congestive heart failure, unstable arrhythmia, or
unstable angina) or significant pulmonary disease (such as obstructive pulmonary
disease or history of bronchospasm)