A Phase 2 Trial of Mosunetuzumab and Zanubrutinib for Patients With Relapsed/Refractory Marginal Zone Lymphoma

To assess the efficacy and safety of mosunetuzumab combined with zanubrutinib in patients with relapsed or refractory MZL.

Primary Objectives:

To determine the safety and efficacy of mosunetuzumab in combination with zanubrutinib as determined by best complete response (CR) rate of combination treatment for patients with relapsed or refractory marginal zone lymphoma (MZL).

Secondary Objectives:

To determine best overall response rate (ORR), duration of response (DOR), time to next treatment, progression-free survival (PFS), overall survival (OS), and evaluation of tolerability of mosunetuzumab and zanubrutinib as treatment for patients with relapsed/refractory MZL.

Exploratory Objective:

To determine the impact of total metabolic tumor volume to ORR, CR rate and survival outcomes

To determine the biomarkers that correlates with response and mechanisms of resistance to mosunetuzumab and zanubrutinib in relapsed/refractory MZL.

To determine the surrogate endpoint for future trials in MZL.

Eligibility Criteria:
Inclusion Criteria:

Histologically diagnosed marginal zone lymphoma (any subtypes) Low grade lymphoma unclassifiable is also eligible Have received at least 1 prior treatment including CD20 monoclonal antibody Stage II, III or IV disease Age ≥18 years. Because no dosing or adverse event data are currently available on the use of mosunetuzumab and zanubrutinib combination in patients \<18 years of age, children are excluded from this study.

Performance status ≤2 on the ECOG scale (≤3 if due to lymphoma) Requiring systemic therapy assessed by investigator based on tumor size, symptoms and/or GELF criteria42 A nodal or extranodal (except spleen) mass \> 7 cm in its greater diameter At least 3 nodal or extranodal sites ≥ 3 cm in diameter Presence of at least one B symptom Fever (\>38 ℃), night sweats, weight loss \> 10% in the past 6 months Symptomatic splenomegaly (or size \>13cm) Impending organ compression or involvement (ureteral, orbital, gastrointestinal) Any of the following cytopenias due to bone marrow involvement of lymphoma Hemoglobin ≤ 10 g/dL Platelets ≤ 100 x 109/L Absolute neutrophil count (ANC) \< 1.5x109/L Pleural effusion or ascites LDH \> ULN or β2 microglobulin \> ULN Bi-dimensionally measurable disease, with at least one nodal lesion ≥ 1.5 cm or one extra-nodal lesion \> 1 cm in longest diameter by CT, PET/CT, and/or MRI Subjects with splenic MZL who do not meet the radiographically measurable disease criteria are eligible for participation is spleen is enlarged over 16 cm and MZL is histologically confirmed by bone marrow biopsy or peripheral blood flow cytometry Subjects with EMZL such as skin of conjunctival EMZL who do not meet the radiographically measurable disease criteria are eligible for participation if at least one of the skin lesions is histologically confirmed as MZL and measures ≥1.5 cm in diameter

Patients must have adequate organ and marrow function as defined below:

Total bilirubin ≤ 1.5 institutional ULN, unless consistent with Gilbert's (ratio between total and direct bilirubin \> 5) AST (SGOT) and ALT (SGPT) ≤ 3 x institutional ULN Alkaline phosphatase \< 2.5 ULN Creatinine clearance ≥ 40 ml/min calculated by modified Cockcroft-Gault formula Blood counts below if without lymphoma cause for cytopenia Hemoglobin ≥ 8 g/dL Platelets ≥ 75 x 109/L Absolute neutrophil count (ANC) ≥ 1.0x109/L\* \*Growth factor permitted during screening Blood counts below if cytopenia are due to lymphoma (such as bone marrow involvement or splenomegaly) Hemoglobin ≥ 6 g/dL (no transfusion within 7 days prior to treatment) Platelets ≥ 50 x 109/L Absolute neutrophil count (ANC) ≥ 0.5x109/L All subjects must Have an understanding that the study drug could have a potential teratogenic risk.

Agree to refrain from donating blood while on study treatment, during dose interruptions and for at least 28 days following the last dose of study treatment.

Agree not to share study medication with another person. Sign an informed consent document indicating that they understand the purpose of and procedures required for the study, including biomarkers, and are willing to participate in the study.

Females must agree to abstain from breastfeeding during study participation and for at least 12 months after treatment discontinuation.

Females of childbearing potential (FCBP§) must:

Have one negative pregnancy tests via serum or urine prior to starting study therapy.

Not engaging in sexual activity for the total duration of the trial and the drug washout period is an acceptable practice. Otherwise, she must agree to use, and be able to comply with two forms of contraception: one highly effective, and one additional effective (barrier) measure of contraception without interruption 28 days prior to starting mosunetuzumab, during the study treatment (including dose interruptions), and for at least 3 months after the completion of treatment.

Approved methods of birth control are as follows: Hormonal contraception (i.e. birth control pills, injection, implant, transdermal patch, vaginal ring), Intrauterine device (IUD), Tubal Ligation or hysterectomy, Subject/Partner post vasectomy, Implantable or injectable contraceptives, and condoms plus spermicide. Not engaging in sexual activity for the total duration of the trial and the drug washout period is an acceptable practice; however periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.

Male subjects must:

A male subject who is sexually active with a female with reproductive potential must agree to use a barrier method of birth control, eg, either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/ suppository (including dose interruptions), even if they have undergone a successful vasectomy, from the time of signing consent and for at least 3 months after the completion of treatment. A male subject must agree not to donate sperm or semen, while taking treatment, during breaks (dose interruptions), and for at least 3 months after the completion of treatment.

Sign an informed consent document indicating that they understand the purpose of and procedures required for the study, including biomarkers, and are willing to participate in the study.

The investigator is responsible for: ensuring that the patient understands the potential risks and benefits of participating in the study; ensuring that informed consent is given by each patient, this includes obtaining the appropriate signatures and dates on the informed consent document prior to the performance of any study procedures and prior to the administration of study treatment; answering any questions the patient may have throughout the study and sharing in a timely manner any new information that may be relevant to the patient's willingness to continue his or her participant in the trial. Subjects will undergo a brief physical exam including a brief exam to determine cognitive review. No one without capacity to personally consent will be enrolled. Patients have medical decision-making capacity if they can demonstrate understanding of the situation, appreciation of the consequences of their decision, and reasoning in their thought process, and if they can communicate their wishes.

A determination of lack of decision-making capacity shall be made after an appropriate medical evaluation that concludes there is little or no likelihood that the participant will regain decision-making capacity in a reasonable period of time.

§A FCBP is a female who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy, or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months).

Exclusion Criteria:

Known active central nervous system lymphoma or leptomeningeal disease. Treatment with any chemotherapeutic agent, or treatment with any other anti-lymphoma agent (investigational or otherwise) within 4 weeks or five half-lives of the drug, whichever is shorter, prior to first investigational agent administration.

Any prior history of other malignancy besides B-NHL, unless the patient has been free of disease for ≥ 3 years and felt to be at low risk for recurrence by the treating physician, except:

Adequately treated localized skin cancer without evidence of disease. Adequately treated cervical carcinoma in situ without evidence of disease. Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of lenalidomide capsules, or put the study outcomes at undue risk.

Uncontrolled human immunodeficiency virus (HIV), or active Hepatitis C Virus, or active Hepatitis B Virus infection, or any uncontrolled active significant infection, including suspected or confirmed JC virus infection and SARS-CoV2.

Patients with inactive hepatitis B infection must adhere to hepatitis B reactivation prophylaxis unless contraindicated. Hepatitis B or C serologic status: subjects who are hepatitis B core antibody (anti-HBc) positive and who are surface antigen negative will need to have a negative polymerase chain reaction (PCR). Those who are hepatitis B surface antigen (HBsAg) positive or hepatitis B PCR positive will be excluded. Subjects who are hepatitis C antibody positive will need to have a negative PCR result. Those who are hepatitis C PCR positive will be excluded. Subjects with a history of Hepatitis C who received antiviral treatment are eligible as long as PCR is negative.

History of immunodeficiency (with the exception of hypogammaglobulinemia) or concurrent systemic immunosuppressant therapy (e.g., cyclosporine, tacrolimus, etc., or chronic administration glucocorticoid equivalent of \>10mg/day of prednisone) within 28 days of the first dose of study drug with exception of steroid used for IV contrast allergy. In addition, use of inhaled, topical, intranasal corticosteroids or local steroid injection (eg, intra- articular injection) is permitted.

Requires chronic treatment with strong CYP3A inhibitors (List in Table 1). However, patients can be eligible after discontinuation of the perpetrator and a sufficient washout period of 7-days or 5 half-lives, whichever is longer. Patients also can be potentially eligible with dose reduction of zanubrutinib through the discussion with primary investigator and medical monitor.

Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification. Subjects with controlled, asymptomatic atrial fibrillation during screening can enroll on study Significant screening electrocardiogram (ECG) abnormalities including 2nd degree atrioventricular (AV) block, type II AV block, or 3rd degree block.

Active bleeding or known bleeding diathesis (e.g., von Willebrand's disease) or hemophilia History of stroke or intracranial hemorrhage within 6 months prior to study entry.

Lactating or pregnant subjects. Administration of any investigational agent within 28 days of first dose of study drug.

Patients who have undergone major surgery within 28 days or minor surgery within 3 days of first dose of study drug.

Patients taking corticosteroids during the last 4 weeks, unless administered at a dose equivalent to \< 10 mg/day prednisone (over these 4 weeks).

Known or suspected chronic active Epstein-Barr virus (CAEBV) infection Administration of a live, attenuated vaccine within 4 weeks before first mosunetuzumab administration or anticipation that such a live, attenuated vaccine will be required during the study Prior solid organ transplantation Prior allogeneic stem cell transplant (autologous stem cell transplants are allowed if conducted at least 100 days prior to C1D1.) Contraindication to tocilizumab Patients who have difficulty with or are unable to swallow oral medication, or have disease significantly affecting gastrointestinal function that would limit absorption of oral medication.

Patients who have an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.

Patients who have a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.