A Phase II Study of Glofitamab Plus Polatuzumab-R-CHP for Patients With High-risk Diffuse Large B-cell Lymphoma

Inclusion Criteria:

• Previously untreated patients with CD20-positive DLBCL, including one of thefollowing diagnoses by 2016 WHO classification of lymphoid neoplasms

• DLBCL, not otherwise specified (NOS)

• T-cell/histiocyte-rich large B-cell lymphoma

• Epstein-Barr virus-positive DLBCL, NOS

• ALK-positive large B-cell lymphoma

• HHV8-positive DLBCL, NOS

• High-grade B-cell lymphoma (HGBCL), NOS

• HGBCL with translocations of MYC and BCL-2, or MYC and BCL-6

• Availability of archival (within 90 days) or freshly collected tumor tissue beforestudy enrollment. If archival tissue is unavailable or is determined to beinadequate, tumor tissue must be obtained from a biopsy performed at screening,unless an exception is given after consultation with the principal investigator.

• IPI score of 2-5

• ECOG Performance Status of 0, 1, or 2 (see Appendix A)

• Greater than or equal to 18 years at the time of signing informed consent

• Left ventricular ejection fraction (LVEF) ≥ 50% on cardiac multiple-gatedacquisition (MUGA) scan or cardiac echocardiogram (ECHO)

• Adequate hematologic function (unless due to underlying disease, as established forexample, by extensive bone marrow involvement or due to hypersplenism secondary tothe involvement of the spleen by DLBCL per the investigator), defined as follows:

• Hemoglobin ≥ 9.0 g/dL without transfusion for 14 days before first treatment

• ANC ≥ 1,000/μL

• Platelet count ≥ 75,000/μL

• Participants must have adequate organ as defined below:

• Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) or < 3 x ULNin participants with Gilbert's disease

• PT or INR > 1.5 the ULN in the absence of therapeutic anticoagulation or lupusanticoagulant

• AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional ULN

• Adequate renal function defined by serum creatinine ≤1.5 x ULN or creatinineclearance (by Cockcroft-Gault) ≥ 40 ml/min

• At least one bi-dimensionally FDG-avid measurable lymphoma lesion on PET/CT scan,defined as > 1.5 cm in its longest dimension on CT scan

• Women of childbearing potential (WOCBP) must agree to use effective contraceptionwhen sexually active. Women must remain abstinent or use methods of contraception,including at least one method with a failure rate of <1% per year, during thetreatment period and for 12 months after the final dose of pola-R-CHP, 2 monthsafter the last dose of glofitamab, and 9 months after the last dose of polatuzumabwhichever is longer. Examples of contraceptive methods with a failure rate of <1%per year include bilateral tubal ligation, male sterilization, hormonalcontraceptives that inhibit ovulation, hormone-releasing intrauterine devices, andcopper intrauterine devices. A woman is considered of childbearing potential, i.e.fertile, following menarche and until becoming post-menopausal unless permanentlysterile. Permanent sterilization methods include but are not limited tohysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausalstate is defined as no menses for continuous 12 months without an alternativemedical cause. A high follicle stimulating hormone (FSH) level in the postmenopausalrange may be used to confirm a post-menopausal state in women not using hormonalcontraception or hormonal replacement therapy. The investigator or a designatedassociate is requested to advise the patient how to achieve highly effective birthcontrol. The use of condoms by male patients is required unless the female partneris permanently sterile.

• For men: agreement to remain abstinent (refrain from heterosexual intercourse) oruse a condom, and agreement to refrain from donating sperm, as defined below: Withfemale partners of childbearing potential or pregnant female partners, men mustremain abstinent or use a condom during the treatment period and for 12 months afterthe final dose of pola-R-CHP, 2 months after the last dose of glofitamab, and 9months after the last dose of polatuzumab whichever is longer. Men must refrain fromdonating sperm during this same period. The reliability of sexual abstinence shouldbe evaluated in relation to the duration of the clinical trial and the preferred andusual lifestyle of the patient. Male patients considering preservation of fertilityshould bank sperm before study treatment.

• For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated. Patients mustbe willing to have monthly testing and antiviral therapy if indicated. Participantswith a history of hepatitis C virus (HCV) infection must have undetectable viralload.

• Ability to understand and the willingness to sign a written informed consentdocument.

Exclusion Criteria:

• Contraindication to any of the individual components of study drugs, including priorreceipt of anthracyclines, or history of severe allergic or anaphylactic reactionsto humanized or murine monoclonal antibodies, or known sensitivity or allergy tomurine products. Patients with a history of hypersensitivity to dexamethasone orsystemic corticosteroids will also be excluded

• Prior organ transplantation

• History of indolent lymphoma or current diagnosis of the following: follicularlymphoma grade 3B; B-cell lymphoma, unclassifiable, with features intermediatebetween DLBCL and classical Hodgkin lymphoma (grey-zone lymphoma); primarymediastinal (thymic) large B-cell lymphoma; Burkitt lymphoma; CNS lymphoma (primaryor secondary involvement), primary effusion DLBCL, and primary cutaneous DLBCL

• Prior therapy for DLBCL with the exception of:

• Palliative, short-term treatment with corticosteroids (up to 7 days).

• One cycle of R-CHOP

• Prior radiotherapy to the mediastinal/pericardial region

• Prior treatment with cytotoxic drugs within 5 years of screening for any condition (e.g., cancer, rheumatoid arthritis) or prior use of any anti-CD20 antibody

• Prior use of any monoclonal antibody within 3 months of the start of Cycle 1; anyinvestigational therapy within 28 days prior to the start of Cycle 1; vaccinationwith live vaccines within 28 days prior the start of Cycle 1

• Corticosteroid use > 30 mg/day of prednisone or equivalent, for purposes other thanlymphoma symptom control. Patients receiving corticosteroid treatment with ≤ 30mg/day of prednisone or equivalent for reasons other than lymphoma symptom controlmust be documented to be on a stable dose of at least 4 weeks' duration prior to thestart of Cycle 1. Patients who require lymphoma symptom control during screening mayreceive steroids in the following manner: Up to 30 mg/day of prednisone orequivalent may be used for lymphoma symptom control during screening, includingprior to finalization of staging (not included as part of pre-phase treatment). Ifglucocorticoid treatment is urgently required at higher doses for lymphoma symptomcontrol prior to the start of study treatment, tumor assessments must be completedprior to initiation of > 30 - 100 mg/day of prednisone or equivalent. Prednisone > 30 - 100 mg/day or equivalent may be given for a maximum of 7 days as a pre-phasetreatment. As part of the pre-phase treatment.

• History of other malignancies, except:

• Malignancy treated medically or surgically with curative intent and with noknown active disease present for ≥2 years before the first dose of study drug

• Adequately treated skin cancer or lentigo maligna without evidence of disease

• Adequately treated carcinoma in situ without evidence of disease.

• Localized prostate cancer and low-risk prostate cancer on active surveillance (Gleason score 6 or below, stage 1 or 2)

• In the opinion of the treating investigator, there is limited potential tointerfere with the safety or efficacy of the investigational regimen. Suchexceptions must be approved by the principal investigator.

• Lactating or pregnant. Women of childbearing potential must have a pregnancy testperformed a maximum of 7 days before the start of treatment, and a negative resultmust be documented

• Known active infection, or reactivation of a latent infection, whether bacterial,viral; or any major episode of infection requiring hospitalization or treatment withIV antibiotics (for IV antibiotics, this pertains to completion of last course ofantibiotic treatment) within 2 weeks of dosing

• Known history of HIV or HTLV-1 seropositive status. HTLV-1 testing is required forpatients from endemic countries (Japan and Melanesia and countries in the Caribbeanbasin, South America, Central America, and sub-Saharan Africa)

• Clinically significant liver disease including active viral hepatitis infection,cirrhosis, or current alcohol abuse

• Evidence of significant or uncontrolled concomitant diseases that could affectcompliance to the protocol or interpretation of the results including significant orextensive history of cardiovascular disease such as New York Heart Association ClassIII or IV or objective Class C or D cardiac disease, myocardial infarction withinthe last 6 months, unstable arrhythmias, or unstable angina, or pulmonary disease

• Known history of central nervous system or neurologic disease including stroke orintracranial hemorrhage within 3 months prior to enrollment or seizure disorder

• Grade 2 or greater peripheral neuropathy at baseline or demyelinating form ofCharcot-Marie-Tooth disease

• Major surgery within 4 weeks prior to the start or cycle 1 other than for diagnosis

• Active autoimmune disease requiring therapy. Patients with autoimmune thyroiddisease on a stable dose of thyroid replacement or type 1 diabetes on a stable doseof insulin are eligible.

• Known or suspected history of HLH.