A Ph2 Study of Glofitamab Alone or With Polatuzumab Vedotin, Pirtobrutinib, or Atezolizumab in Richter's Transformation

Inclusion Criteria:

• Must have a confirmed diagnosis of chronic lymphocytic leukemia or small lymphocyticlymphoma as per IW-CLL 2018 criteria with biopsy proven transformation to diffuselarge B-cell lymphoma (DLBCL), consistent with Richter's Transformation. Thediagnostic sample must be reviewed by the treating institution. Tumor sample may beobtained by core needle or excisional surgical biopsy. A fresh biopsy is encouraged,but an archival sample is acceptable if the following provisions are met: 1)availability of a tumor-containing formalin-fixed, paraffin-embedded (FFPE) tissueblock, 2) if the tumor containing FFPE tissue block cannot be provided in total,sections from this block should be provided. Biopsy can be obtained up to 3 monthsprior to first day of treatment.

• Cohort-specific eligibility criteria:

• Glofitamab monotherapy cohort: Patients with either relapsed/refractory orpreviously untreated Richter's Transformation.

• Glofitamab + polatuzumab vedotin cohort: Patients with previously untreated RT.After the first 10 patients are enrolled in this cohort irrespective of priorBTKi exposure status, the remainder of the patients enrolled to this cohortmust have previously untreated RT and no prior BTK inhibitor. Patients cannothave prior polatuzumab vedotin exposure.

• Glofitamab + pirtobrutinib cohort: Patients with previously untreated RT andprior BTK inhibitor exposure (with enrollment to begin only after the first 10patients are accrued to the polatuzumab combination cohort). Patients cannothave prior pirtobrutinib exposure.

• Glofitamab + atezolizumab cohort: Patients with relapsed/refractory RT.Patients are required to have received ≥ 1 prior line of therapy. Patientscannot have prior atezolizumab exposure.

• Age ≥18 years.

• ECOG performance status of 0-2 (Appendix A).

• For patients receiving glofitamab monotherapy, glofitamab in combination withpolatuzumab vedotin, or glofitamab in combination with atezolizumab, participantsmust meet the following organ and marrow function as defined below:

• Absolute neutrophil count must be > 1.0 x10^9/L (growth factor allowed toachieve), unless patients have significant bone marrow involvement of theirmalignancy confirmed on biopsy.

• Platelets must be > 30 x10^9/L, independent of transfusion within 7 days ofscreening, unless patients have bone marrow involvement of their malignancyconfirmed on biopsy

• Creatinine < 2.0 x ULN (upper limit of normal) or estimated CrCl > 50 ml/min

• Total bilirubin < 1.5 X ULN

• Subjects with Gilbert's Syndrome or resolving autoimmune hemolytic anemia mayhave a bilirubin up to 3.0 X ULN

• AST/ALT < 3.0 X ULN, unless documented liver involvement by lymphoma

• For patients receiving glofitamab in combination with pirtobrutinib, participantsmust meet the following:

• Absolute neutrophil count must be > 1.0 x109/L (growth factor >7 days priorallowed to achieve), unless patients have significant bone marrow involvementof their malignancy confirmed on biopsy.

• Hemoglobin > 8 g/dL, independent of transfusion within 7 days of screening,unless patients have bone marrow involvement of their malignancy confirmed onbiopsy

• Platelets must be > 50 x109/L, independent of transfusion within 7 days ofscreening

• Estimated CrCl > 50 ml/min according to Cockcroft/Gault formula

• AST/ALT < 3.0 X ULN, or < 5.0 X ULN with documented liver involvement bylymphoma

• Total bilirubin < 1.5 X ULN or < 3.0 x ULN with documented liver involvement bylymphoma and/or Gilbert's Disease

• Adequate coagulation, defined as activated partial thromboplastin time (aPTT)or partial thromboplastin time (PTT) and prothrombin (PT) or (internationalnormalized ratio (INR) not greater than 1.5 x ULN.

• The patient is able to take oral medications

• Patients who have undergone prior allogeneic transplantation are potentiallyeligible if their transplant day 0 is > 6 months from their first dose of treatmentand as follows:

• For patients receiving glofitamab monotherapy or glofitamab in combination withpolatuzumab vedotin, all of the following must additionally be true:

• No current or prior Grade 3/4 graft versus host disease (GVHD)

• Stable off of immunosuppression for at least 2 months prior to receivingtheir first dose of treatment on study

• For patients receiving glofitamab in combination with pirtobrutinib, all of thefollowing must additionally be true:

• No active/current GVHD

• No prior history of Grade 3/4 GVHD

• Stable off of immunosuppression for at least 2 months prior to receivingtheir first dose of treatment on study

• For patients receiving atezolizumab, no prior allogeneic hematopoietic celltransplantation is allowed.

• Willingness to remain abstinent (refrain from heterosexual intercourse) or to useeffective contraceptive methods that result in a failure rate of <1% per year duringthe treatment period and for at least the following durations listed below:

• Female patients: at least 18 months after pre-treatment with obinutuzumab, or 2months after the last dose of glofitamab, or 5 months after the last dose ofatezolizumab, or 9 months after the last dose of polatuzumab vedotin, 3 monthsafter the last dose of tocilizumab (if applicable), or 1 month after the lastdose of pirtobrutinib, whichever whichever is longest.

• Male patients: at least 3 months after pre-treatment with obinutuzumab, or 2months after the last dose of glofitamab, or 5 months after the last dose ofpolatuzumab vedotin, or 2 months after the last dose of tocilizumab (ifapplicable), whichever is longest.

• Examples of highly effective contraceptive methods with a failure rate of <1%per year include: Tubal ligation, male sterilization, hormonal implants,established proper use of hormonal contraceptives that inhibit ovulation,hormone-releasing intrauterine devices, and copper intrauterine devices.Alternatively, two methods (e.g., two barrier methods such as a condom and acervical cap) may be combined to achieve a failure rate of <1% per year.Barrier methods must always be supplemented with the use of a spermicide.

• For female patients, willingness to refrain from donating ova during the sameperiods described in section 3.1.6 for female patients. For male patients,willingness to refrain from donating sperm during the same periods described insection 3.1.6 for male patients.

• Ability to understand and the willingness to sign a written informed consentdocument. (Providing consents in as many languages as possible is encouraged)

Exclusion Criteria:

• Patients with the Hodgkin variant transformation of CLL will be excluded.

• No prior anti-CD20 bispecific antibody is allowed. No prior, polatuzumab vedotin isallowed for patients in the polatuzumab vedotin-containing combination arm. Noprior, or atezolizumab therapy is allowed for patients in theatezolizumab-containing combination arm. No prior pirtobrutinib is allowed forpatients in the pirtobrutinib-containing arm.

• Subject has received any of the following within 14 days or 5 drug half-lives (whichever is shortest) prior to the first dose of treatment: investigationalagents, targeted therapies, e.g. tyrosine kinase inhibitors, systemicimmunotherapeutic/immunostimulating agents, including, but not limited to, CD137agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1,and anti-PD-L1 therapeutic antibodies, radio-immunoconjugates, antibody-drugconjugates (patients in the pirtobrutinib combination arm may not have received anantibody-drug conjugate within 28 days prior to the first dose of study treatment),immune/cytokines and monoclonal antibodies. Patients who are currently receivingtreatment with a Bruton's tyrosine kinase inhibitor may continue this agent untilthe day prior to starting treatment, to reduce the risk of tumor flare on treatmentcessation.

• Prior treatment with CAR T-cell therapy within 30 days before first study treatmentadministration.

• Subject has not recovered to less than Grade 1 clinically significant adverseeffect(s)/toxicity from prior anti-cancer therapy including immunotherapy, with theexception of alopecia, endocrinopathy managed with replacement therapy, and stablevitiligo.

• Patients with bulky cervical adenopathy that is compressing the upper airway andcould result in significant further airway compression during a tumor flare event.

• History of other malignancies, except:

• CLL/SLL

• Malignancy treated with curative intent and with no known active diseasepresent before the first dose of study drug and felt to be at low risk forrecurrence by treating physician

• Adequately treated non-melanoma skin cancer or lentigo maligna without evidenceof disease

• Adequately treated carcinoma in situ without evidence of disease

• Low-risk prostate cancer on active surveillance

• For patients receiving polatuzumab vedotin: Current > Grade 1 peripheral neuropathy.

• Any history of immune-related ≥ Grade 3 AE with the exception of endocrinopathymanaged with replacement therapy.

• Patient with history of confirmed progressive multifocal leukoencephalopathy (PML).

• Current or past history of central nervous system (CNS) disease involvement orhistory of leptomeningeal disease.

• Current or past history of CNS disease, such as stroke, epilepsy, CNS vasculitis orneurodegenerative disease (Note: patients with a history of stroke who have notexperienced a stroke or transient ischemic attack in the past 2 years and have noresidual neurologic deficits, as judged by the investigator, are permitted).

• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitisobliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence ofactive pneumonitis on screening chest CT scan.

• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrentdrainage procedures (once monthly or more frequently).

• Prior solid organ transplantation.

• History of known or suspected hemophagocytic lymphohistiocytosis (HLH).

• Active or history of autoimmune disease, including but not limited to myocarditis,pneumonitis, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupuserythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosisassociated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren'ssyndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, orglomerulonephritis.

• Patients with a remote history of, or well controlled, autoimmune disease maybe eligible to enroll after consultation with the study PI.

• Patients with a history of autoimmune-related hypothyroidism who are onthyroid-replacement hormone and patients with controlled Type 1 diabetesmellitus who are on an insulin regimen can be included.

• Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo withdermatologic manifestations only (e.g., patients with psoriatic arthritis areexcluded) are eligible for the study provided that the disease is wellcontrolled (Rash <10% of BSA, and no acute exacerbations requiringmethotrexate, retinoids, biologics, or high potency oral corticosteroids) atbaseline and requires only low-potency topical corticosteroids.

• For patients enrolling to the pirtobrutinib combination arm, patients with thefollowing should be discussed with the Sponsor-Investigator prior toenrollment: active uncontrolled auto-immune cytopenia (e.g., autoimmunehemolytic anemia [AIHA], idiopathic thrombocytopenic purpura [ITP]) for whichnew therapy was introduced or existing therapy was escalated within the 4 weeksprior to study enrollment to maintain adequate blood counts.

• Patients who require systemic immunosuppressive therapy for an ongoing medicalcondition will be excluded with the exception of corticosteroid use fordisease-related symptom control. Treatment for autoimmune disease with systemicimmunosuppressive medications including, but not limited to, prednisone,azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents arenot allowed within 2 weeks prior to Day 1 of Cycle 1.

• Note the following are permitted: use of inhaled corticosteroids, use ofmineralocorticoids for management of orthostatic hypotension.

• Corticosteroids for lymphoma symptom control is allowed provided patients areon a stable dose as per discretion of the treating investigator and indiscussion with the Sponsor-Investigator.

• History of severe allergic or anaphylactic reactions to monoclonal antibody therapyunless in consultation with an allergy specialist they are deemed eligible forretreatment with desensitization.

• Patients, who have had a major surgery or significant traumatic injury within 4weeks of start of study drug, patients who have not recovered from the side effectsof any major surgery (defined as requiring general anesthesia).

• History of Human Immunodeficiency Virus (HIV):

• For patients receiving glofitamab in combination with pirtobrutinib, patientswho have tested positive for HIV are excluded due to risk of opportunisticinfections with both HIV and BTK inhibitors. For patients with unknown HIVstatus, HIV testing will be performed at screening and result must be negativefor enrollment.

• For patients in all other cohorts, only those without controlled disease (controlled disease defined as CD4 count greater than or equal to 200 permicroliter, undetectable viral load, and stable anti-retroviral therapy) willbe excluded.

• History of Human T-Cell Leukemia Virus 1 (HTLV-1) infection.

• Known active cytomegalovirus (CMV) infection.

• Clinically significant liver disease, including cirrhosis and active viral ornon-viral hepatitis. Patients who are positive for hepatitis B core antibody orhepatitis B surface antigen must have a negative viral load (by PCR testing), bewilling to undergo regular testing, and be able to be treated with a prophylacticagent (e.g. entecavir). Patients with hepatitis C seropositivity are eligible onlyif they have a negative viral load (by PCR testing).

• Patients with a known active infection or any major episode of infection requiringhospitalization or treatment with IV antimicrobial within 4 weeks prior to firststudy drug. Patients receiving prophylactic antibiotics (e.g., to prevent a urinarytract infection or chronic obstructive pulmonary disease exacerbation), antivirals,or antifungals may participate.

• Patients should not have received immunization with live vaccines within 28 daysprior to start of study treatment. In addition, patients must not receive live,attenuated vaccines (e.g., FluMist®) while receiving study treatment or after thelast dose until B-cell recovery to the normal ranges. Inactivated influenzavaccination is permitted during influenza season.

• Patients with any one of the following currently or in the previous 6 months will beexcluded: myocardial infarction, congenital long QT syndrome, torsade de pointes,unstable angina, or coronary/peripheral artery bypass graft.

• Patients with New York Heart Association Class III or IV heart failure or withObjective Assessment Class C or D cardiac disease.

• For patients receiving pirtobrutinib:

• Significant cardiovascular disease defined as:

• unstable angina or acute coronary syndrome within the past 2 months priorto randomization

• history of myocardial infarction within 3 months prior to randomization or

• documented LVEF by any method of ≤ 40% in the 12 months prior torandomization

• Uncontrolled or symptomatic arrhythmias

• Note: patients with atrial fibrillation are allowed as long as they areadequately rate-controlled.)

• Note: Patients with pacemakers are eligible if they have no history offainting or clinically relevant arrhythmias while using the pacemaker

• Prolongation of the QT interval corrected for heart rate (QTcF) > 470 msec.QTcF is calculated using Fridericia's Formula (QTcF): QTcF = QT/(RR0.33).

• Correction of suspected drug-induced QTcF prolongation can be attempted atthe investigator's discretion and only if clinically safe to do so witheither discontinuation of the offending drug or switch to another drug notknown to be associated with QTcF prolongation.

• Correction for underlying bundle branch block (BBB) allowed.

• Clinically significant active malabsorption syndrome or other condition likelyto affect gastrointestinal (GI) absorption of the study drug.

• Active uncontrolled auto-immune cytopenia (e.g., autoimmune hemolytic anemia [AIHA], idiopathic thrombocytopenic purpura [ITP]) for which new therapy wasintroduced or existing therapy was escalated within the 4 weeks prior to studyenrollment to maintain adequate blood counts.

• Patients requiring therapeutic anticoagulation with warfarin or another vitaminK antagonist.

• Have a known hypersensitivity to any of the excipients of Pirtobrutinib or toany intended study medications.

• Patients who experienced a major bleeding event or grade ≥ 3 arrhythmia onprior treatment with a BTK inhibitor. Note: Major bleeding is defined asbleeding having one or more of the following features: potentiallylife-threatening bleeding with signs or symptoms of hemodynamic compromise;bleeding associated with a decrease in the hemoglobin level of at least 2g perdeciliter; or bleeding in a critical area or organ (e.g., retroperitoneal,intraarticular, pericardial, epidural, or intracranial bleeding orintramuscular bleeding with compartment syndrome)

• History of bleeding disorders (e.g. von Willebrand's disease, hemophilia).

• History of stroke or intracranial hemorrhage within 6 months of starting studytherapy.

• Inability to comply with protocol mandated hospitalizations and restrictions.

• Patients who are pregnant, breast-feeding, or intending to become pregnant duringthe study.

• Any other diseases, metabolic dysfunction, physical examination finding, mentalstatus or clinical laboratory finding giving reasonable suspicion of a disease orcondition that would contraindicate the use of an investigational drug.