A Ph 2 Study of Glofitamab Alone or in Combination With Polatuzumab Vedotin or Atezolizumab in Richter's Transformation

Study Overview
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Brief Summary
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This research is being done to evaluate Glofitamab by itself or in combination with Polatuzumab Vedotin or Atezolizumab as possible treatments for Chronic Lymphocytic Leukemia (CLL) that has transformed into Richter's Transformation (RT). The names of the study drugs involved in this research study are: Glofitamab (a T-cell bispecific humanized monoclonal antibody) Obinutuzumab (a humanized glycoengineered type II anti-CD20 monoclonal antibody) Polatuzumab vedotin (an antibody-drug conjugate) Atezolizumab (a humanized immunoglobulin monoclonal antibody) Tocilizumab (a recombinant, humanized, anti-human monoclonal antibody)

Detailed Description
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This is an open-label, multicenter phase II study to evaluate the efficacy and safety of glofitamab as monotherapy and in combination with polatuzumab vedotin or atezolizumab for participants with Richter's Transformation (RT) that has transformed from chronic lymphocytic leukemia (CLL). The U.S. Food and Drug Administration (FDA) has not approved glofitamab, obinutuzumab, polatuzumab vedotin, atezolizumab and tocilizumab for CLL with RT, but each drug has been approved for other uses. Glofitamab has been approved by the FDA for certain people with diffuse large B-cell lymphoma (DLBCL), which is similar to Richter's Transformation. Glofitamab has been studied as a single therapy and in combination with polatuzumab vedotin and atezolizumab in people with DLBCL. Polatuzumab vedotin is already an approved therapy for diffuse large B-cell lymphoma in combination with chemoimmunotherapy. Atezolizumab is an approved therapy for other cancers. Obinutuzumab is an approved therapy for chronic lymphocytic leukemia. Tocilizumab is approved for the treatment of an entity called cytokine release syndrome following another therapy called chimeric antigen receptor T-cell therapy; it will be used to treat cytokine release syndrome if a participant develops it in this study. Study procedures include screening for eligibility, clinic visits for study treatment, blood and urine tests, Positron Emission Tomography (PET) or Computed Topography (CT) scans, bone marrow biopsies, echocardiograms, and electrocardiograms (ECGs). Participants will receive study treatment for about 9 months and will be followed every 3-6 months for up to 10 years thereafter. It is expected that about 66 people will take part in this research study. Genentech, Inc. is funding this research study by providing study drugs.

Official Title
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A Phase 2 Study of Glofitamab as Monotherapy or in Combination With Polatuzumab Vedotin or Atezolizumab in Richter's Transformation

Conditions
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Chronic Lymphocytic Leukemia, Richter's Transformation

Intervention / Treatment
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* Drug: Glofitamab
* Drug: Obinutuzumab
* Drug: Polatuzumab Vedotin
* Drug: Atezolizumab
* Drug: Tocilizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have a confirmed diagnosis of chronic lymphocytic leukemia or small lymphocytic lymphoma as per IW-CLL 2018 criteria with biopsy proven transformation to diffuse large B-cell lymphoma (DLBCL), consistent with Richter's Transformation. Patients with either previously treated or previously untreated Richter's Transformation are eligible. Tumor sample may be obtained 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) tissue block, 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 months prior to first day of treatment. For patients receiving glofitamab monotherapy or glofitamab in combination with polatuzumab vedotin, those who have undergone prior allogeneic transplantation are eligible provided all of the following: 1) they do not have either current, or a history of, Grade 3/4 graft versus host disease (GVHD), 2) they have been stable off of immunosuppression for at least 2 months prior to receiving their first dose of treatment on study, and 3) that their transplant day 0 is > 6 months from their first dose of treatment. For patients receiving atezolizumab, no prior allogeneic hematopoietic cell transplantation is allowed. Age ≥18 years. ECOG performance status of 0-2 (Appendix A). Participants must meet the following organ and marrow function as defined below: Absolute neutrophil count must be > 1.0 x10^9/L (growth factor allowed to achieve), unless patients have significant bone marrow involvement of their malignancy confirmed on biopsy. Platelets must be > 30 x10^9/L, independent of transfusion within 7 days of screening, unless patients have bone marrow involvement of their malignancy confirmed 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 may have a bilirubin up to 3.0 X ULN AST/ALT < 3.0 X ULN, unless documented liver involvement by lymphoma Willingness to remain abstinent (refrain from heterosexual intercourse) or to use effective contraceptive methods that result in a failure rate of <1% per year during the treatment period and for at least the following durations listed below: Female patients: at least 18 months after pre-treatment with obinutuzumab, or 2 months after the last dose of glofitamab, or 5 months after the last dose of atezolizumab, or 9 months after the last dose of polatuzumab vedotin, or 3 months after the last dose of tocilizumab (if applicable), whichever is longest. Male patients: at least 3 months after pre-treatment with obinutuzumab, or 2 months after the last dose of glofitamab, or 5 months after the last dose of polatuzumab vedotin, or 2 months after the last dose of tocilizumab (if applicable), whichever is longest. Examples of 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 a cervical 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 same periods described in section 3.1.6 for female patients. For male patients, willingness to refrain from donating sperm during the same periods described in section 3.1.6 for male patients. Ability to understand and the willingness to sign a written informed consent document. (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, polatuzumab vedotin, or atezolizumab therapy is allowed. 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: targeted therapies, e.g. tyrosine kinase inhibitors, systemic immunotherapeutic/immunostimulating agents, including, but not limited to, CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies, radio-immunoconjugates, antibody-drug conjugates, immune/cytokines and monoclonal antibodies. Patients who are currently receiving treatment with a Bruton's tyrosine kinase inhibitor may continue this agent until the day prior to starting treatment, to reduce the risk of tumor flare on treatment cessation. Prior treatment with CAR T-cell therapy within 30 days before first study treatment administration. Subject has not recovered to less than Grade 1 clinically significant adverse effect(s)/toxicity from prior anti-cancer therapy including immunotherapy, with the exception of alopecia, endocrinopathy managed with replacement therapy, and stable vitiligo. Patients with bulky cervical adenopathy that is compressing the upper airway and could 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 disease present before the first dose of study drug and felt to be at low risk for recurrence by treating physician Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of 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 endocrinopathy managed with replacement therapy. Patient with history of confirmed progressive multifocal leukoencephalopathy (PML). Current or past history of central nervous system (CNS) lymphoma or history of leptomeningeal disease. Current or past history of CNS disease, such as stroke, epilepsy, CNS vasculitis or neurodegenerative disease (Note: patients with a history of stroke who have not experienced a stroke or transient ischemic attack in the past 2 years and have no residual neurologic deficits, as judged by the investigator, are permitted). History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 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 lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. Patients with a remote history of, or well controlled, autoimmune disease may be eligible to enroll after consultation with the study PI. Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone and patients with controlled Type 1 diabetes mellitus who are on an insulin regimen can be included. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided that the disease is well controlled (Rash <10% of BSA, and no acute exacerbations requiring methotrexate, retinoids, biologics, or high potency oral corticosteroids) at baseline and requires only low-potency topical corticosteroids. Patients who require systemic immunosuppressive therapy for an ongoing medical condition will be excluded with the exception of corticosteroid use for disease-related symptom control. Treatment for autoimmune disease with systemic immunosuppressive medications including, but not limited to, prednisone, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents are not allowed within 2 weeks prior to Day 1 of Cycle 1. Note the following are permitted: use of inhaled corticosteroids, use of mineralocorticoids for management of orthostatic hypotension. Corticosteroids for lymphoma symptom control is allowed provided patients are on a stable dose. History of severe allergic or anaphylactic reactions to monoclonal antibody therapy unless in consultation with an allergy specialist they are deemed eligible for retreatment with desensitization. Patients, who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia). History of Human Immunodeficiency Virus (HIV) without controlled disease (controlled disease defined as CD4 count ≥ 200/µL, undetectable viral load, and stable anti-retroviral therapy). History of Human T-Cell Leukemia Virus 1 (HTLV-1) infection. Clinically significant liver disease, including cirrhosis and active viral or non-viral hepatitis. Patients who are positive for hepatitis B core antibody or hepatitis B surface antigen must have a negative viral load (by PCR testing), be willing to undergo regular testing, and be able to be treated with a prophylactic agent (e.g. entecavir). Patients with hepatitis C seropositivity are eligible only if they have a negative viral load (by PCR testing). Patients with a known active infection or any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks prior to first study drug. Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) may participate. Patients should not have received immunization with live vaccines within 28 days prior to start of study treatment. In addition, patients must not receive live, attenuated vaccines (e.g., FluMist®) while receiving study treatment or after the last dose until B-cell recovery to the normal ranges. Inactivated influenza vaccination is permitted during influenza season. Patients with any one of the following currently or in the previous 6 months will be excluded: 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 with Objective Assessment Class C or D cardiac disease. Inability to comply with protocol mandated hospitalizations and restrictions. Patients who are pregnant, breast-feeding, or intending to become pregnant during the study. Any other diseases, metabolic dysfunction, physical examination finding, mental status or clinical laboratory finding giving reasonable suspicion of a disease or condition that would contraindicate the use of an investigational drug.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Monotherapy Cohort: Obinutuzumab and Glofitamab<br>Study procedures will be conducted as follows: Baseline visit with screening procedures, including bone marrow biopsy and Positron Emission Tomography (PET) or Computed Topography (CT) scans. PET/CT scans after 4, 8, and 12 cycles of therapy and at 6 and 15 months after end-of-treatment. Cycle 1: Day 1, 2, and 7 of 21- day Cycle: Predetermined dose of Obinutuzumab 1x daily. Day 8 and 15 of 21- day Cycle: Predetermined dose of Glofitamab 1x daily. Hospitalization will be required for initial dose and post-dose observation. Cycle 2 - 12 --Day 1 of 21-day Cycle: Predetermined dose of Glofitamab 1x daily. Hospitalization will be required for second dose and post-dose observation End of treatment visit. Follow up visits: for months 10 - 24, visits will be every 3 months. For months 25 - 60 visits will be every 6 months. After completion of a 10-patient safety lead-in cohort, enrollment will open to the other two cohorts. | Drug: Glofitamab<br>* 2:1 T-cell bispecific humanized monoclonal antibody, 2.5 mL or 10 mL single-use vial, via intravenous infusion per protocol.<br>* Other names: RO7082859;Drug: Obinutuzumab<br>* Humanized glycoengineered type II anti-CD20 monoclonal antibody, 50 mL single-use vial, via intravenous infusion per protocol.<br>* Other names: RO5072759, GA101, GAZYVA, GAZYVARO;Drug: Tocilizumab<br>* For the treatment of Cytokine Release Syndrome. Recombinant, humanized, anti-human monoclonal antibody, 20 mg/mL single-dose vials, via intravenous infusion per protocol.<br>* Other names: Actemra;|
| Experimental: Combination A Group: Obinutuzumab, Glofitamab, and Polatuzumab Vedotin<br>Study procedures will be conducted as follows: Baseline visit with screening procedures, including bone marrow biopsy and PET/CT scans. PET/CT scans after 4, 8, and 12 cycles of therapy and at 6 and 15 months after end-of-treatment. Cycle 1: Day 1, 2, and 7 of 21- day Cycle: Predetermined dose of Obinutuzumab 1x daily. Day 8 and 15 of 21- day Cycle: Predetermined dose of Glofitamab 1x daily. Hospitalization will be required for initial dose and post-dose observation. Cycle 2 - 7: - Day 1 of 21-day Cycle: Predetermined dose of Glofitamab 1x daily. Predetermined dose of Polatuzumab Vedotin 1x daily. Cycle 8 - 12 - Day 1 of 21-day Cycle: Predetermined dose of Glofitamab 1x daily. End of treatment visit. Follow up visits: for months 10 - 24, visits will be every 3 months. For months 25 - 60 visits will be every 6 months. | Drug: Glofitamab<br>* 2:1 T-cell bispecific humanized monoclonal antibody, 2.5 mL or 10 mL single-use vial, via intravenous infusion per protocol.<br>* Other names: RO7082859;Drug: Obinutuzumab<br>* Humanized glycoengineered type II anti-CD20 monoclonal antibody, 50 mL single-use vial, via intravenous infusion per protocol.<br>* Other names: RO5072759, GA101, GAZYVA, GAZYVARO;Drug: Polatuzumab Vedotin<br>* Antibody-drug conjugate, 30 mg or 140 mg vial, via intravenous infusion per protocol.<br>Drug: Tocilizumab<br>* For the treatment of Cytokine Release Syndrome. Recombinant, humanized, anti-human monoclonal antibody, 20 mg/mL single-dose vials, via intravenous infusion per protocol.<br>* Other names: Actemra;|
| Experimental: Combination B Group: Obinutuzumab, Glofitamab,and Atezolizumab<br>Study procedures will be conducted as follows: Baseline visit with screening procedures, including bone marrow biopsy and PET/CT scans. PET/CT scans after 4, 8, and 12 cycles of therapy and at 6 and 15 months after end-of-treatment. Cycle 1: Day 1, 2, and 7 of 21- day Cycle: Predetermined dose of Obinutuzumab 1x daily. Day 8 and 15 of 21- day Cycle: Predetermined dose of Glofitamab 1x daily. Hospitalization will be required for initial dose and post-dose observation. Cycle 2 - 12 - Day 1 of 21-day Cycle: Predetermined dose of Glofitamab 1x daily. Predetermined dose of Atezolizumab 1x daily. End of treatment visit. Follow up visits: for months 10 - 24, visits will be every 3 months. For months 25 - 60 visits will be every 6 months. | Drug: Glofitamab<br>* 2:1 T-cell bispecific humanized monoclonal antibody, 2.5 mL or 10 mL single-use vial, via intravenous infusion per protocol.<br>* Other names: RO7082859;Drug: Obinutuzumab<br>* Humanized glycoengineered type II anti-CD20 monoclonal antibody, 50 mL single-use vial, via intravenous infusion per protocol.<br>* Other names: RO5072759, GA101, GAZYVA, GAZYVARO;Drug: Atezolizumab<br>* Humanized immunoglobulin monoclonal antibody, 840 mg/14 mL or 1200 mg/20 mL single-use vial, via intravenous infusion per protocol.<br>* Other names: Tecentriq;Drug: Tocilizumab<br>* For the treatment of Cytokine Release Syndrome. Recombinant, humanized, anti-human monoclonal antibody, 20 mg/mL single-dose vials, via intravenous infusion per protocol.<br>* Other names: Actemra;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Complete Response (CR) Rate | Best Complete Response (CR) rate is defined as the proportion of participants achieving CR at any of the 3 timepoints (after 4, 8 and 12 cycles). CR is defined per Lugano 2014 criteria. | Disease evaluation will be performed at 12, 24 and 36 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response Rate (ORR) | Best Overall response rate (ORR) is defined as the proportion of participants achieving complete response (CR) or partial response (PR) at any of the 3 timepoints (after 4, 8 and 12 cycles). CR and PR are defined per Lugano 2014 criteria. | Disease evaluation will be performed at 12, 24 and 36 weeks | 
| Best Partial Response (PR) Rate | Best Partial response (PR) rate is defined as the proportion of participants achieving partial response at any of the 3 timepoints (after 4, 8, 12 cycles). PR is defined per Lugano 2014 criteria. | Disease evaluation will be performed at 12, 24 and 36 weeks | 
| Overall Response Rate at 36 weeks | Overall response rate (ORR) at 36 weeks is defined as the proportion of participants who achieve complete response (CR) or partial response (PR) at the time of disease evaluation at 12 cycles (36 weeks). CR and PR are defined per Lugano 2014 criteria. | 36 weeks | 
| Partial Response (PR) Rate at 36 weeks | Partial Response (PR) rate at 36 weeks is defined as the proportion of participants achieving PR at the time of disease evaluation at 12 cycles (36 weeks). PR defined per Lugano 2014 criteria. | 36 weeks | 
| Complete Response (CR) Rate at 36 weeks | Complete Response (CR) rate at 36 weeks is defined as the proportion of participants achieving CR at the time of disease evaluation at 12 cycles (36 weeks). CR defined per Lugano 2014 criteria. | 36 weeks | 
| Duration of Response (DOR) | Duration of Response (DOR) is defined as the time from date of first documented confirmed objective response (CR + PR) to date of first documented progressive disease (PD) per Lugano 2014 criteria. | Disease evaluation will be performed every 3 months, up to 2 years. | 
| Duration of Complete Response (DOCR) | Duration of complete response (DOCR) is defined as the time from date of first documented complete response to date of first documented progressive disease (PD) per Lugano 2014 criteria. | In long-term follow-up, participants were assessed every 6 months, up to 2 years | 
| Progression Free Survival (PFS) at 2 years | PFS at 2 years is the percent probability estimate at 2 years based on the Kaplan-Meier method. PFS will be calculated as the time from start of treatment to the date of progressive disease (PD, defined per Lugano 2014 criteria), death, or last follow-up. Participants alive and progression-free at time of last follow-up will be censored. | Participants will be followed up to 2 years. | 
| Median Progression Free Survival (PFS) | PFS will be calculated as the time from start of treatment to the date of progressive disease (PD, defined per Lugano 2014 criteria), death, or last follow-up. Participants alive and progression-free at time of last follow-up will be censored. | Participants will be followed up to 2 years. | 
| Overall Survival (OS) at 2 years | OS at 2 years is the percent probability at 2 years based on Kaplan-Meier methodology. OS will be calculated as the time from the start of treatment to the date of death, or last follow-up. Participants alive at time of last follow-up will be censored. | Participants will be followed up to 2 years. | 
| Median Overall Survival | OS will be calculated as the time from the start of treatment to the date of death, or last follow-up. Participants alive at time of last follow-up will be censored. | Participants will be followed up to 10 years. | 
| Minimal Residual Disease (MRD) Negativity | MRD negativity is defined as the proportion of participants that achieve MRD negative, where it measured by multiparametric flow cytometry (Mayo Clinic Laboratories) or the clonoSEQ assay (Adaptive). | MRD testing will be performed every 3 months, up to 2 years, then every 6 months, up to 3 years (5 years in total) | 
| Rate and severity of Cytokine Release Syndrome (CRS) | CRS rate and severity will be summarized based on American Society of Transplantation and Cellular Therapy (ASTCT) Consensus grading. | Adverse events will be collected at each study visit plus 30 days post treatment end, up to 10 months. | 
| Tocilizumab Usage Rate | Tocilizumab usage rate is defined as the proportion of participants requiring tocilizumab usage of management of CRS. | Within the first year on study | 
| Median Tocilizumab Usage | Median tocilizumab usage is defined as median number of doses of tocilizumab administered per participant | Within the first year on study | 
| Rate and Severity of Neurologic Adverse Events (AEs) | Neurologic AEs are defined as adverse events reported in nervous system disorders and psychiatric disorders system organ class based on revised NCE Common Terminology Criteria for Adverse Events (CTCAE) | Adverse events will be collected at each study visit plus 30 days post treatment end, up to 10 months. | 
| Grade 3-5 Adverse Events Rate | Grade 3-5 AE rate is defined as the proportion of patients who experienced grade 3-5 adverse event based on the Common Toxicity Criteria for Adverse Events version 5.0 as reported on case report form. | Adverse events will be collected at each study visit plus 30 days post treatment end | 
| Treatment-related Adverse Events Rate | Treatment-related adverse event rate is defined as the proportion of participants who experienced treatment-related adverse event based on the Common Toxicity Criteria for Adverse Events version 5.0. | Adverse events will be collected at each study visit plus 30 days post treatment end | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Lymphocytic Leukemia, CLL, Richter's Transformation