Phase 2 Study of Glofitamab Monotherapy & With Polatuzumab Vedotin, Pirtobrutinib, or Atezolizumab in Richter's Transformation
A Phase 2 Study of Glofitamab as Monotherapy or in Combination With Polatuzumab Vedotin, Pirtobrutinib, or Atezolizumab in Richter's Transformation
1 other identifier
interventional
70
1 country
5
Brief Summary
This research is being done to evaluate Glofitamab by itself or in combination with Polatuzumab Vedotin, Pirtobrutinib, 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)
- Pirtobrutinib (a selective inhibitor of BTK)
- Atezolizumab (a humanized immunoglobulin monoclonal antibody)
- Tocilizumab (a recombinant, humanized, anti-human monoclonal antibody)
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P50-P75 for phase_2
Started Jan 2024
Longer than P75 for phase_2
5 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
September 12, 2023
CompletedFirst Posted
Study publicly available on registry
September 21, 2023
CompletedStudy Start
First participant enrolled
January 22, 2024
CompletedPrimary Completion
Last participant's last visit for primary outcome
January 15, 2028
ExpectedStudy Completion
Last participant's last visit for all outcomes
January 15, 2033
January 7, 2026
January 1, 2026
4 years
September 12, 2023
January 5, 2026
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
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 Outcomes (17)
Best Overall Response Rate (ORR)
Disease evaluation will be performed at 12, 24 and 36 weeks
Best Partial Response (PR) Rate
Disease evaluation will be performed at 12, 24 and 36 weeks
Overall Response Rate at 36 weeks
36 weeks
Partial Response (PR) Rate at 36 weeks
36 weeks
Complete Response (CR) Rate at 36 weeks
36 weeks
- +12 more secondary outcomes
Study Arms (4)
Monotherapy Cohort: Obinutuzumab and Glofitamab
ACTIVE COMPARATORStudy 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.
Combination A Group: Obinutuzumab, Glofitamab, and Polatuzumab Vedotin
EXPERIMENTALStudy 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.
Combination B Group: Obinutuzumab, Glofitamab, and Pirtobrutinib
EXPERIMENTALStudy 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 Pirtobrutinib 1x daily. Days 2-21 of each cycle: Pirtobrutinib will be taken once 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.
Combination C Group: Obinutuzumab, Glofitamab, and Atezolizumab
EXPERIMENTALStudy 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.
Interventions
For the treatment of Cytokine Release Syndrome. Recombinant, humanized, anti-human monoclonal antibody, administered via intravenous infusion per protocol.
Selective inhibitor of BTK, 50 mg or 100 mg tablet, via oral administration per protocol.
"2:1" T-cell bispecific humanized monoclonal antibody, administered via intravenous infusion per protocol.
Humanized glycoengineered type II anti-CD20 monoclonal antibody, administered via intravenous infusion per protocol.
Antibody-drug conjugate, administered via intravenous infusion per protocol.
Humanized immunoglobulin monoclonal antibody, administered via intravenous infusion per protocol.
Eligibility Criteria
You may qualify if:
- 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. The diagnostic sample must be reviewed by the treating institution. 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.
- Cohort-specific eligibility criteria:
- Glofitamab monotherapy cohort: Patients with either relapsed/refractory or previously 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 prior BTKi exposure status, the remainder of the patients enrolled to this cohort must have previously untreated RT and no prior BTK inhibitor. Patients cannot have prior polatuzumab vedotin exposure.
- Glofitamab + pirtobrutinib cohort: Patients with previously untreated RT and prior BTK inhibitor exposure (with enrollment to begin only after the first 10 patients are accrued to the polatuzumab combination cohort). Patients cannot have prior pirtobrutinib exposure.
- Glofitamab + atezolizumab cohort: Patients with relapsed/refractory RT. Patients are required to have received ≥ 1 prior line of therapy. Patients cannot have prior atezolizumab exposure.
- Age ≥18 years.
- ECOG performance status of 0-2 (Appendix A).
- For patients receiving glofitamab monotherapy, glofitamab in combination with polatuzumab vedotin, or glofitamab in combination with atezolizumab, 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
- +24 more criteria
You may not qualify if:
- Patients with the Hodgkin variant transformation of CLL will be excluded.
- No prior anti-CD20 bispecific antibody is allowed. No prior, polatuzumab vedotin is allowed for patients in the polatuzumab vedotin-containing combination arm. No prior, or atezolizumab therapy is allowed for patients in the atezolizumab-containing combination arm. No prior pirtobrutinib is allowed for patients 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: investigational agents, 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 (patients in the pirtobrutinib combination arm may not have received an antibody-drug conjugate within 28 days prior to the first dose of study treatment), 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).
- +47 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- Christine Ryanlead
- Genentech, Inc.collaborator
- Loxo Oncology, Inc.collaborator
- Eli Lilly and Companycollaborator
Study Sites (5)
Winship Cancer Institute at Emory University
Atlanta, Georgia, 30322, United States
Brigham and Women's Hospital
Boston, Massachusetts, 02215, United States
Dana Farber Cancer Institute
Boston, Massachusetts, 02215, United States
The University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, 27599, United States
The Ohio State University Comprehensive Cancer Center
Columbus, Ohio, 43210, United States
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Christine Ryan, MD
Dana-Farber Cancer Institute
Central Study Contacts
Study Design
- Study Type
- interventional
- Phase
- phase 2
- Allocation
- NON RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- SEQUENTIAL
- Sponsor Type
- OTHER
- Responsible Party
- SPONSOR INVESTIGATOR
- PI Title
- Principal Investigator
Study Record Dates
First Submitted
September 12, 2023
First Posted
September 21, 2023
Study Start
January 22, 2024
Primary Completion (Estimated)
January 15, 2028
Study Completion (Estimated)
January 15, 2033
Last Updated
January 7, 2026
Record last verified: 2026-01
Data Sharing
- IPD Sharing
- Will share
- Shared Documents
- STUDY PROTOCOL, SAP
- Time Frame
- Data can be shared no earlier than 1 year following the date of publication
- Access Criteria
- Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu
The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: \[contact information for Sponsor Investigator or designee\]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.