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

Status: Recruiting
Location: See all (4) locations...
Intervention Type: Drug
Study Type: Interventional
Study Phase: Phase 2
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)

Eligibility
Participation Requirements
Sex: All
Minimum Age: 18
Healthy Volunteers: f
View:

• 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

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

‣ Absolute neutrophil count must be \> 1.0 x109/L (growth factor \>7 days prior allowed to achieve), unless patients have significant bone marrow involvement of 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 on biopsy

⁃ Platelets must be \> 50 x109/L, independent of transfusion within 7 days of screening

⁃ 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 by lymphoma

⁃ Total bilirubin \< 1.5 X ULN or \< 3.0 x ULN with documented liver involvement by lymphoma and/or Gilbert's Disease

⁃ Adequate coagulation, defined as activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) and prothrombin (PT) or (international normalized 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 potentially eligible if their transplant day 0 is \> 6 months from their first dose of treatment and as follows:

‣ For patients receiving glofitamab monotherapy or glofitamab in combination with polatuzumab 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 receiving their first dose of treatment on study

⁃ For patients receiving glofitamab in combination with pirtobrutinib, all of the following 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 receiving their first dose of treatment on study

⁃ For patients receiving atezolizumab, no prior allogeneic hematopoietic cell transplantation is allowed.

• 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, 3 months after the last dose of tocilizumab (if applicable), or 1 month after the last dose of pirtobrutinib, whichever 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 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 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)

Locations
United States
Massachusetts
Brigham and Women's Hospital
RECRUITING
Boston
Dana Farber Cancer Institute
RECRUITING
Boston
North Carolina
The University of North Carolina at Chapel Hill
RECRUITING
Chapel Hill
Ohio
The Ohio State University Wexner Medical Center
RECRUITING
Columbus
Contact Information
Primary
DFCI Clinical Trials Hotline
DFCILymphomaResearchNurses@partners.org
877-DF-TRIAL
Backup
Christine Ryan, MD
Time Frame
Start Date: 2024-01-22
Estimated Completion Date: 2033-01-15
Participants
Target number of participants: 70
Treatments
Active_comparator: Monotherapy Cohort: Obinutuzumab and Glofitamab
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.
Experimental: Combination A Group: Obinutuzumab, Glofitamab, and Polatuzumab Vedotin
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.
Experimental: Combination B Group: Obinutuzumab, Glofitamab, and Pirtobrutinib
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 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.
Experimental: Combination C Group: Obinutuzumab, Glofitamab, and Atezolizumab
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.
Sponsors
Collaborators: Loxo Oncology, Inc., Genentech, Inc., Eli Lilly and Company
Leads: Christine Ryan

This content was sourced from clinicaltrials.gov

Similar Clinical Trials