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

Recruiting now · Phase 2

Conditions studied: Chronic Lymphocytic Leukemia, Richter's Transformation

In brief

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)

Key facts

Study ID

NCT06043674

Run by

Christine Ryan

People needed

70

Starts

2024-01-22

Expected to finish

2033-01-15

Last updated by the study team

2026-01-07

Who can join

Age: 18 and older. Sex: any. Healthy volunteers: not accepted.

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
• 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:

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

Where it is running

• Winship Cancer Institute at Emory University — Atlanta, Georgia, United States (enrolling)
• Brigham and Women's Hospital — Boston, Massachusetts, United States (enrolling)
• Dana Farber Cancer Institute — Boston, Massachusetts, United States (enrolling)
• The University of North Carolina at Chapel Hill — Chapel Hill, North Carolina, United States (enrolling)
• The Ohio State University Comprehensive Cancer Center — Columbus, Ohio, United States (enrolling)

Full record on ClinicalTrials.gov

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