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

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 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 conjugates1, immune/cytokines and monoclonal antibodies. Patients who are currently receiving treatment with an agent targeting Bruton's tyrosine kinase may continue this agent until the day prior to starting treatment, to reduce the risk of tumor flare on treatment cessation (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).

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 2 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 6 months 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.

For patients enrolling to the pirtobrutinib combination arm, patients with the following will be excluded: active uncontrolled auto-immune cytopenia (e.g., autoimmune hemolytic anemia \[AIHA\], idiopathic thrombocytopenic purpura \[ITP\]) for which new therapy was introduced or existing therapy was escalated within the 4 weeks prior to study enrollment to maintain adequate blood counts.

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 as per discretion of the treating investigator and in discussion with the Sponsor-Investigator.

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 2 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):

For patients receiving glofitamab in combination with pirtobrutinib, patients who have tested positive for HIV are excluded due to risk of opportunistic infections with both HIV and BTK inhibitors. For patients with unknown HIV status, HIV testing will be performed at screening and result must be negative for enrollment.

For patients in all other cohorts, only those without controlled disease (controlled disease defined as CD4 count ≥ 200/uL, undetectable viral load, and stable anti-retroviral therapy) will be 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 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) if indicated (see Section 5.5). Patients with hepatitis C seropositivity are eligible only if they have a negative viral load (by PCR testing).

Patients with a known active infection.

Patients with any major episode of infection requiring hospitalization within 2 weeks prior to first study drug or treatment-directed antimicrobials within 1 week prior to first study drug. Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation), antivirals, or antifungals 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.

For patients receiving pirtobrutinib:

Significant cardiovascular disease defined as:

* unstable angina or acute coronary syndrome within the past 2 months prior to randomization

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

* documented LVEF by any method of ≤ 40% in the 12 months prior to randomization

Uncontrolled or symptomatic arrhythmias

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

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

What this study is about

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

What this study is about