A Phase 2 Study of glofitamab as monotherapy or in combination with polatuzumab vedotin or atezolizumab in Richter?s Transformation

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)

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.