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

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)

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. 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)

Exclusion Criteria:

- 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.

- For patients enrolling to the pirtobrutinib combination arm, patients with the
following should be discussed with the Sponsor-Investigator prior to
enrollment: 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 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):

- 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 greater than or equal to 200 per
microliter, 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). 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 antimicrobial 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), 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.)

- Note: Patients with pacemakers are eligible if they have no history of
fainting or clinically relevant arrhythmias while using the pacemaker

- Prolongation of the QT interval corrected for heart rate (QTcF) > 470 msec.
QTcF is calculated using Fridericia's Formula (QTcF): QTcF = QT/(RR0.33).

- Correction of suspected drug-induced QTcF prolongation can be attempted at
the investigator's discretion and only if clinically safe to do so with
either discontinuation of the offending drug or switch to another drug not
known to be associated with QTcF prolongation.

- Correction for underlying bundle branch block (BBB) allowed.

- Clinically significant active malabsorption syndrome or other condition likely
to affect gastrointestinal (GI) absorption of the study drug.

- 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 requiring therapeutic anticoagulation with warfarin or another vitamin
K antagonist.

- Have a known hypersensitivity to any of the excipients of Pirtobrutinib or to
any intended study medications.

- Patients who experienced a major bleeding event or grade ≥ 3 arrhythmia on
prior treatment with a BTK inhibitor. Note: Major bleeding is defined as
bleeding having one or more of the following features: potentially
life-threatening bleeding with signs or symptoms of hemodynamic compromise;
bleeding associated with a decrease in the hemoglobin level of at least 2g per
deciliter; or bleeding in a critical area or organ (e.g., retroperitoneal,
intraarticular, pericardial, epidural, or intracranial bleeding or
intramuscular bleeding with compartment syndrome)

- History of bleeding disorders (e.g. von Willebrand's disease, hemophilia).

- History of stroke or intracranial hemorrhage within 6 months of starting study
therapy.

- 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.