Study of the PD-L1 Inhibitor Atezolizumab With or Without Low-dose, Local Radiation in Patients With Relapsed or Refractory Advanced Stage Follicular Lymphoma

Inclusion Criteria:

- Signed Informed Consent Form (ICF) Ability and willingness to comply with the
requirements of the study protocol

- Age ≥ 18 years

- Histologically documented relapsed or refractory (defined as having relapsed within 6
months to the previous treatment) follicular lymphoma grade I-IIIA

- Stage III/IV disease (Stage II is also eligible if disease is not encompassible within
a single radiation field).

- At least 1 prior treatment (no restriction to number of prior therapies)

- Site of disease amenable to low-dose, local radiotherapy (2 x 2Gy)

- At least one bi-dimensionally measurable nodal lesion > 1.5 cm in its longest diameter
by CT scan or magnetic resonance imaging, as defined by the Lugano Classification

- Site of disease deemed amenable to low-dose, local radiotherapy (2 x 2Gy) should
not be counted as target lesions.

- Previously irradiated lesions should not be counted as target lesions.

- Lesions that are intended to be used to collect tissue samples for biopsy should
not be counted as target lesions.

- Bone lesions should not be counted as target lesions.

- Adequate hematologic and end organ function, defined by the following laboratory
results obtained within 14 days prior to the first study treatment (Cycle 1, Day 1):

- ANC ≥ 1500 cells/µL

- WBC > counts 2500/µL

- Lymphocyte count ≥ 300/µL

- platelet count ≥ 75,000/µL

- Hemoglobin ≥ 9.0 g/dL

- Total bilirubin ≤ 1.5 x upper limit of normal (ULN) with the following exception:

- Patients with known Gilbert disease who have serum bilirubin level ≤ 3 x ULN may be
enrolled.

°AST and ALT ≤ 3.0 x ULN with the following exception:

- Patients with liver involvement: AST and/or ALT ≤ 5 x ULN

Alkaline phosphatase ≤ 2.5 x ULN with the following exception:

- Patients with documented liver involvement or bone metastases:

alkaline phosphatase ≤ 5 x ULN

- Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min on the basis of the
Cockcroft-Gault glomerular filtration rate estimation:

(140 - age) x (weight in kg) x (0.85 if female) 72 x (serum creatinine in mg/dL)

- For female patients of childbearing potential and male patients with partners of
childbearing potential, agreement (by patient and/or partner) to use highly effective
form(s) of contraception (i.e., one that results in a low failure rate [< 1% per year]
when used consistently and correctly) and to continue its use for 90 days after the
last dose of ATEZOLIZUMAB

- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

- Patient must require a new pre-treatment biopsy as part of their standard of care
work-up

- Willingness to undergo pre- and on-treatment biopsies unless not clinically feasible
while on treatment

- INR and aPTT ≤ 1.5 x ULN °This applies only to patients who do not receive therapeutic
anticoagulation; patients receiving therapeutic anticoagulation (such as
low-molecular-weight heparin or warfarin) should be on a stable dose.

Exclusion Criteria:

- Any approved anticancer therapy, including chemotherapy, hormonal therapy, or
radiotherapy, within 3 weeks prior to initiation of study treatment; however, the
following are allowed:

- Hormone-replacement therapy or oral contraceptives

- Herbal therapy ≥ 3 weeks prior to Cycle 1, Day 1 (herbal therapy intended as
anticancer therapy must be discontinued at least 1 week prior to Cycle 1, Day 1)

- Palliative radiotherapy for bone metastases > 2 weeks prior to Cycle 1, Day 1

- AEs from prior anticancer therapy that have not resolved to Grade ≤ 1 except for
alopecia

- Bisphosphonate therapy for symptomatic hypercalcemia

° Use of bisphosphonate therapy for other reasons (e.g., bone metastasis or
osteoporosis) is allowed.

- Known clinically significant liver disease, including active viral, alcoholic, or
other hepatitis; cirrhosis; fatty liver; and inherited liver disease

- Known central nervous system (CNS) involvement of lymphoma

- Pregnancy, lactation, or breastfeeding

- Known hypersensitivity to Chinese hamster ovary cell products or other recombinant
human antibodies

- Inability to comply with study and follow-up procedures (i.e. unwilling to undergo
protocolmandated biopsies if feasible)

- Patient does not require a pre-treatment biopsy as part of their standard of care
work- up

- History or risk of autoimmune disease, including but not limited to systemic lupus
erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis
associated with antiphospholipid syndrome, Wegener‟s granulomatosis, Sjögren‟s
syndrome, Bell‟s palsy, Guillain-Barré syndrome, multiple sclerosis, autoimmune
thyroid disease, vasculitis, or glomerulonephritis

- Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid
replacement hormone may be eligible.

- Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen may
be eligible.

- Patients with inactive inflammatory bowel disease, not currently receiving
therapy, may be eligible.

- Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis would
be excluded) are permitted provided that they meet the following conditions:

- Patients with psoriasis must have a baseline ophthalmologic exam to rule out
ocular manifestations

- Rash must cover less than 10% of body surface area (BSA)

- Disease is well controlled at baseline and only requiring low potency topical
steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, flucinolone
0.01%, desonide 0.05%, aclometasone dipropionate 0.05%)

- No acute exacerbations of underlying condition within the last 12 months (not
requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids,
biologic agents, oral calcineurin inhibitors; high potency or oral steroids)

- History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced),
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing
pneumonia, etc.), or evidence of active pneumonitis on screening chest computed
tomography (CT) scan

°History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

- Any other diseases, metabolic dysfunction, physical examination finding, or clinical
laboratory finding giving reasonable suspicion of a disease or condition that
contraindicates the use of an investigational drug or that may affect the
interpretation of the results or render the patient at high risk from treatment
complications

- History of HIV infection or active hepatitis B (chronic or acute) or hepatitis C
infection

- Patients with past or resolved hepatitis B infection (defined as having a
negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc
[antibody to hepatitis B core antigen] antibody test) are eligible.

- Patients positive for hepatitis C virus (HCV) antibody are eligible only if
polymerase chain reaction (PCR) is negative for HCV RNA.

- Active tuberculosis

- Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited to
hospitalization for complications of infection, bacteremia, or severe pneumonia

- Major surgical procedure within 28 days prior to Cycle 1, Day 1 or anticipation of
need for a major surgical procedure during the course of the study

- Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 or
anticipation that such a live, attenuated vaccine will be required during the study

° Influenza vaccination should be given during influenza season only (approximately
October to March). Patients must not receive live, attenuated influenza vaccine (e.g.,
FluMist®) within 4 weeks prior to Cycle 1, Day 1 or at any time during the study.

- Malignancies other than the disease under study within 3 years prior to Cycle 1, Day
1, with the exception of those with a negligible risk of metastasis or death and with
expected curative outcome (such as adequately treated carcinoma in situ of the cervix,
basal or squamous cell skin cancer, localized prostate cancer treated surgically with
curative intent, or ductal carcinoma in situ treated surgically with curative intent)
or undergoing active surveillance per standard-of-care management (e.g., chronic
lymphocytic leukemia Rai Stage 0, prostate cancer with Gleason score ≤ 6, and
prostate-specific antigen [PSA] ≤ 10 mg/mL, etc.)

Medication-Related Exclusion Criteria:

- Prior treatment with anti-PD-1, or anti-PD-L1 therapeutic antibody or
pathway-targeting agents

- Patients who have received prior treatment with anti-CTLA-4 may be enrolled,
provided the following requirements are met:

- Minimum of 12 weeks from the first dose of anti-CTLA-4 and > 6 weeks from the
last dose No history of severe immune-related adverse effects from anti-CTLA-4
(NCI CTCAE Grade 3 and 4)

- No history of severe immune-related adverse effects from anti-CTLA-4 (NCI CTCAE
Grade 3 and 4)

- Treatment with systemic immunostimulatory agents (including but not limited to
interferon [IFN]-a or interleukin [IL]-2) within 6 weeks or five half-lives of the
drug (whichever is shorter) prior to Cycle 1, Day 1

- Treatment with investigational agent within 4 weeks prior to Cycle 1, Day 1 (or within
five half-lives of the investigational product, whichever is longer)

- Treatment with systemic immunosuppressive medications (including but not limited to
prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor
necrosis factor [anti-TNF] agents) within 2 weeks prior to Cycle 1, Day 1

- Patients who have received acute, low-dose, systemic immunosuppressant
medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled.

- The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone)
for patients with orthostatic hypotension or adrenocortical insufficiency is
allowed.

- History of severe allergic, anaphylactic, or other hypersensitivity reactions to
chimeric or humanized antibodies or fusion proteins

- Patients with prior allogeneic bone marrow transplantation or prior solid organ
transplantation