RITUXIMAB + IMMUNOTHERAPY IN FOLLICULAR LYMPHOMA

This research study is a Phase 1 clinical trial. Phase 1 clinical trials test the safety of
an investigational intervention and also try to define the appropriate dose of the
investigational intervention to use for further studies. "Investigational" means that the
intervention is being studied.

Utomilumab and avelumab are drugs which may stimulate the immune system against tumor cells.
Because they activate the immune system, they are sometimes called immunotherapy drugs. The
FDA (the U.S. Food and Drug Administration) has not approved utomilumab or avelumab for
treatment of this cancer.

Rituximab is approved by the FDA (the U.S. Food and Drug Administration) as a treatment
option for this disease.

The purpose of this research is to learn about the effects of combining the immunotherapy
drugs utomilumab and avelumab with rituximab in follicular lymphoma. The investigators hope
to learn how safe the combinations of treatments are for participants with follicular
lymphoma.

Inclusion Criteria:

- Patients must have histologically determined follicular lymphoma, grade 1-3A, with
pathologic review at the participating institutions, that has either:

- Relapsed or primary refractory after at least one line of therapy including
anti-CD-20 monoclonal antibody treatment (part A) or;

- Has had no previous anti-lymphoma therapy other than corticosteroids or
radiotherapy (part B).

- Patients with active histologic transformation are excluded. Relapsed/refractory
patients with prior transformation may be included as long as there is no evidence of
transformation at the time of study entry by pathology, imaging, or clinical status

- Patients in part B, without prior anti-lymphoma therapy, must be in need of treatment
as defined by any of the following criteria:

- Symptomatic adenopathy

- Organ function impairment due to disease involvement, including cytopenias due to
marrow involvement (WBC <1.5x109/L; absolute neutrophil count [ANC] <1.0x109/L,
Hgb <10g/dL; platelets <100x109/L)

- Constitutional symptoms

- Maximum diameter of disease > 7cm

-->3 nodal sites of involvement

- Risk of local compressive symptoms

- Splenomegaly (craniocaudal diameter > 16cm on CT imaging)

- Clinically significant pleural or peritoneal effusion

- Leukemic phase (>5x109/L circulating malignant cells)

- Rapid generalized disease progression

- Renal infiltration

- Bone lesions

- Patients may have had a prior autologous stem cell transplant and may have been
treated with autologous chimeric antigen receptor T-cells (CAR T-cells).

- Not in need of urgent cytoreductive therapy in the opinion of the investigator

- Measurable disease that has not been previously irradiated on CT scans of at least 1.5
cm, OR if the patient has had previous radiation to the marker lesion(s), there must
be evidence of progression since the radiation. Imaging must be completed no greater
than 6 weeks prior to study enrollment.

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (see Appendix A)

- Adequate hematologic and organ function:

- Absolute neutrophil count > 1.0x109/L unless due to marrow involvement by
lymphoma in which case ANC must be >0.5x109/L

- Platelets > 75 x109/L, unless due to marrow involvement by lymphoma, in which
case platelets must be >50 x109/L

- Creatinine < 1.5 x ULN (upper limit of normal) or estimated GFR > 40ml/min

- Total bilirubin < 1.5 X ULN, unless Gilbert syndrome, in which case direct
bilirubin must be < 3 x ULN

- AST/ALT < 2.5 X ULN, unless documented liver involvement by lymphoma, in which case
AST/ALT must be <5 x ULN

- Age >18 years

- Ability to understand and the willingness to sign a written informed consent document.

- Willingness to provide pre-treatment (or recent archival w/o intervening therapy), and
on-treatment tumor samples by core needle or excisional surgical biopsy

Exclusion Criteria:

- Patients currently receiving anticancer therapies or who have received anticancer
therapies within 28 days of the start of study drug (including chemotherapy, radiation
therapy, antibody based therapy, etc.), or 56 days for radioimmunotherapy. Steroids
for symptom palliation are allowed, but must be either discontinued or on stable doses
of < 10mg daily of prednisone (or the equivalent) at the time of initiation of
protocol therapy.

- Patients may not be receiving any other investigational agents, or have received
investigational agents within 4 weeks (or 3 half-lives, whichever is longer) of
beginning treatment.

- 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 previously received therapy with any drug that works by a similar
mechanism of action as any drug being tested in a given cohort will be excluded from
that cohort but will be allowed to enroll in other open cohorts.

- Patients who have undergone prior allogeneic stem cell transplantation

- Patients with a history of or active autoimmune disease (except controlled asthma,
Hashimoto thyroiditis, atopic dermatitis, and/or vitiligo), or requiring systemic
corticosteroids at a dose of 10mg prednisone equivalent daily. Patients with a history
of autoimmune disease who never required corticosteroids and with no evidence of
disease activity, and in whom the risk of reactivation is felt not to be serious, may
be enrolled after discussion with the overall study chair. Exceptions to this are
patients with a history of inflammatory bowel disease (ulcerative colitis and Crohn's
disease). These patients are excluded regardless of whether their disease is active or
inactive.

- Patients with active pneumonitis or colitis, or patients with chronic liver disease
and/or cirrhosis

- 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) or patients that may require
major surgery during the course of the study.

- Patients with known leptomeningeal or brain metastases. Imaging or spinal fluid
analysis to exclude CNS involvement is not required, unless there is clinical
suspicion by the treating investigator.

- Patients with known HIV infection or hepatitis B or C infection. Testing for HIV is
optional. Testing for hepatitis B and C is mandatory. Patients with hepatitis B core
Ab positivity but negative surface antigen and negative viral load may be enrolled if
they can be treated with a prophylactic agent (eg, entecavir); patients with hepatitis
C seropositivity who have undergone successful treatment with negative viral load can
also be enrolled.

- Patients with a systemic fungal, bacterial, viral, or other infection not controlled
(defined as exhibiting ongoing signs/symptoms related to the infection and without
improvement, despite appropriate antibiotics or other treatment).

- Prior history of another malignancy (except for non-melanoma skin cancer or in situ
cervical or breast cancer) unless disease free for at least three years. Patients with
prostate cancer are allowed if PSA is less than 1.

- Patients should not have received immunization with attenuated live vaccine within one
week of study entry or during study period.

- Female patients who are pregnant or breast feeding, or adults of reproductive
potential who are not using effective birth control methods. Women of child bearing
potential (WOCBP) or male study participants of reproductive potential must agree to
use double barrier birth control method of contraception during the course of the
study treatment period and for 3 months after completing study treatment. WOCBP are
defined as sexually mature women who have not undergone a hysterectomy or who are not
postmenopausal (no menses) for at least 12 consecutive months. WOCBP must have a
negative urine or serum pregnancy test within 14 days prior to administration of
treatment.

- History of noncompliance to medical regimens.

- Patients who have any severe and/or uncontrolled medical conditions or other
conditions that could affect their participation in the study such as:

- New York Heart Association Class III or IV cardiac disease, including
pre-existing clinically significant arrhythmia, congestive heart failure, or
cardiomyopathy

- Patients with a history of previous anthracycline treatment and are at risk of
cardiac failure (New York Heart Association Class II or above) are excluded from
cohorts A2, A3, and B2 (cohorts that include PF04518600)

- Unstable angina pectoris, symptomatic congestive heart failure, myocardial
infarction within 6 months of start of study drug, serious uncontrolled cardiac
arrhythmia or any other clinically significant cardiac disease

- Patients with any one of the following currently on or in the previous 6 months will
be excluded from cohorts A2, A3, and B2 (any cohort that includes treatment with
PF04518600) myocardial infarction, congenital long QT syndrome, torsade's de points,
left anterior hemiblock (bifascicular block), unstable angina, coronary/peripheral
artery bypass graft, cerebrovascular accident, transient ischemic attack or
symptomatic pulmonary embolism or other clinically significant episode of
thrombo-embolic disease*. Ongoing cardiac dysrhythmias of NCI CTCAE grade > 2, atrial
fibrillation of any grade, or QTcF interval >470msec at screening (except in case of
right bundle branch block, these cases must be discussed with the principal
investigator). *Cases must be discussed in detail with the principal investigator to
judge eligibility. Anticoagulation (heparin only, no vitamin K antagonists or factor
Xa inhibitors will be allowed if indicated.

- Other uncontrolled intercurrent illness that would limit adherence to study
requirements