Phase I Study to Assess the Tolerability and Efficacy of Nivolumab in Patients With Hematologic Malignancies

Nivolumab will be administrated intravenously. Standard dose escalation will be used for the
intensification phase with starting dose at 1m/kg every 2 weeks for 4 doses. The DLT
observation period is 29 days starting with the first dose taken on Day 1, The study
treatment will continue until one of the discontinuation criteria is met. Each dose level
(1-2) will be tested using the 3+3 design. If level 2 of 3mg/kg is reached without DLTs,
3mg/kg will be used for the dose expansion cohort. After the intensification phase, patients
will start Nivolumab every 12 weeks maintenance phase till 2 years post allo-SCT. Patients
will also receive best supportive care (BSC), including blood product transfusions,
antimicrobials, and (as appropriate) granulocyte colony stimulating factors for neutropenic
infection or poor graft function.

Inclusion Criteria:

- Patients with hematologic malignancies status post allogeneic SCT without evidence of
disease relapse, active GVHD or history of more than Stage I skin acute GVHD; and off
immunosuppression for at least 4 weeks. At least 60 days after allo-SCT.

- Patients with high risk myeloid or lymphoid malignancies at stem cell transplant
following ASBMT criteria
(http://www.asbmt.org/displaycommon.cfm?an=1&subarticlenbr=35, under disease
classification), including but not limited to conditions listed. Refractory acute
myelogenous or lymphoid leukemia Relapsed acute myelogenous or lymphoid leukemia
Myelodysplastic syndromes with 5% or more blasts Chronic myelogenous leukemia in
chronic phase 3 or more, blast phase presently, or second accelerated phase, Recurrent
or refractory malignant lymphoma or Hodgkin's disease with less than a partial
response at transplant High risk chronic lymphocytic leukemia defined as no response
or stable disease to the most recent treatment regimen.

- Age ≥18 years. Because no dosing or adverse event data are currently available on the
use of nivolumab in patients <18 years of age, children are excluded from this study,
but will be eligible for future pediatric trials.

- ECOG/Karnofsky performance status of 0 or 1 (Karnofsky ≥70%, see Appendix A).

- Screening laboratory values must meet the following criteria and should be obtained
within 14 days prior to treatment.

- leukocytes ≥2000/mcL

- absolute neutrophil count ≥1,000/mcL(In the absence of growth factor support)

- platelets ≥50,000/mcL or recovery to the baseline count(in the absence of
transfusion)Hgb >9.0g/dL

- total bilirubin ≤1.5× institutional upper limit of normal (ULN) (except patients with
Gilbert Syndrome, who can have total bilirubin <3.0 mg/dL)

- AST(SGOT)/ALT(SGPT) ≤3 × ULN 17

- Serum creatinine ≤1.5× ULN OR

- creatinine clearance (CrCl) ≥40 mL/min (if using the Cockcroft-Gault formula below):
Female CrCl = (140 - age in years) x weight in kg x 0.85 72 x serum creatinine in
mg/dL Male CrCl = (140 - age in years) x weight in kg x 1.00 72 x serum creatinine in
mg/dL

- The effects of nivolumab on the developing human fetus are unknown. For this reason,
women of child-bearing potential (WOCBP) and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to study
entry and for the duration of study participation. WOCBP should use an adequate method
to avoid pregnancy for 23 weeks) after the last dose of investigational drug
Nivolumab. Women of childbearing potential must have a negative serum or urine
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24
hours prior to the start of nivolumab. Women must not be breastfeeding. Men who are
sexually active with WOCBP must use any contraceptive method with a failure rate of
less than 1% per year. Men receiving nivolumab and who are sexually active with WOCBP
will be instructed to adhere to contraception for a period of 31 weeks after the last
dose of investigational product. Women who are not of childbearing potential (i.e.,
who are postmenopausal or surgically sterile as well as azoospermic men) do not
require contraception. Women of childbearing potential (WOCBP) is defined as any
female who has experienced menarche and who has not undergone surgical sterilization
(hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause is
defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of
other biological or physiological causes. WOCBP receiving nivolumab will be instructed
to adhere to contraception for a period of 23 weeks (30 days plus the time required
for nivolumab to undergo five half-lives) after the last dose of investigational
product. Men receiving nivolumab and who are sexually active with WOCBP will be
instructed to adhere to contraception for a period of 31 weeks after the last dose of
investigational product. These durations have been calculated using the upper limit of
the half-life for nivolumab (25 days) and are based on the protocol requirement that
WOCBP use contraception for 5 half-lives plus 30 days and men who are sexually active
with WOCBP use contraception for 5 half-lives plus 90 days. Should a woman become
pregnant or suspect she is pregnant while she or her partner is participating in this
study, she (or the participating partner) should inform the treating physician
immediately. 18

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

Exclusion Criteria:

- History of allergy to study drug components.

- Patients who have disease relapse, active GVHD or history of more than Stage 1 skin
acute GVHD, history of cGVHD.

- Patients with active infection, un-resolving more than grade 2 transplant-related
toxicities.

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events (AEs) due to agents administered more than 4 weeks
earlier.

- Patients who are receiving any other investigational agents.

- Patients with known CNS involvement may be excluded because of poor prognosis and
concerns regarding progressive neurologic dysfunction that would confound the
evaluation of neurologic and other adverse events. However, if CNS disease is cleared
before the treatment with Nivolumab, patients could be allowed if no permanent CNS
damage.

- History of severe hypersensitivity reaction to any monoclonal antibody.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Pregnant women are excluded from this study because Nivolumab is an agent with the
potential for teratogenic or abortifacient effects. Because there is an unknown but
potential risk for adverse events in nursing infants secondary to treatment of the
mother with Nivolumab, breastfeeding should be discontinued if the mother is treated
with Nivolumab.

- Patients with known history of testing positive for human immunodeficiency virus (HIV)
or known acquired immunodeficiency syndrome (AIDS) might be enrolled if the viral load
by PCR is undetectable with/without active treatment and absolute lymphocyte count >=
350/ul. Patients with a positive test for hepatitis B virus surface antigen (HBV sAg)
or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic
infection might be enrolled if the viral load by PCR is undetectable with/without
active treatment.

- Patients with active autoimmune disease or history of autoimmune disease that might
recur, which may affect vital organ function or require immune suppressive treatment
including systemic corticosteroids, should be excluded. These include but are not
limited to patients with a history of immune related neurologic disease, multiple
sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia
gravis; systemic autoimmune disease such as SLE, connective tissue diseases,
scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis;
and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson
syndrome, or phospholipid syndrome should be excluded because of the risk of
recurrence or exacerbation of disease. Patients with vitiligo, endocrine deficiencies
including thyroiditis managed with replacement hormones including physiologic
corticosteroids are eligible. Patients with rheumatoid arthritis and other
arthropathies, Sjögren's syndrome and psoriasis controlled with topical medication and
patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid
antibodies should be evaluated for the presence of target organ involvement and
potential need for systemic treatment but should otherwise be eligible.

- Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus,
residual hypothyroidism due to autoimmune condition only requiring hormone
replacement, psoriasis not requiring systemic treatment, or conditions not expected to
recur in the absence of an external trigger (precipitating event).

- Patients should be excluded if they have a condition requiring systemic treatment with
either corticosteroids (>10 mg daily prednisone equivalents) or other
immunosuppressive medications within 14 days of study drug administration. Inhaled or
topical steroids and adrenal replacement doses <10 mg daily prednisone equivalents are
permitted in the absence of active autoimmune disease. Patients are permitted to use
topical, ocular, intraarticular, intranasal, and inhalational corticosteroids (with
minimal systemic absorption).

Physiologic replacement doses of systemic corticosteroids are permitted, even if <10 mg/day
prednisone equivalents. A brief course of corticosteroids for prophylaxis (e.g., contrast
dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type
hypersensitivity reaction caused by contact allergen) is permitted.

- Patients who have had evidence of active or acute diverticulitis, intra-abdominal
abscess, GI obstruction and abdominal carcinomatosis which are known risk factors for
bowel perforation should be evaluated for the potential need for additional treatment
before coming on study.eligible. Patients with rheumatoid arthritis and other
arthropathies, Sjögren's syndrome and psoriasis controlled with topical medication and
patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid
antibodies should be evaluated for the presence of target organ involvement and
potential need for systemic treatment but should otherwise be eligible.

- Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus,
residual hypothyroidism due to autoimmune condition only requiring hormone
replacement, psoriasis not requiring systemic treatment, or conditions not expected to
recur in the absence of an external trigger (precipitating event).

- Patients should be excluded if they have a condition requiring systemic treatment with
either corticosteroids (>10 mg daily prednisone equivalents) or other
immunosuppressive medications within 14 days of study drug administration. Inhaled or
topical steroids and adrenal replacement doses <10 mg daily prednisone equivalents are
permitted in the absence of active autoimmune disease. Patients are permitted to use
topical, ocular, intraarticular, intranasal, and inhalational corticosteroids (with
minimal systemic absorption).

Physiologic replacement doses of systemic corticosteroids are permitted, even if <10 mg/day
prednisone equivalents. A brief course of corticosteroids for prophylaxis (e.g., contrast
dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type
hypersensitivity reaction caused by contact allergen) is permitted.

- Patients who have had evidence of active or acute diverticulitis, intra-abdominal
abscess, GI obstruction and abdominal carcinomatosis which are known risk factors for
bowel perforation should be evaluated for the potential need for additional treatment
before coming on study.