Nivolumab and Tocilizumab for Relapsed Hematological Malignancy Post-allogeneic Transplant

Study disease: Hematologic malignancies including, but not exclusive to, multiple myeloma,
acute/chronic leukemia, lymphoma, and myelodysplastic syndrome that has relapsed after
allogeneic transplant.

Study Rationale: Phase 1 Safety/Dose Finding Study: To determine the safety and maximum
tolerated dose of Nivolumab in combination with Tocilizumab.

Study Agent Description:

Tocilizumab is a monoclonal antibody and immunosuppressant; specifically, tocilizumab is an
interleukin-6 (IL-6) receptor antagonist.

Nivolumab is a human immunoglobulin IgG4 monoclonal antibody that binds to the PD-1 receptor
of T cells blocking its interaction with PD-L1 and PD-L2, thereby enhancing T-cell
proliferation and allowing the immune system to attack the tumor.

Number of Subjects: A maximum of 12 patients will be enrolled on this Phase 1 study.

Duration of Follow-up: Patients will be followed for up to one year post-treatment for
survival and response.

Inclusion Criteria

1. Age≥18 years with hematological malignancies who have undergone allogeneic transplant
for hematological malignancy

2. Relapsed disease post-allogeneic transplant defined as follows i. Acute or Chronic
Leukemia or myelodysplastic or myeloproliferative disorders or NK cell neoplasms: Bone
marrow (BM) with ≥5% disease involvement or peripheral blood evidence of overt relapse
ii. Lymphoma: BM evidence of relapsed/persistent disease or PET/CT or CT evidence of
persistent/progressive lymphadenopathy consistent with active lymphoma. Active disease
defined as nodal lesions greater than 20 mm in the long axis or extranodal lesions >10
mm in long and short axis or bone marrow involvement that is biopsy proven

3. Karnofsky performance status ≥70 (See Appendix A for details)

4. Creatinine ≤ 2x upper limit of normal (ULN)

5. Adequate hepatic function, defined as AST and ALT ≤3 x ULN. Serum bilirubin and
alkaline phosphatase ≤3 x ULN, or considered not clinically significant (e.g.
Gilbert's or indirect hyperbilirubinemia) or felt to be due to underlying disease.

6. Without evidence of active acute or chronic GVHD

7. Off all immunosuppression and corticosteroids (other than replacement dose steroids
defined as equivalent to a maximum of 10 mg Prednisone daily) for ≥10 days from first
treatment.

8. Off all disease targeted treatments for ≥10 days to first treatment day

9. Able to provide written informed consent

10. Women of child-bearing potential and men must agree to use adequate contraception for
the duration of study participation and for 120 days after the last treatment with
nivolumab.

11. No FDA approved, more appropriate therapies available for disease control as
determined by the treating physician

Exclusion Criteria

1. Positive beta-HCG in female of child-bearing potential

2. CD3 donor chimerism <5% within 4 weeks of starting study treatment

3. Evidence of active acute or chronic GVHD and/or on treatment for GVHD.

4. Prior administration of donor lymphocyte infusion post-allogeneic transplant within
the last 6 months of study treatment

5. History of or active autoimmune disease, or other syndrome that requires systemic
steroids.

6. History of allergic reactions attributed to compounds of similar chemical or biologic
composition to nivolumab.

7. Uncontrolled or active infections on treatment

8. Confirmed active human immunodeficiency virus (HIV), Hepatitis B or C infection.

9. Presence of ≥grade 3 non-hematologic toxicities as per CTCAE version 5 from any
previous treatment unless it is felt to be due to underlying disease.

10. Concurrent use of investigational therapeutic agents or enrollment on another
therapeutic clinical trial at any institution.

a. Minimum of 4 weeks from last dose of investigational agent

11. Prior exposure to PD-1 or CTLA4 antibodies in the post-allogeneic transplant setting.
Patients who received such agents pre-allogeneic transplant will NOT be excluded

12. Prior exposure to daratumumab in the post-allogeneic transplant setting within 2
months of start date of treatment with this investigational protocol. Patients who
received this agent pre-allogeneic transplant will NOT be excluded

13. Concurrent therapies targeted at disease relapse. However, previous treatments for
relapsed disease are allowed. Concurrent active malignancy (exceptions: treated solid
malignancy in >2 years' remission, treated basal or squamous cell carcinomas of the
skin)

14. History of Crohn's disease or ulcerative colitis

15. History of demyelinating disorder

16. Prior intolerance or allergy to Tocilizumab