Nivolumab and Oral Cyclophosphamide for R/R AML and HIgh Risk MDS
Condition: Acute Myeloid Leukemia; Higher Risk Myelodysplastic Syndrome
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Myelodysplastic Syndromes
Intervention: Nivolumab; Low dose Cyclophosphamide (CTX) Daily; Low dose Cyclophosphamide (CTX) Every 7 Days
Intervention description: 3mg/kg IV (or if prior alloHSCT, 1 mg/kg) over 30 minutes every 14 days on Days 1 and 15 for up to four 28-day courses.; Oral cyclophosphamide 50mg + nivolumab 3 mg/kg IV every 2 weeks for up to 4 courses of treatment; Oral cyclophosphamide 350 mg every 7 days + nivolumab 3mg/kg IV every 2 weeks for up to 4 courses of treatment
Intervention MeSH terms: Cyclophosphamide; Nivolumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 12.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: AML; MDS

Summary:

      This is a phase II trial of nivolumab and low dose cyclophosphamide (CTX) when given in
      combination to patients with relapsed/refractory acute myeloid leukemia (AML) and higher-risk
      myelodysplastic syndrome (MDS) who are not eligible for or decline hematopoietic stem cell
      transplant. It includes a randomized pilot sub-study during stage 1.
    

Eligibility criteria:

        Inclusion Criteria:

          -  ≥18 years of age

          -  Meets one of the following disease criteria:

               -  Primary (de novo) AML or higher-risk MDS with induction failure: No CR after 2 or
                  more induction attempts with high dose chemotherapy or hypomethylating agents or
                  other agents; no CR after 1 induction attempt and not eligible for a 2nd
                  induction.. Higher risk MDS defined as risk score > 4.5 based on the revised IPSS
                  criteria.

               -  Secondary AML (from antecedent hematologic malignancy or treatment-related): Not
                  in CR after 1 or more cycles of chemotherapy.

               -  Relapsed AML: Blasts ≥5% in bone marrow or peripheral blood after prior
                  attainment of CR; relapse at any time but currently ≥100 days following
                  allogeneic HCT.

               -  Relapsed MDS: Morphologic evidence of relapse or increase in blasts ≥5% in bone
                  marrow or peripheral blood after prior attainment of hematologic improvement; or
                  partial or complete response ; relapse at any time but currently ≥100 days
                  following allogeneic HCT..

          -  ECOG Performance Status ≤ 2 - refer to Appendix II

          -  Adequate organ function within 14 days of study registration defined as:

               -  Absolute Lymphocyte Count: ≥ 500 cells/mm3

               -  Hepatic: total bilirubin ≤ 3 x upper limit of institutional normal (ULN); ALT and
                  AST ≤ 5 x ULN

               -  Renal: Serum creatinine ≤ 2 mg/dL

               -  Pulmonary: No oxygen requirement on room air or requiring ≤ 2L supplemental O2

          -  Sexually active females of child bearing potential and males with partners of child
             bearing potential must agree to use effective contraception during therapy and
             continuing (23 weeks for females, 31 weeks for males) after the last dose of nivolumab

          -  Voluntary written consent

        Exclusion Criteria:

          -  Pregnant or breastfeeding -The agents used in this study fall under Pregnancy Category
             D - Drugs which have caused, are suspected to have caused or may be expected to cause,
             an increased incidence of human fetal malformations or irreversible damage. Women of
             childbearing potential must have a negative pregnancy test (urine or serum) within 7
             days of study drug administration.

          -  Prior allogeneic hematopoietic stem cell transplantation within previous 100 days
             (note patients with a prior alloHSCT receive nivolumab at the reduced dose of 1 mg/kg)

          -  Signs or symptoms of active graft versus host disease

          -  Active pneumonitis or uncontrolled infection

          -  Received chemotherapy drugs within previous 2 weeks

          -  Estimated life expectancy <28 days in the opinion of the enrolling investigator