Nivolumab and Oral Cyclophosphamide for R/R AML and HIgh Risk MDS

• Nivolumab (Drug), also known as Opdivo: 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.
• Low dose Cyclophosphamide (CTX) Daily (Drug), also known as CTX: Oral cyclophosphamide 50mg + nivolumab 3 mg/kg IV every 2 weeks for up to 4 courses of treatment
• Low dose Cyclophosphamide (CTX) Every 7 Days (Drug), also known as CTX: Oral cyclophosphamide 350 mg every 7 days + nivolumab 3mg/kg IV every 2 weeks for up to 4 courses of treatment

Primary outcomes

• Stage 1: Dosing Schedule of Low-dose Cyclophosphamide [4 weeks from start of treatment]: Number of participants with adverse events
• Clinical Benefit and Immunologic Response of the Combination Therapy [90 days from start of treatment]: Overall response rate at 90 days from treatment start. Response is defined as CR + CRi + CRp + PR in AML and CR/PR/hematologic improvement (HI) in MDS. Complete Remission (CR) - subjects must have bone marrow regenerating normal hematopoietic cells and achieve a morphologic leukemia-free state, an ANC > 1 x 109/L and platelet count ≥ 100 x 109/L and normal marrow differential with < 5% blasts, and they will be RBC and platelet transfusion independent (defined as 1 week without RBC transfusion and 1 week without platelet transfusion). There should be no evidence of extramedullary leukemia Complete Remission with Incomplete Hematologic Recovery (CRi) - subjects must fulfill all the criteria for CR except for incomplete hematological recovery Complete Remission with Incomplete Platelet Recovery (CRp) - subjects must achieve CR except for incomplete platelet recovery Partial Remission (PR) - subjects must have ≥50% bone marrow blast reduction or decrease to 5 to 25%

Secondary outcomes

• Objective Response Rate (ORR) [30 days from start of treatment]: Incidence of overall response.
• Progression Free Survival (PFS) [6 months from start of treatment]: Incidence of progression free survival.
• Overall Survival (OS) [6 months from start of treatment]: Incidence of overall survival.

Sex: All, ages: 18 Years to any

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

Participant flow

Outcome results

• Stage 1: Dosing Schedule of Low-dose Cyclophosphamide (Primary), Count of participants, Participants: Arm 1: Nivolumab Every 2 Weeks and Cyclophosphamide Daily 6; Arm 2: Nivolumab Every 2 Weeks and Cyclophosphamide Every 7 Days 6
• Clinical Benefit and Immunologic Response of the Combination Therapy (Primary), Count of participants, Participants: Arm 1: Nivolumab Every 2 Weeks and Cyclophosphamide Daily 0; Arm 2: Nivolumab Every 2 Weeks and Cyclophosphamide Every 7 Days 0
• Objective Response Rate (ORR) (Secondary), Count of participants, Participants: Arm 1: Nivolumab Every 2 Weeks and Cyclophosphamide Daily 0; Arm 2: Nivolumab Every 2 Weeks and Cyclophosphamide Every 7 Days 0
• Progression Free Survival (PFS) (Secondary), Count of participants, Participants: Arm 1: Nivolumab Every 2 Weeks and Cyclophosphamide Daily 0; Arm 2: Nivolumab Every 2 Weeks and Cyclophosphamide Every 7 Days 0
• Overall Survival (OS) (Secondary), Count of participants, Participants: Arm 1: Nivolumab Every 2 Weeks and Cyclophosphamide Daily 4; Arm 2: Nivolumab Every 2 Weeks and Cyclophosphamide Every 7 Days 5

Adverse events

Time frame: Adverse events were collected from on treatment date up until 6 months after the off treatment date, on average of 1 year.

Serious adverse events by term

Other adverse events by term

• Study Protocol and Statistical Analysis Plan (PDF, 2021-05-12)
• Informed Consent Form (PDF, 2021-09-23)

• Fiona He, MD, Principal investigator, Division of Hematology, Oncology and Transplantation, Masonic Cancer Center