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

Study Overview
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Brief Summary
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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.

Official Title
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Nivolumab and Oral Cyclophosphamide for Relapsed/Refractory Acute Myeloid Leukemia (AML) and Higher-Risk Myelodysplastic Syndrome (MDS)

Conditions
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Acute Myeloid Leukemia, Higher Risk Myelodysplastic Syndrome

Intervention / Treatment
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* Drug: Nivolumab
* Drug: Low dose Cyclophosphamide (CTX) Daily
* Drug: Low dose Cyclophosphamide (CTX) Every 7 Days


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: Nivolumab every 2 weeks and Cyclophosphamide daily<br> | Drug: Nivolumab<br>* 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.<br>* Other names: Opdivo;Drug: Low dose Cyclophosphamide (CTX) Daily<br>* Oral cyclophosphamide 50mg + nivolumab 3 mg/kg IV every 2 weeks for up to 4 courses of treatment<br>* Other names: CTX;|
| Experimental: Arm 2: Nivolumab every 2 weeks and Cyclophosphamide every 7 days<br> | Drug: Nivolumab<br>* 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.<br>* Other names: Opdivo;Drug: Low dose Cyclophosphamide (CTX) Every 7 Days<br>* Oral cyclophosphamide 350 mg every 7 days + nivolumab 3mg/kg IV every 2 weeks for up to 4 courses of treatment<br>* Other names: CTX;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stage 1: Dosing Schedule of Low-dose Cyclophosphamide | Number of participants with adverse events | 4 weeks from start of treatment | 
| Clinical Benefit and Immunologic Response of the Combination Therapy | 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% | 90 days from start of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | Incidence of overall response. | 30 days from start of treatment | 
| Progression Free Survival (PFS) | Incidence of progression free survival. | 6 months from start of treatment | 
| Overall Survival (OS) | Incidence of overall survival. | 6 months from start of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AML, MDS