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

Phase 2

Completed

• Conditions: Acute Myeloid Leukemia; Higher Risk Myelodysplastic Syndrome
• Interventions: Drug: Nivolumab; Drug: Low dose Cyclophosphamide (CTX) Daily; Drug: Low dose Cyclophosphamide (CTX) Every 7 Days

• Registration Number: NCT03417154
• Lead Sponsor: Masonic Cancer Center, University of Minnesota

Brief 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.

Detailed Description

Not available

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2018-01-02
• Study First Submitted QC: 2018-01-29
• Study First Posted: 2018-01-31
• Study Start: 2018-08-13
• Primary Completion: 2022-01-25
• Study Completion: 2022-01-25
• Results First Submitted: 2023-02-07
• Status Verified: 2023-05
• Results First Submitted QC: 2023-05-02
• Last Update Submitted: 2023-05-02
• Results First Posted: 2023-05-26
• Last Update Posted: 2023-05-26

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 12

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm 1: Nivolumab every 2 weeks and Cyclophosphamide daily	Low dose Cyclophosphamide (CTX) Daily	-
Arm 2: Nivolumab every 2 weeks and Cyclophosphamide every 7 days	Nivolumab	-
Arm 2: Nivolumab every 2 weeks and Cyclophosphamide every 7 days	Low dose Cyclophosphamide (CTX) Every 7 Days	-
Arm 1: Nivolumab every 2 weeks and Cyclophosphamide daily	Nivolumab	-

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.

Trial Locations

Locations (1)

University of Minnesota Masonic Cancer Center; 🇺🇸 Minneapolis, Minnesota, United States