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

Sponsor

Masonic Cancer Center, University of Minnesota (Other)

Overall Status

Completed

CT.gov ID

NCT03417154

Collaborator

(none)

Enrollment

Location

Arms

41.1

Actual Duration (Months)

0.3

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia Higher Risk Myelodysplastic Syndrome	Drug: Nivolumab Drug: Stage 1 Arm 1: Low dose Cyclophosphamide (CTX) Drug: Stage 1 Arm 2: Low dose Cyclophosphamide (CTX) Drug: Stage 2: Low dose Cyclophosphamide (CTX)	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

12 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Aug 13, 2018

Actual Primary Completion Date :

Jan 14, 2022

Actual Study Completion Date :

Jan 14, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Stage 1 Arms 1&2: Nivolumab and Cyclophosphamide	Drug: Nivolumab 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. Other Names: Opdivo Drug: Stage 1 Arm 1: Low dose Cyclophosphamide (CTX) Oral cyclophosphamide 50mg + nivolumab 3 mg/kg IV every 2 weeks for up to 4 courses of treatment Other Names: CTX Drug: Stage 1 Arm 2: Low dose Cyclophosphamide (CTX) Oral cyclophosphamide 350 mg every 7 days + nivolumab 3mg/kg IV every 2 weeks for up to 4 courses of treatment Other Names: CTX
Experimental: Stage 2: Nivolumab and Cyclophosphamide	Drug: Nivolumab 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. Other Names: Opdivo Drug: Stage 2: Low dose Cyclophosphamide (CTX) Stage 2: Oral cyclophosphamide as assigned for up to 4 treatment courses with each treatment course equal to 28 days. Other Names: CTX

Arm

Intervention/Treatment

Experimental: Stage 1 Arms 1&2: Nivolumab and Cyclophosphamide

Drug: Nivolumab

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.

Other Names:

Opdivo

Drug: Stage 1 Arm 1: Low dose Cyclophosphamide (CTX)

Oral cyclophosphamide 50mg + nivolumab 3 mg/kg IV every 2 weeks for up to 4 courses of treatment

Other Names:

CTX

Drug: Stage 1 Arm 2: Low dose Cyclophosphamide (CTX)

Oral cyclophosphamide 350 mg every 7 days + nivolumab 3mg/kg IV every 2 weeks for up to 4 courses of treatment

Other Names:

CTX

Experimental: Stage 2: Nivolumab and Cyclophosphamide

Drug: Nivolumab

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.

Other Names:

Opdivo

Drug: Stage 2: Low dose Cyclophosphamide (CTX)

Stage 2: Oral cyclophosphamide as assigned for up to 4 treatment courses with each treatment course equal to 28 days.

Other Names:

CTX

Outcome Measures

Primary Outcome Measures

Stage 1: Dosing Schedule of low-dose Cyclophosphamide [4 weeks from start of treatment]
Incidence of adverse events (AEs)
Stage 2: 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.

Secondary Outcome Measures

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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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