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

Primary Purpose

Acute Myeloid Leukemia, Higher Risk Myelodysplastic Syndrome

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Nivolumab

Low dose Cyclophosphamide (CTX) Daily

Low dose Cyclophosphamide (CTX) Every 7 Days

About this trial

This is an interventional treatment trial for Acute Myeloid Leukemia focused on measuring AML, MDS

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

University of Minnesota Masonic Cancer Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Arm 1: Nivolumab every 2 weeks and Cyclophosphamide daily

Arm 2: Nivolumab every 2 weeks and Cyclophosphamide every 7 days

Arm Description

Outcomes

Primary Outcome Measures

Stage 1: Dosing Schedule of Low-dose Cyclophosphamide

Number of participants with adverse events

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%

Secondary Outcome Measures

Objective Response Rate (ORR)

Incidence of overall response.

Progression Free Survival (PFS)

Incidence of progression free survival.

Overall Survival (OS)

Incidence of overall survival.

Full Information

NCT ID

NCT03417154

First Posted

January 2, 2018

Last Updated

May 2, 2023

Sponsor

Masonic Cancer Center, University of Minnesota

1. Study Identification

Unique Protocol Identification Number

NCT03417154

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

May 2023

Overall Recruitment Status

Completed

Study Start Date

August 13, 2018 (Actual)

Primary Completion Date

January 25, 2022 (Actual)

Study Completion Date

January 25, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Masonic Cancer Center, University of Minnesota

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Acute Myeloid Leukemia, Higher Risk Myelodysplastic Syndrome

Keywords

AML, MDS

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

12 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm 1: Nivolumab every 2 weeks and Cyclophosphamide daily

Arm Type

Experimental

Arm Title

Arm 2: Nivolumab every 2 weeks and Cyclophosphamide every 7 days

Arm Type

Experimental

Intervention Type

Drug

Intervention Name(s)

Nivolumab

Other Intervention Name(s)

Opdivo

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.

Intervention Type

Drug

Intervention Name(s)

Low dose Cyclophosphamide (CTX) Daily

Other Intervention Name(s)

CTX

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Low dose Cyclophosphamide (CTX) Every 7 Days

Other Intervention Name(s)

CTX

Intervention Description

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

Primary Outcome Measure Information:

Title

Stage 1: Dosing Schedule of Low-dose Cyclophosphamide

Description

Number of participants with adverse events

Time Frame

4 weeks from start of treatment

Title

Clinical Benefit and Immunologic Response of the Combination Therapy

Description

Time Frame

90 days from start of treatment

Secondary Outcome Measure Information:

Title

Objective Response Rate (ORR)

Description

Incidence of overall response.

Time Frame

30 days from start of treatment

Title

Progression Free Survival (PFS)

Description

Incidence of progression free survival.

Time Frame

6 months from start of treatment

Title

Overall Survival (OS)

Description

Incidence of overall survival.

Time Frame

6 months from start of treatment

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Fiona He, MD

Organizational Affiliation

Division of Hematology, Oncology and Transplantation, Masonic Cancer Center

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Minnesota Masonic Cancer Center

City

Minneapolis

State/Province

Minnesota

ZIP/Postal Code

55455

Country

United States

12. IPD Sharing Statement

Learn more about this trial

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

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