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

• ClinicalTrials.gov Identifier: NCT03417154
• Recruitment Status: Recruiting
• First Posted: January 31, 2018
• Last Update Posted: December 28, 2018
• Sponsor: Masonic Cancer Center, University of Minnesota
• Information provided by (Responsible Party): Masonic Cancer Center, University of Minnesota

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 (Clinical Trial)
• Estimated Enrollment: 32 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: August 13, 2018
• Estimated Primary Completion Date: February 2021
• Estimated Study Completion Date: February 2023

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 Name: 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 Name: 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 Name: 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 Name: 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 Name: CTX

Outcome Measures

Primary Outcome Measures :

1. Stage 1: Dosing Schedule of low-dose Cyclophosphamide [ Time Frame: 4 weeks from start of treatment ]
   Incidence of adverse events (AEs)
2. Stage 2: Clinical benefit and immunologic response of the combination therapy [ Time Frame: 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 :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Contacts

Contact: Amy Hays, RN; 612-626-0461; hays0024@umn.edu

Contact: Fiona He, MD; (612) 624-6982; fionahe@umn.edu

Locations

United States, Minnesota

University of Minnesota Masonic Cancer Center; Recruiting

Minneapolis, Minnesota, United States, 55455

Contact: Kim Nelson, RN 612-273-2925 knelso62@fairview.org

Sponsors and Collaborators

Masonic Cancer Center, University of Minnesota

Investigators

• Principal Investigator: Fiona He, MD; Division of Hematology, Oncology and Transplantation, Masonic Cancer Center

More Information

• Responsible Party: Masonic Cancer Center, University of Minnesota
• ClinicalTrials.gov Identifier: NCT03417154 History of Changes
• Other Study ID Numbers: 2017LS116; HM2017-33 ( Other Identifier: University of Minnesota Division of Hematology, Oncology and Transplantation )
• First Posted: January 31, 2018
• Last Update Posted: December 28, 2018
• Last Verified: December 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Masonic Cancer Center, University of Minnesota:

AML; MDS

Additional relevant MeSH terms:

Preleukemia; Myelodysplastic Syndromes; Nivolumab; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Syndrome; Disease; Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Cyclophosphamide; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological