MT2014-25: Haplo NK With SQ IL-15 in Adult Relapsed or Refractory AML Patients

MT2014-25: Haploidentical Donor Natural Killer (NK) Cell Infusion With Subcutaneous Recombinant Human IL-15 (rhIL-15) in Adults With Refractory or Relapsed Acute Myelogenous Leukemia (AML)

A phase II trial of CD3/CD19 depleted, IL-15 activated, donor natural killer (NK) cells in adults and subcutaneous IL-15 given after a preparative regimen for the treatment of relapsed or refractory acute myelogenous leukemia (AML). The primary objective is to study the potential efficacy of NK cells and IL-15 to achieve complete remission while maintaining safety.

Study Overview

• Status: Completed
• Conditions: Acute Myelogenous Leukemia
• Intervention / Treatment: Biological: IL-15

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Masonic Cancer Center at University of Minnesota

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 66 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria (Recipient):

• Meets ONE of the following disease criteria:

  1. Primary AML induction failure: no CR after 2 or more induction attempts
  2. Relapsed AML or Secondary AML (from MDS or treatment related): not in CR after 1 or more cycles of standard re-induction therapy
  3. AML relapsed > 2 months after transplant: No re-induction required, and no more than 1 re-induction cycle is allowed.

  4. Relapsed AML for patients > 60 years of age the 1 cycle of standard chemotherapy is not required if either of the following criteria is met:

     • Relapse within 6 months of last chemotherapy
     • BM blast count < 30% within 10 days of starting protocol therapy
• Available related HLA-haploidentical donor (aged 14 to 75 years) by at least Class I serologic typing at the A&B locus
• Karnofsky Performance Status ≥ 60%
• Patients must have adequate organ within 14 days (28 days for pulmonary and cardiac) of study registration
• Able to be off prednisone or other immunosuppressive medications for at least 3 days prior to NK cell infusion (excluding preparative regimen pre-medications).
• Agrees to use contraception prior to study entry and for the duration of study participation.

Exclusion Criteria (Recipient):

• Bi-phenotypic acute leukemia.
• Transplant < 60 days prior to study enrollment.
• Active autoimmune disease.
• History of severe asthma
• Uncontrolled intercurrent illness
• New or progressive pulmonary infiltrates on screening chest x-ray or chest CT scan that has not been evaluated with bronchoscopy
• Pleural effusion large enough to be detectable on chest x-ray.
• Pregnant women
• History of HIV, active or chronic hepatitis B, hepatitis C or HTLV-I infection
• Known hypersensitivity to any of the study agents used
• Received investigational drugs within the 14 days of study registration.
• Known active CNS involvement.

Criteria For Initial Donor Selection:

• Related donors (sibling, parent, offspring, parent or offspring of an HLA identical sibling).
• 14-75 years of age.
• At least 40 kilogram body weight.
• In general good health as determined by the evaluating medical provider.
• HLA-haploidentical donor/recipient match by at least Class I serologic typing at the A&B locus.
• Not pregnant.
• Able and willing to undergo apheresis.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Preparative Regimen and SubQ rHuIL-15; Preparative Regimen of Fludarabine and Cyclophosphamide IL-15 Activation of Donor NK Cells: IL-15 to Facilitate NK Cell Survival and Expansion

Biological: IL-15; Preparative Regimen: Fludarabine 25 mg/m2 x 5 days start day -6 Cyclophosphamide 60 mg/kg x 2 days on day -5 and -4 (if < 4 months from prior transplant, omit day -4 dose) IL-15 Activated Donor NK Cells: The apheresis product (collected day -1) will be enriched for NK cells with the large-scale CliniMacs® device (Miltenyi) by depletion of CD3+ cells to remove T-lymphocytes and depletion of CD19+ cells to remove B-lymphocytes. The NK cell enriched product will be activated by overnight incubation with10 ng/ml IL-15 under GMP conditions and infused on day 0. IL-15 to Facilitate NK Cell Survival and Expansion: IL-15 at 2 mcg/kg subcutaneously (SC) beginning day +1, once a day for 5 days followed by a 2 day rest, and then once a day for 5 days for 10 doses total; Other Names: Interleukin-15

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
< 5% Marrow Blast, no Circulating Peripheral Blasts and Neutrophil Count of > 1 x 10^9/L	Without platelet recovery	Day 42 post NK cell infusion

Secondary Outcome Measures

Outcome Measure	Time Frame
In Vivo Expansion (>100) of NK Cells (Defined at CD56+/CD3- Lymphocytes)	Day 14 post NK cell infusion
Proportion of Patients Experiencing Grade, 3, 4, and 5 Toxicities (Assessed by CTCAE v. 4)	Days 1-5 and Days 8-12, 24 hours after the last IL-15 dose, Day +28, Day +42
Treatment Related Mortality	6 months post-therapy
Number of Subjects Achieving Complete Response, Defined as in Vivo Donor Derived NK Cell Expansion of > 100 Donor Derived NK Cells.	Day 42 post NK cell infusion

Collaborators and Investigators

• Sponsor: Masonic Cancer Center, University of Minnesota
• Investigators: Principal Investigator: Jeffrey Miller, MD, Masonic Cancer Center, University of Minnesota

Publications and helpful links

General Publications

• Cooley S, He F, Bachanova V, Vercellotti GM, DeFor TE, Curtsinger JM, Robertson P, Grzywacz B, Conlon KC, Waldmann TA, McKenna DH, Blazar BR, Weisdorf DJ, Miller JS. First-in-human trial of rhIL-15 and haploidentical natural killer cell therapy for advanced acute myeloid leukemia. Blood Adv. 2019 Jul 9;3(13):1970-1980. doi: 10.1182/bloodadvances.2018028332.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2015
• Primary Completion (Actual): December 1, 2016
• Study Completion (Actual): December 1, 2016

Study Registration Dates

• First Submitted: February 16, 2015
• First Submitted That Met QC Criteria: March 17, 2015
• First Posted (Estimate): March 24, 2015

Study Record Updates

• Last Update Posted (Actual): February 20, 2018
• Last Update Submitted That Met QC Criteria: January 22, 2018
• Last Verified: December 1, 2017

More Information

Terms related to this study

• Keywords: Relapsed; Refractory; AML
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
• Other Study ID Numbers: 2014LS092