Cytokine Induced Memory-like NK Cell Adoptive Therapy After Haploidentical Donor Hematopoietic Cell Transplantation

• ClinicalTrials.gov Identifier: NCT02782546
• Recruitment Status: Recruiting
• First Posted: May 25, 2016
• Last Update Posted: June 11, 2019
• Sponsor: Washington University School of Medicine
• Collaborators: National Institutes of Health (NIH); The V Foundation for Cancer Research; National Cancer Institute (NCI)
• Information provided by (Responsible Party): Washington University School of Medicine

Study Description

Brief Summary:

This is a standard phase 2 study powered to demonstrate improvement in the 100 day leukemia free survival to 30% from <10% expected with the use of reduced intensity haplo-HCT in this extremely high-risk patient cohort (based on the institutional experience using non-myeloablative / reduced intensity conditioning in a similar patient cohort).

A formal safety evaluation will be done after every 6th patient enrolled and the trial will be stopped if noted to have unusually higher engraftment failure (acute GVHD rates (>60% any grades or >30% grade III/IV or ≥ 50% severe cGVHD) or engraftment failure rates (≥15%).

Condition or disease	Intervention/treatment	Phase
Acute Myeloid Leukemia	Drug: Fludarabine; Drug: Cyclophosphamide; Radiation: Single dose total body irradiation; Procedure: Graft cell infusion; Drug: Tacrolimus; Drug: Mycophenolate mofetil; Drug: G-CSF; Procedure: CIML NK cell infusion; Drug: ALT-803; Procedure: Leukapheresis	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 60 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Cytokine Induced Memory-like NK Cell Adoptive Therapy After Haploidentical Donor Hematopoietic Cell Transplantation
• Actual Study Start Date: January 30, 2017
• Estimated Primary Completion Date: November 30, 2020
• Estimated Study Completion Date: February 28, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Recipient; Standard of care reduced intensity preparative regimen consisting of fludarabine, cyclophosphamide, and single dose total body irradiation (TBI) on Day -1; Graft cell infusion on Day 0; Post-transplant cyclophosphamide on Days +3 and +4; GvHD prophylaxis with tacrolimus and mycophenolate mofetil (MMF) will start on Day +5. MMF will continue till Day +35 and tacrolimus till Day +180 in the absence of GvHD; G-CSF will start on Day +7 and will continue until neutrophil engraftment as per institutional guidelines; The cytokine-induced memory like natural killer (CIML NK) cells will be infused on Day +7 without a filter or pump, slowly by gravity over at least 15 minutes.; ALT-803 will start approximately 4 hours after the CIML NK cell infusion. ALT-803 will be administered subcutaneously at a dose of 10 mcg/kg subcutaneously from Day +7 (on the day of CIML NK cell infusion), Day +12, Day +17, and Day +22 for a total of 4 doses.	Drug: Fludarabine; -Standard of care; Other Names: Fludara; 2-Fluoro-ara-A Monophosphate; 2-Fluoro-ara AMP; FAMP; Drug: Cyclophosphamide; -Standard of care; Other Names: Cytoxan; Neosar; CPM; CTX; CYT; Radiation: Single dose total body irradiation; -Standard of care; Other Name: TBI; Procedure: Graft cell infusion; -Day 0; Other Name: HCT; Drug: Tacrolimus; -GVHD prophylaxis; Other Name: Prograf; Drug: Mycophenolate mofetil; -GVHD prophylaxis; Other Names: CellCept; Myfortic; Drug: G-CSF; -Continue until neutrophil engraftment as per institutional guidelines; Other Name: Granulocyte-colony stimulating factor; Procedure: CIML NK cell infusion; -Day +7; Drug: ALT-803; -Start approximately 4 hours after CIML NK cell infusion
Experimental: Donor; Donors will receive subcutaneous G-CSF from Day -4 till Day 0 and undergo 20L apheresis per institutional guidelines.; Two consecutive days for collection are allowed in case of the target CD34+ cell dose being less than the target 4 x106/kg-bw from the first day of collection.; On Day +6 (one day before the planned CIML NK cell infusion), peripheral blood mononuclear cells will be collected by a single standard 20-L apheresis over 4-5 hours from the same haploidentical related donor that provided the HCT graft.	Procedure: Leukapheresis; -Day +6

Outcome Measures

Primary Outcome Measures :

1. Leukemia free survival rate (LFS) [ Time Frame: 1 year post transplantation ]
   -LFS is defined as the time from achievement of CR to the time of relapse, death in remission, or last follow-up.

Secondary Outcome Measures :

1. Leukemia free survival rate (LFS) [ Time Frame: 3 months post transplantation ]
   -LFS is defined as the time from achievement of CR to the time of relapse, death in remission, or last follow-up.
2. Rate of overall survival (OS) [ Time Frame: 1 year post transplantation ]
   -OS is defined as the time from the date of Day 0 until death from any cause.
3. Incidence of relapse in patients who are found to be CR (complete remission) [ Time Frame: Day 28 post transplantation ]
   -CR: Morphologically leukemia free state (i.e. bone marrow with <5% blasts by morphologic criteria and no blasts with Auer rods, no evidence of extramedullary leukemia) and absolute neutrophil count ≥1000 /μL and platelets ≥100,000 /μL. Patient must be independent of transfusions

Eligibility Criteria

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

Criteria

Recipient Inclusion Criteria:

• Refractory AML without complete remission (CR) after 2 or more cycles of induction therapy (primary induction failure), or AML relapsed after obtaining a CR and failed one or more cycles of re-induction therapy. Standard dose 10-day decitabine (20 mg/m2 daily IV x 10 days) or 7-day azacitidine (75-100 mg/m2 daily SC/IV x 7 days) will be considered as one cycle of induction therapy.
• At least 18 years of age
• Deemed to be not otherwise eligible for a non-myeloablative hematopoietic cell transplant by the treating physician.
• Available HLA-haploidentical donor that meets the criteria in the protocol
• Patients with known CNS involvement with AML are eligible provided that they have been treated and CSF is clear for at least 2 weeks prior to enrollment into the study. CNS therapy (chemotherapy or radiation) should continue as medically indicated during the study treatment.
• Karnofsky performance status > 60 %

• Adequate organ function as defined below:

  • Total bilirubin < 2 mg/dl
  • AST(SGOT)/ALT(SGPT) < 3.0 x IULN
  • Creatinine within normal institutional limits OR creatinine clearance > 60 mL/min/1.73 m2 by Cockcroft-Gault Formula
  • Oxygen saturation ≥90% on room air and adjusted DLCO of at least 40%
  • Ejection fraction ≥40%
• Able to be off of corticosteroids (10 mg or less of prednisone or equivalent doses of other systemic steroids are allowed) and any other immune suppressive medications beginning on Day -3
• Women of childbearing potential must have a negative pregnancy test within 28 days prior to study registration. Female and male patients (along with their female partners) must agree to use two forms of acceptable contraception, including one barrier method, during participation in the study and throughout the DLT evaluation period.
• Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).

Recipient Exclusion Criteria:

• Relapsed after allogeneic transplantation.
• Circulating blast count >30,000/uL by morphology or flow cytometry (cyto-reductive therapies including leukapheresis or hydroxyurea are allowed).
• Uncontrolled bacterial or viral infections, or known HIV, Hepatitis B or C infection.
• Presence of donor specific antibodies (DSA) with Mean Fluorescence Intensity (MFI) of >5000 as assessed by the single antigen bead assay, < 6 weeks prior to starting transplant conditioning
• Uncontrolled angina, severe uncontrolled ventricular arrhythmias, or EKG suggestive of acute ischemia or active conduction system abnormalities.
• New progressive pulmonary infiltrates on screening chest x-ray or chest CT scan that have not been evaluated with bronchoscopy. Infiltrates attributed to infection must be stable/ improving after 1 week of appropriate therapy (4 weeks for presumed or proven fungal infections)
• Known hypersensitivity to one or more of the study agents
• Received any investigational drugs within the 14 days prior to the first day of transplant conditioning
• Pregnant and/or breastfeeding

Donor Inclusion Criteria:

• Related donor (sibling, offspring, or offspring of sibling)
• At least 18 years of age
• HLA-haploidentical donor/recipient match by at least Class I serologic typing at the A&B locus.
• In general good health, and medically able to tolerate leukapheresis required for harvesting the NK cells for this study.
• Ability to understand and willingness to sign an IRB approved written informed consent document

Donor Exclusion Criteria:

• Positive for hepatitis, HTLV, or HIV infection
• Pregnant and/or breastfeeding

Contacts and Locations

Contacts

Contact: Amanda Cashen, M.D.; (314) 454-8323; acashen@wustl.edu

Locations

United States, Missouri

Washington University School of Medicine; Recruiting

Saint Louis, Missouri, United States, 63110

Contact: Amanda Cashen, M.D. 314-454-8323 acashen@wustl.edu

Principal Investigator: Amanda Cashen, M.D.

Sub-Investigator: Todd Fehniger, M.D., Ph.D.

Sub-Investigator: John DiPersio, M.D., Ph.D.

Sub-Investigator: Peter Westervelt, M.D., Ph.D.

Sub-Investigator: Geoffrey Uy, M.D.

Sub-Investigator: Ravi Vij, M.D.

Sub-Investigator: Camille Abboud, M.D.

Sub-Investigator: Meagan Jacoby, M.D., Ph.D.

Sub-Investigator: Iskra Pusic, M.D.

Sub-Investigator: Armin Ghobadi, M.D.

Sub-Investigator: Mark Schroeder, M.D.

Sub-Investigator: Keith Stockerl-Goldstein, M.D.

Sponsors and Collaborators

Washington University School of Medicine

National Institutes of Health (NIH)

The V Foundation for Cancer Research

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Amanda Cashen, M.D.; Washington University School of Medicine

More Information

Additional Information:

Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine 

• Responsible Party: Washington University School of Medicine
• ClinicalTrials.gov Identifier: NCT02782546 History of Changes
• Other Study ID Numbers: 201610088; 1P50CA171963-01A1 ( U.S. NIH Grant/Contract ); 2P50CA171963-06 ( U.S. NIH Grant/Contract )
• First Posted: May 25, 2016
• Last Update Posted: June 11, 2019
• Last Verified: June 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Additional relevant MeSH terms:

Mycophenolic Acid; Cyclophosphamide; Fludarabine; Fludarabine phosphate; Tacrolimus; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Myeloablative Agonists; Calcineurin Inhibitors; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antibiotics, Antineoplastic; Antibiotics, Antitubercular; Antitubercular Agents; Anti-Bacterial Agents; Anti-Infective Agents