NK Cell Based Non-Myeloablative Transplantation in Acute Myeloid Diseases

NCT ID: NCT01370213

Last Updated: 2020-05-13

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 25 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-09-30
• Study Completion Date: 2017-04-30

Brief Summary

This is a phase II multi-institutional therapeutic study of NK-cell based nonmyeloablative haploidentical transplantation for the treatment of high-risk acute myeloid diseases. Enrollment will use a two-stage design. Stage 1 will enroll 15 patients unless an early stopping rule is met. If 9 or more of these first 15 patients achieve leukemia free neutrophil engraftment at day +28 accrual will move to stage 2. In stage 2, an additional 28 patients will be enrolled for a total of 43 patients. Patients will be followed for disease response for 2 years.

Detailed Description

A reduced intensity conditioning using Fludara, Cytoxan, and irradiation will start on day -22, followed by infusion of donor NK (natural killer) cells on day-17, 6 doses of interleukin-2 (IL-2) to promote NK expansion (day -17 to day -7), 2 doses of ATG for additional immunosuppression to promote engraftment (day -5 to -4), and infusion of a TCR α/β-depleted same donor graft on day 0.

Conditions

Acute Myeloid Leukemia; Myelodysplastic Syndrome

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

CD34 Schema - High-Risk Acute Myeloid Disease

Patients with high risk acute myeloid disease treated with preparative regimen including Fludara, Cytoxan and total body irradiation followed by haploidentical donor NK cells, Interleukin-2, rabbit anti-thymocyte globulin, and filgrastim mobilized CD34+ selected peripheral blood stem cell graft from the same donor.

Group Type: EXPERIMENTAL

Preparative Regimen

Intervention Type: DRUG

Preparative Regimen:

1) fludarabine 40 mg/m^2 x 4 doses on Days -22 through -19 pretransplant, 2) cyclophosphamide 50 mg/kg x 2 doses on Days -20 and -19 pretransplant, 3) total body irradiation 200 cGy twice a day (BID) (at least 6 hours apart) on Day -18 pretransplant,

NK Cells

Intervention Type: BIOLOGICAL

CD3\^- CD19\^- selected, interleukin-2 (IL-2) activated, haploidentical donor natural killer (NK) cells infused on Day -17 pretransplant.

Interleukin-2

Intervention Type: DRUG

Interleukin-2 6 million units (MU) subcutaneously (SQ) every other day for 6 doses beginning evening of NK cell infusion

CD34 Graft/Anti-thymocyte globulin

Intervention Type: BIOLOGICAL

Single donor filgrastim mobilized CD34+ selected peripheral blood stem cell graft (minimum cell dose of 5 x 10\^6/kg) on day 0. Rabbit anti-thymocyte globulin (ATG) will be administered on day -1 (0.5 mg/kg) and day +1 and +2 (2.5 mg/kg) pretransplant per institutional guidelines. ATG dosing not identical for all patients.

TCRα/β Schema - High-Risk Acute Myeloid Disease

Patients with high risk acute myeloid disease treated with preparative regimen including Fludara, Cytoxan and total body irradiation followed by haploidentical donor NK cells, Interleukin-2, rabbit anti-thymocyte globulin, and same donor TCR α/β-depleted cells infusion.

Group Type: EXPERIMENTAL

Preparative Regimen

Intervention Type: DRUG

Preparative Regimen:

1) fludarabine 40 mg/m^2 x 4 doses on Days -22 through -19 pretransplant, 2) cyclophosphamide 50 mg/kg x 2 doses on Days -20 and -19 pretransplant, 3) total body irradiation 200 cGy twice a day (BID) (at least 6 hours apart) on Day -18 pretransplant,

NK Cells

Intervention Type: BIOLOGICAL

CD3\^- CD19\^- selected, interleukin-2 (IL-2) activated, haploidentical donor natural killer (NK) cells infused on Day -17 pretransplant.

Interleukin-2

Intervention Type: DRUG

Interleukin-2 6 million units (MU) subcutaneously (SQ) every other day for 6 doses beginning evening of NK cell infusion

Donor TCR α/β-depleted Graft/ATG

Intervention Type: BIOLOGICAL

Single donor TCR α/β-depleted filgrastim-mobilized peripheral blood stem cells (PBSC) graft (minimum cell dose of 5 x 10\^6/kg) on day 0. ATG will be administered on days -6 and -5 (3mg/kg) for most patients.

Interventions

Preparative Regimen

Preparative Regimen:

1) fludarabine 40 mg/m^2 x 4 doses on Days -22 through -19 pretransplant, 2) cyclophosphamide 50 mg/kg x 2 doses on Days -20 and -19 pretransplant, 3) total body irradiation 200 cGy twice a day (BID) (at least 6 hours apart) on Day -18 pretransplant,

Intervention Type: DRUG

NK Cells

CD3\^- CD19\^- selected, interleukin-2 (IL-2) activated, haploidentical donor natural killer (NK) cells infused on Day -17 pretransplant.

Intervention Type: BIOLOGICAL

Interleukin-2

Interleukin-2 6 million units (MU) subcutaneously (SQ) every other day for 6 doses beginning evening of NK cell infusion

Intervention Type: DRUG

CD34 Graft/Anti-thymocyte globulin

Single donor filgrastim mobilized CD34+ selected peripheral blood stem cell graft (minimum cell dose of 5 x 10\^6/kg) on day 0. Rabbit anti-thymocyte globulin (ATG) will be administered on day -1 (0.5 mg/kg) and day +1 and +2 (2.5 mg/kg) pretransplant per institutional guidelines. ATG dosing not identical for all patients.

Intervention Type: BIOLOGICAL

Donor TCR α/β-depleted Graft/ATG

Single donor TCR α/β-depleted filgrastim-mobilized peripheral blood stem cells (PBSC) graft (minimum cell dose of 5 x 10\^6/kg) on day 0. ATG will be administered on days -6 and -5 (3mg/kg) for most patients.

Intervention Type: BIOLOGICAL

Other Intervention Names

Fludara; Cytoxan; radiation; Natural Killer cells; IL-2; ATG; stem cell graft

Eligibility Criteria

Inclusion Criteria

• Acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS)

RAEB-1 or RAEB-2 fitting within one of the following disease groups:

• Primary induction failure (PIF): Patients who have not achieved a complete remission (CR) after two induction cycles of cytotoxic therapy (i.e. 7+ 3, MEC, FLAG, etc.) and having ≤ 10,000 absolute circulating blasts measured at least 21 days from prior therapy. Hydroxyurea may be used to control blasts count. Demethylating agents do not count as induction therapy; however early re-induction therapy based on residual disease on a day 14 BM will count as a 2nd cycle
• Relapsed Disease with low disease burden (AML or MDS with ≤ 10,000 absolute circulating blasts. No re-induction attempts are required, but a maximum of 2 reinduction attempts are allowed to be eligible.
• CR3 or greater: This will include CRp defined as CR without platelet recovery to 100,000/mcL.
• CR1 or CR2 with high risk features: Includes therapy induced, prior MDS or MPD, high risk cytogenetic or molecular phenotype with no available donor (sibling or unrelated adult)

Patients with known prior central nervous system (CNS) involvement are eligible provided that it has been treated and CSF is clear for at least 2 weeks prior to enrollment. CNS therapy (chemotherapy or radiation) should continue as medically indicated during the study treatment.

• Available related HLA-haploidentical adult donor by at least Class I serologic typing at the A&B locus
• Karnofsky score > 50%
• Adequate organ function within 28 days of study registration defined as:

• Hepatic: AST ≤ 3 x upper limit of institutional normal, total bilirubin ≤ 2.0 mg/dl
• Renal: estimated glomerular filtration rate (GFR) ≥ 50 mL/min/1.73m^2
• Pulmonary: Oxygen saturation ≥ 90% on room air and DLCOcor ≥ 40%
• Cardiac: Ejection Fraction ≥ 35% and no uncontrolled angina, severe uncontrolled ventricular or arterial arrhythmias, or any evidence of acute ischemia or active conduction system abnormalities (rate controlled atrial fibrillation is not an exclusion)
• Able to be off prednisone or other immunosuppressive medications for at least 3 days prior to NK cell infusion (except for those prescribed as part of the study)
• Women of child bearing potential must have a negative pregnancy test within 28 days prior to study registration and agree to use adequate birth control during study treatment
• Voluntary written consent

Exclusion Criteria

• Biphenotypic leukemia
• Allogeneic transplant for AML within previous 6 months
• New or progressive pulmonary infiltrates on screening chest x-ray or chest CT scan that has not been evaluated with bronchoscopy, if feasible. Infiltrates attributed to infection must be stable/improving (with associated clinical improvement) after 1 week of appropriate therapy (4 weeks for presumed or documented fungal infections).
• Uncontrolled bacterial, fungal or viral infections including HIV - chronic asymptomatic viral hepatitis is allowed
• Known hypersensitivity to any of the study agents
• Received any investigational drugs within the 14 days before 1st dose of fludarabine
• Requires agents other than hydroxyurea to control blast count

Donor Selection:

• Related donor (sibling, parent, offspring, parent or offspring of an HLA identical sibling) 12-75 years of age. (It is recognized individual institutions may have differing donor age guidelines. This is acceptable as long as no donor is younger than 12 years or older than 75 years).
• Body weight of at least 40 kilograms
• In general good health as determined by the medical provider
• HLA-haploidentical donor/recipient match by at least Class I serologic typing at the A&B locus
• Able and willing to have up to 4 separate apheresis collections
• Not pregnant
• Voluntary written consent

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Masonic Cancer Center, University of Minnesota

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jeffrey Miller, M.D.

Role: PRINCIPAL_INVESTIGATOR

Masonic Cancer Center, University of Minnesota

Locations

Emory University

Atlanta, Georgia, United States

University of Minnesota, Masonic Cancer Center

Minneapolis, Minnesota, United States

Washington University

St Louis, Missouri, United States

Ohio State University

Columbus, Ohio, United States

Countries

United States

Other Identifiers

MT2011-05

Identifier Type: OTHER

Identifier Source: secondary_id

2011LS027

Identifier Type: -

Identifier Source: org_study_id