Clinical trial NCT01639456: CD3/CD19 Depleted or CD3 Depleted/CD56 Selected Haploid Donor Natural Killer Cell Treatment in Older AML in First Complete Remission
Official title: A Randomized Trial Comparing CD3/CD19 Depleted or CD3 Depleted/CD56 Selected Haploidentical Donor Natural Killer (NK) Cell Based Therapy in Older Adults With Acute Myelogenous Leukemia in First Complete Remission
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE2
Conditions: Acute Myelogenous Leukemia
Keywords: acute myelogenous leukemia
Lead sponsor: Masonic Cancer Center, University of Minnesota
Sponsor class: OTHER
Collaborators: name: Miltenyi Biomedicine GmbH
First posted: 2012-07-12
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a phase II trial designed to test the safety and efficacy (disease free survival \[DFS\]) of related donor HLA-haploidentical NK-cell based therapy for the treatment of acute myelogenous leukemia (AML). The natural killer (NK) cell product will be given to patients 60 years and older who are in a first complete remission after 1 or 2 courses of standard AML induction. After a preparative regimen of cyclophosphamide and fludarabine, patients will receive a single infusion of either CD3-/CD19- NK cells or CD3-/CD56+ NK cells followed by a short course of Interleukin-2 (IL-2) to facilitate NK cell survival and expansion.

Detailed description: The trial will use a single-stage design and will take place in two parts. The first part will support the selection of the better NK cell product as measured by in vivo NK cell expansion. Successful in vivo NK cell expansion is defined as 40% donor DNA and 40% of lymphocytes are NK cells at day 7 post infusion OR 20% donor DNA and 20% of lymphocytes are NK cells at day 14 post infusion.

Part 1: 1:1 randomization with 10 patients per cohort to either:

1. CD3-/CD19- NK cell product or
2. CD3-/CD56+ purified NK cell product The product with better NK cell expansion will be used for the rest of the trial. If the results and safety profile are equivalent, the CD56+ selection approach will be used. If neither approach results in successful NK cell expansion, the trial will be stopped and the platform redesigned.

Part 2: complete the trial by enrolling an additional 26 patients using the product deemed successful during part 1 to estimate the primary endpoint (DFS at 12 months)

Eligibility criteria: Inclusion Criteria:

* Diagnosis of acute myelogenous leukemia (except acute promyelocytic leukemia) in a first complete remission (CR1) and meet the following criteria:

  * Meets the definition of complete remission by morphologic criteria including \<5% blasts in a moderately cellular (\> 20% cellularity) or cellular marrow.
  * Complete remission (CR) was achieved after no more than 2 cycles of standard induction chemotherapy. Early re-induction therapy based on residual disease on a day 14 bone marrow (BM) will count as a 2nd cycle. Prior therapy with demethylating agents (i.e. azacitidine) is allowed, but patients must have attained CR after standard cytotoxic therapy (defined as absolute neutrophil count (ANC) \> 1000 cells/μL, platelets \> 100 x 10\^9/L)
  * No more than 3 months have lapsed from attainment of CR1
  * No acute myelogenous leukemia (AML) consolidation therapy administered prior to enrollment
  * Not a candidate for allogeneic stem cell transplantation
* ≥ 60 years of age
* Karnofsky performance status ≥ 70%
* Available related HLA haploidentical natural killer (NK) cell donor (sibling, offspring, or offspring of an HLA identical sibling) by at least Class I serologic typing at the A\&B locus (donor age 18-75 years)
* At least 30 days since last dose of chemotherapy
* Adequate organ function within 14 days of enrollment defined as:

  * Creatinine: ≤ 2.0 mg/dL
  * Hepatic: aspartate aminotransferase (SGOT) and alanine aminotransferase (SGPT) \< 5 x upper limit of institutional normal (ULN)
  * Pulmonary: oxygen saturation ≥ 90% on room air
  * Cardiac: left ventricular ejection fraction (LVEF) by echocardiogram (ECHO or MUGA) ≥ 40%, no uncontrolled angina, uncontrolled atrial or ventricular arrhythmias, or evidence of acute ischemia or active conduction system abnormalities (rate controlled a-fib is not an exclusion)
* Ability to be off prednisone and other immunosuppressive drugs for at least 3 days prior to the NK cell infusion (excluding preparative regimen pre-meds)
* Voluntary written consent

Exclusion Criteria:

* Biphenotypic acute leukemia
* New progressive pulmonary infiltrates on screening chest x-ray or chest Computed Tomography scan that has not been evaluated with bronchoscopy (when 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 human immunodeficiency virus (HIV) - chronic asymptomatic viral hepatitis is allowed
* Pleural effusion large enough to be detectable on chest x-ray
* Known hypersensitivity to one or more of the study agents

Donor Selection:

* Related donor (sibling, offspring, or offspring of an HLA identical sibling) 18-75 years of age
* At least 40 kilograms
* In general good health as determined by the medical provider
* Negative for hepatitis and HIV on donor viral screen
* HLA-haploidentical donor/recipient match by at least Class I serologic typing at the A\&B locus
* Not pregnant
* Voluntary written consent

Primary outcomes:
measure: Disease-Free Survival
timeFrame: 1 Year
Secondary outcomes:
measure: Incidence of Infusional Toxicities
timeFrame: Day 100
measure: Incidence of Chronic Graft-Versus-Host Disease (GVHD)
timeFrame: 1 Year
measure: Incidence of Acute Graft-Versus-Host Disease (GVHD)
timeFrame: Day 100
measure: Treatment-Related Mortality
timeFrame: Day 100, 1 Year and 2 Years
measure: Overall Survival
timeFrame: 1 Year and 2 Years
measure: Disease-Free Survival
timeFrame: 2 Years
Other outcomes:
Locations:
city: Minneapolis
country: United States
facility: Masonic Cancer Center, University of Minnesota
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
Study officials:
affiliation: Masonic Cancer Center, University of Minnesota
name: Jeffrey S. Miller, M.D.
role: PRINCIPAL_INVESTIGATOR
References: