CD3/CD19 Depleted or CD3 Depleted/CD56 Selected Haploidentical Donor Natural Killer (NK) Cell Based Therapy for AML Patients Not in CR

• Sponsor: Miltenyi Biotec B.V. & Co. KG (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03152526
• Collaborator: Masonic Cancer Center, University of Minnesota (Other), University of Chicago (Other), Ohio State University (Other)
• Enrollment: 1
• Locations: 3
• Arm: 1
• Actual Duration (Months): 5.1
• Patients Per Site: 0.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is a phase II trial designed to test the safety and efficacy (complete response [CR]) of related donor HLA-haploidentical NK-cell based therapy for the treatment of acute myelogenous leukemia (AML).

Patients with newly diagnosed AML who failed to achieve a complete remission (CR) after one or two standard induction attempts receive after a preparative regimen of cyclophosphamide and fludarabine a single infusion of 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.

Condition or Disease	Intervention/Treatment	Phase
Acute Myelogenous Leukemia	Device: Interventions	N/A

Detailed Description

This trial uses a Simon's two-stage design to estimate the complete remission rate at day +42 post NK cell infusion. The trial includes an initial randomized sub- study of 24 patients during stage 1 to choose which of the enriched NK cell products (CD3-/CD19- versus CD3-/CD56+) should be used to complete the trial based on successful in vivo NK cell expansion. This parameter 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. Twelve patients will be randomized to each product.

Enrollment Plan:

Stage 1: Enroll 24 patients with 1:1 randomization for NK cell processing (CD3-/CD19- versus CD3-/CD56+) Stage 2: Enroll an additional 17 patients using the optimal NK cell product identified during stage 1.

If neither product achieves success at the end of stage 1, the study will stop and the platform redesigned

Study Design

• Study Type: Interventional
• Actual Enrollment: 1 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: In summary, the study will take place in two parts: Stage 1: Enroll 24 patients with 1:1 randomization for NK cell processing (CD3-/CD19- versus CD3-/CD56+) Stage 2: Enroll an additional 17 patients using the optimal NK cell product identified during stage 1. If neither product achieves success at the end of stage 1, the study will stop and the platform redesignedIn summary, the study will take place in two parts:Stage 1: Enroll 24 patients with 1:1 randomization for NK cell processing (CD3-/CD19- versus CD3-/CD56+) Stage 2: Enroll an additional 17 patients using the optimal NK cell product identified during stage 1. If neither product achieves success at the end of stage 1, the study will stop and the platform redesigned
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Trial Comparing CD3/CD19 Depleted or CD3 Depleted/CD56 Selected Haploidentical Donor Natural Killer (NK) Cell Based Therapy for Adults With Acute Myelogenous Leukemia Who Have Failed 1 or 2 Induction Attempts
• Actual Study Start Date: Oct 18, 2017
• Actual Primary Completion Date: Mar 21, 2018
• Actual Study Completion Date: Mar 21, 2018

Arms and Interventions

Arm	Intervention/Treatment
Other: Single-arm trial Multi-center, open-label, single-arm, phase I/II clinical trial	Device: Interventions; CliniMACS® CD3 and CD19 Reagent System; Other Names: Devise

Outcome Measures

Primary Outcome Measures

1. The Primary Endpoint of the Study is Complete Remission (±3 Days) [On Day+42 (+/- 3 days) after NK cell infusion]

   Both the number of patients with leukemia in complete remission and the number of patients with leukemia not in complete remission will be reported. Leukemia remission status will be assessed according to the Revised Recommendations of The International Working Group (J Clin Oncol 21:4642-4649, 2003).

Secondary Outcome Measures

1. The Secondary Endpoint is the Expansion and Persistence of NK Cells to be Used for the Remainder of the Study. [Day+7 to Day+42 after NK cell infusion]

   Successful expansion and persistence of NK cells is defined as ≥ 100 donor derived NK cells per µl blood.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Newly diagnosed with acute myelogenous leukemia (except acute promyelocytic leukemia) and has failed one or two prior standard induction attempts. Failure is defined as:

• ≥ 30% bone marrow blasts with at least 20% cellularity at mid-cycle bone marrow biopsy or residual AML on subsequent~ day 28 bone marrow biopsy by morphology, flow, PCR or FISH

• Patients enrolling after only 1 failed induction attempt must meet at least one of the following additional eligibility criteria of high risk: ≥ 60 years of age adverse cytogenetics or molecular characteristics

• AML that progressed out of myelodysplastic syndrome (MDS) is eligible if the patient did not receive treatment directed at the MDS

• HLA-haploidentical related donor (aged 12 to 70 years)

• ≥ 18, but < 75 years of age

• Karnofsky performance status ≥ 60%

• Adequate organ function within 14 days of study registration (30 days for pulmonary and cardiac) as defined in section 4.5

• 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)

• No prior hematopoietic transplant

• Not pregnant or lactating

• Sexually active females of childbearing potential and males with partners of child bearing potential must agree to use birth control

Exclusion Criteria:

• Pregnant or lactating as the treatments used in this study includes drugs that are FDA Pregnancy Category D.

• Acute leukemias of ambiguous lineage

• AML that transformed from previously treated myelodysplastic syndromes

• Prior hematopoietic transplant

• New or progressive pulmonary infiltrates on screening chest x-ray or chest CT scan that has not been cleared by Pulmonary. 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 one or more of the study agents used

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Universtiy of Chicago	Chicago	Illinois	United States	60637
2	University of Minnesota	Minneapolis	Minnesota	United States	55455
3	Ohio State University	Columbus	Ohio	United States	43210

Sponsors and Collaborators

• Miltenyi Biotec B.V. & Co. KG
• Masonic Cancer Center, University of Minnesota
• University of Chicago
• Ohio State University

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 9, 2017

More Information

Publications

None provided.

• Responsible Party: Miltenyi Biotec B.V. & Co. KG
• ClinicalTrials.gov Identifier: NCT03152526
• Other Study ID Numbers: MT-2014-02; NCT03290664
• First Posted: May 15, 2017
• Last Update Posted: Jul 9, 2020
• Last Verified: Feb 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute

Study Results

Participant Flow

Arm/Group Title	CD3-/CD19- NK Cells Followed by IL-2	CD3-/CD56+ NK Cells Followed by IL-2
Arm/Group Description	After a preparative regimen (day -6 to day -1) of fludarabine and cyclophosphamide participants receive allogeneic CD3-/CD19- NK Cell Product (NK Cell, CD3-/CD56+: ≥ 3-fold enrichment) on Day 0, followed by administration of interleukin-2 (after the NK cell infusion every other day for a total of 6 doses).	After a preparative regimen (day -6 to day -1) of fludarabine and cyclophosphamide participants receive allogeneic CD3-/CD56+ Purified NK Cell Product (NK Cell, CD3-/CD56+: ≥ 70%) on Day 0, followed by administration of interleukin-2 (after the NK cell infusion every other day for a total of 6 doses).
Period Title: Overall Study
STARTED	0	1
COMPLETED	0	0
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	CD3-/CD19- NK Cells Followed by IL-2	CD3-/CD56+ NK Cells Followed by IL-2	Total
Arm/Group Description	After a preparative regimen (day -6 to day -1) of fludarabine and cyclophosphamide participants receive allogeneic CD3-/CD19- NK Cell Product (NK Cell, CD3-/CD56+: ≥ 3-fold enrichment) on Day 0, followed by administration of interleukin-2 (after the NK cell infusion every other day for a total of 6 doses).	After a preparative regimen (day -6 to day -1) of fludarabine and cyclophosphamide participants receive allogeneic CD3-/CD56+ Purified NK Cell Product (NK Cell, CD3-/CD56+: ≥ 70%) on Day 0, followed by administration of interleukin-2 (after the NK cell infusion every other day for a total of 6 doses).	Total of all reporting groups
Overall Participants	0	1	1
Age, Customized (years) [Number]
Participant age (years)	52	52
Sex: Female, Male (Count of Participants)
Female	1 Infinity	1 100%
Male	0 NaN	0 0%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 NaN

Outcome Measures

1. Primary Outcome

Title	The Primary Endpoint of the Study is Complete Remission (±3 Days)
Description	Both the number of patients with leukemia in complete remission and the number of patients with leukemia not in complete remission will be reported. Leukemia remission status will be assessed according to the Revised Recommendations of The International Working Group (J Clin Oncol 21:4642-4649, 2003).
Time Frame	On Day+42 (+/- 3 days) after NK cell infusion

Outcome Measure Data

Analysis Population Description

As a result of poor subject accrual (n=1), statistically relevant efficacy data cannot be defined according to the protocol.

Arm/Group Title	CD3-/CD19- NK Cells Followed by IL-2	CD3-/CD56+ NK Cells Followed by IL-2
Arm/Group Description	After a preparative regimen (day -6 to day -1) of fludarabine and cyclophosphamide participants receive allogeneic CD3-/CD19- NK Cell Product (NK Cell, CD3-/CD56+: ≥ 3-fold enrichment) on Day 0, followed by administration of interleukin-2 (after the NK cell infusion every other day for a total of 6 doses).	After a preparative regimen (day -6 to day -1) of fludarabine and cyclophosphamide participants receive allogeneic CD3-/CD56+ Purified NK Cell Product (NK Cell, CD3-/CD56+: ≥ 70%) on Day 0, followed by administration of interleukin-2 (after the NK cell infusion every other day for a total of 6 doses).
Measure Participants	0	0

2. Secondary Outcome

Title	The Secondary Endpoint is the Expansion and Persistence of NK Cells to be Used for the Remainder of the Study.
Description	Successful expansion and persistence of NK cells is defined as ≥ 100 donor derived NK cells per µl blood.
Time Frame	Day+7 to Day+42 after NK cell infusion

Outcome Measure Data

Analysis Population Description

As a result of poor subject accrual (n=1), statistically relevant efficacy data cannot be defined according to the protocol.

Arm/Group Title	CD3-/CD19- NK Cells Followed by IL-2	CD3-/CD56+ NK Cells Followed by IL-2
Arm/Group Description	After a preparative regimen (day -6 to day -1) of fludarabine and cyclophosphamide participants receive allogeneic CD3-/CD19- NK Cell Product (NK Cell, CD3-/CD56+: ≥ 3-fold enrichment) on Day 0, followed by administration of interleukin-2 (after the NK cell infusion every other day for a total of 6 doses).	After a preparative regimen (day -6 to day -1) of fludarabine and cyclophosphamide participants receive allogeneic CD3-/CD56+ Purified NK Cell Product (NK Cell, CD3-/CD56+: ≥ 70%) on Day 0, followed by administration of interleukin-2 (after the NK cell infusion every other day for a total of 6 doses).
Measure Participants	0	0

Adverse Events

Time Frame	3 months
Adverse Event Reporting Description	No participants were enrolled on the CD3-/CD19- NK Cells arm, therefore no participants on this arm were at risk of adverse events.
Arm/Group Title	CD3-/CD19- NK Cells Followed by IL-2		CD3-/CD56+ NK Cells Followed by IL-2
Arm/Group Description	After a preparative regimen (day -6 to day -1) of fludarabine and cyclophosphamide participants receive allogeneic CD3-/CD19- NK Cell Product (NK Cell, CD3-/CD56+: ≥ 3-fold enrichment) on Day 0, followed by administration of interleukin-2 (after the NK cell infusion every other day for a total of 6 doses).		After a preparative regimen (day -6 to day -1) of fludarabine and cyclophosphamide participants receive allogeneic CD3-/CD56+ Purified NK Cell Product (NK Cell, CD3-/CD56+: ≥ 70%) on Day 0, followed by administration of interleukin-2 (after the NK cell infusion every other day for a total of 6 doses).
All Cause Mortality
	CD3-/CD19- NK Cells Followed by IL-2		CD3-/CD56+ NK Cells Followed by IL-2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		1/1 (100%)
Serious Adverse Events
	CD3-/CD19- NK Cells Followed by IL-2		CD3-/CD56+ NK Cells Followed by IL-2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		1/1 (100%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Serious adverse event	0/0 (NaN)	0	1/1 (100%)	1
Respiratory, thoracic and mediastinal disorders
Serious adverse event	0/0 (NaN)	0	1/1 (100%)	1
Other (Not Including Serious) Adverse Events
	CD3-/CD19- NK Cells Followed by IL-2		CD3-/CD56+ NK Cells Followed by IL-2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		1/1 (100%)
Blood and lymphatic system disorders
Febrile neutropenia	0/0 (NaN)		1/1 (100%)
General disorders
Chills, edema limbs, fever, injection site reaction	0/0 (NaN)		1/1 (100%)
Respiratory, thoracic and mediastinal disorders
Dyspnea, pneumonitis	0/0 (NaN)		1/1 (100%)
Vascular disorders
Hypertension, hypotension	0/0 (NaN)		1/1 (100%)

Limitations/Caveats

As a result of poor subject accrual (n=1), statistically relevant efficacy data cannot be defined according to the protocol.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Institution conducted study as an independent contractor, supervised by the PI. PI may publish results provided that 12 months have elapsed since the completion of the study and sponsor has not initiated publication of a study report and at least 30 days prior to submission sponsor receives a draft to review. This study did not result in any publications.