QUILT-3.033: Haplo NK With SQ ALT-803 for Adults With Relapsed or Refractory AML
Study Details
Study Description
Brief Summary
This is a multi-institutional Simon's optimal two-stage phase II trial of CD3/CD19 depleted, ALT-803 activated, haploidentical donor NK cells and subcutaneous ALT-803 given after lymphodepleting chemotherapy (CY/FLU) for the treatment of refractory or released acute myelogenous leukemia (AML).
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
|
Phase 2 |
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: Cy, FLU, Haplo NK and ALT-803 Preparative Regimen of Fludarabine and Cyclophosphamide ALT-803 Activation of Donor NK Cells ALT-803 to Facilitate NK Cell Survival and Expansion |
Biological: ALT-803
Preparative Regimen:
Fludarabine 25 mg/m2 x 5 days start day -6 Cyclophosphamide 60 mg/kg x 2 days on day -5 and -4
ALT-803 Stimulated 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 stimulated by overnight incubation with 36.1 ng/mL ALT-803 under GMP conditions and infused on day 0.
ALT-803 to Facilitate NK Cell Survival and Expansion:
ALT-803 at 10 mcg/kg subcutaneously (SC) with the 1st dose administered on day 0 (no sooner than 4 hours post NK cells), day +5 and day +10 for 3 doses total
|
Outcome Measures
Primary Outcome Measures
- Number of Participants With Complete Remission With or Without Incomplete Platelet Recovery [Day 42 post NK cell infusion]
To estimate the rate of complete remission with incomplete platelet recovery (CRp) - defined as leukemic clearance and neutrophil recovery without platelet recovery - by day 42 after the infusion of CD3/CD19 depleted, ALT-803 stimulated, donor NK cells and subcutaneous ALT-803 given after a non-myeloablative preparative regimen for the treatment of refractory or released acute myelogenous leukemia (AML)
Secondary Outcome Measures
- Incidence of in Vivo Expansion ≥100 of Donor Derived NK Cells Per /μl Blood [Day 14 post NK cell infusion]
Number of patients with successful in vivo NK-cell expansion which is defined by measuring an absolute circulating donor-derived NK cell count of ≥100 cells/μl in patient's peripheral blood.
- Number of Participants Experiencing ALT-803 Associated Toxicity [Day 0]
Toxicity will be classified and graded according to NCI's Common Terminology Criteria for Adverse Events V 4.0 (CTCAE)
- Number of Participants Experiencing ALT-803 Associated Toxicity [Day 5]
Toxicity will be classified and graded according to NCI's Common Terminology Criteria for Adverse Events V 4.0 (CTCAE)
- Number of Participants Experiencing ALT-803 Associated Toxicity [Day 7]
Toxicity will be classified and graded according to NCI's Common Terminology Criteria for Adverse Events V 4.0 (CTCAE)
- Number of Participants Experiencing ALT-803 Associated Toxicity [Day 10]
Toxicity will be classified and graded according to NCI's Common Terminology Criteria for Adverse Events V 4.0 (CTCAE)
- Number of Participants With Treatment Related Mortality [6 months post-therapy]
To evaluate the safety of the therapy as measured by rate of treatment related mortality (TRM) at 6 months
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Diagnosis of acute myeloid leukemia (AML) and meets one of the following disease criteria:
-
Primary induction failure:
-
De novo AML - no CR after 2 or more chemotherapy induction attempts
-
Secondary AML (from MDS or treatment related): no CR after 1 or more chemotherapy induction attempts
-
Relapse after chemotherapy: not in CR after 1, 2, or 3 re-induction attempts
-
Patients > 60 years of age, the 1 cycle of chemotherapy is not required
-
Relapse after hematopoietic stem cell transplant:
-
Relapse must have occurred > 18 months after transplant
-
No re-induction required and no more than 1 re-induction attempt is allowed
-
Notes:
-
For hypomethylating agents (i.e. decitabine, azacitidine) to count as an induction/re-induction attempt, the patient must have completed a minimum of 3 monthly cycles
-
For targeting agents (i.e. sorafenib) to count as an induction/re-induction attempt, the patient must have completed a minimum of 1 month without attaining CR
-
7+3 followed by 5+2 counts as TWO induction attempts
-
Use of hydroxyurea is permitted to control blasts until Day -3 per Section 8.7
-
A history of AML related CNS involvement is allowed if CSF analysis is negative on 2 test dates at least 2 weeks apart prior to study treatment. The use of ongoing CNS maintenance therapy is allowed while on study.
-
HLA-haploidentical related donor (aged 12 to 75 years) with donor/recipient match based on a minimum of intermediate resolution DNA based Class I typing of the A and B locus (at least 2/4 class I allele)
-
Karnofsky Performance Status ≥ 60%
-
Adequate organ function within 14 days of study registration (28 days for pulmonary and cardiac) defined as:
-
Creatinine: ≤ 2.0 mg/dL
-
Hepatic: AST and ALT < 3 x upper limit of institutional normal
-
Pulmonary Function: oxygen saturation ≥ 90% on room air; PFT's required only if symptomatic or prior known impairment - must have pulmonary function >50% corrected DLCO and FEV1.
-
Cardiac Function: LVEF ≥ 40% by echocardiography, MUGA or cardiac MRI, no uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.
-
Able to be off prednisone or other systemic immunosuppressive medications for at least 3 days prior to NK cell infusion (excluding preparative regimen pre-medications) .
-
Sexually active females of child bearing potential and males with partners of child bearing potential must agree to use effective contraception during therapy and for 4 months after completion of therapy .
-
Voluntary written consent prior to the performance of any research related procedures.
Exclusion Criteria:
-
Acute leukemias of ambiguous lineage
-
Pregnant or breastfeeding - The agents used in this study include those that fall under Pregnancy Category D - have known teratogenic potential. Women of child bearing potential must have a negative pregnancy test at screening
-
Active autoimmune disease requiring systemic immunosuppressive therapy
-
History of severe asthma and currently on systemic chronic medications (mild asthma requiring inhaled steroids only is eligible)
-
New or progressive pulmonary infiltrates on screening chest X-ray or chest CT scan unless cleared for study 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-1/2 or active hepatitis C/B - chronic asymptomatic viral hepatitis is allowed
-
Received any investigational agent within the 14 days before the start of study treatment (1st dose of fludarabine)
-
Prior ALT-803
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Masonic Cancer Center at University of Minnesota | Minneapolis | Minnesota | United States | 55455 |
Sponsors and Collaborators
- Masonic Cancer Center, University of Minnesota
Investigators
- Principal Investigator: Claudio Brunstein, MD, PhD, Masonic Cancer Center, University of Minnesota
Study Documents (Full-Text)
More Information
Publications
None provided.- 2016LS056
- MT2016-05
Study Results
Participant Flow
Recruitment Details | |
---|---|
Pre-assignment Detail |
Arm/Group Title | Cy, FLU, Haplo NK and ALT-803 |
---|---|
Arm/Group Description | Fludarabine 25 mg/m2 x 5 days start Day -6 ; Cyclophosphamide 60 mg/kg x 2 days on Day -5 and -4 ; The Alt-803 stimulated NK cell enriched product on Day 0 followed by ALT-803 at 10 mcg/kg subcutaneously on Day 0, Day 5 and Day 10 |
Period Title: Overall Study | |
STARTED | 8 |
COMPLETED | 8 |
NOT COMPLETED | 0 |
Baseline Characteristics
Arm/Group Title | Cy, FLU, Haplo NK and ALT-803 |
---|---|
Arm/Group Description | Fludarabine 25 mg/m2 x 5 days start Day -6 ; Cyclophosphamide 60 mg/kg x 2 days on Day -5 and -4 ; The Alt-803 stimulated NK cell enriched product on Day 0 followed by ALT-803 at 10 mcg/kg subcutaneously on Day 0, Day 5 and Day 10 |
Overall Participants | 8 |
Age (Count of Participants) | |
<=18 years |
0
0%
|
Between 18 and 65 years |
7
87.5%
|
>=65 years |
1
12.5%
|
Sex: Female, Male (Count of Participants) | |
Female |
3
37.5%
|
Male |
5
62.5%
|
Ethnicity (NIH/OMB) (Count of Participants) | |
Hispanic or Latino |
0
0%
|
Not Hispanic or Latino |
8
100%
|
Unknown or Not Reported |
0
0%
|
Race (NIH/OMB) (Count of Participants) | |
American Indian or Alaska Native |
0
0%
|
Asian |
0
0%
|
Native Hawaiian or Other Pacific Islander |
0
0%
|
Black or African American |
0
0%
|
White |
8
100%
|
More than one race |
0
0%
|
Unknown or Not Reported |
0
0%
|
Region of Enrollment (participants) [Number] | |
United States |
8
100%
|
Outcome Measures
Title | Number of Participants With Complete Remission With or Without Incomplete Platelet Recovery |
---|---|
Description | To estimate the rate of complete remission with incomplete platelet recovery (CRp) - defined as leukemic clearance and neutrophil recovery without platelet recovery - by day 42 after the infusion of CD3/CD19 depleted, ALT-803 stimulated, donor NK cells and subcutaneous ALT-803 given after a non-myeloablative preparative regimen for the treatment of refractory or released acute myelogenous leukemia (AML) |
Time Frame | Day 42 post NK cell infusion |
Outcome Measure Data
Analysis Population Description |
---|
One patient died after receiving 2 days of chemotherapy and never received any elements of research, NK cells or ALT-803. So only 7 participants' data were analyzed |
Arm/Group Title | Cy, FLU, Haplo NK and ALT-803 |
---|---|
Arm/Group Description | Fludarabine 25 mg/m2 x 5 days start Day -6 ; Cyclophosphamide 60 mg/kg x 2 days on Day -5 and -4 ; The Alt-803 stimulated NK cell enriched product on Day 0 followed by ALT-803 at 10 mcg/kg subcutaneously on Day 0, Day 5 and Day 10 |
Measure Participants | 7 |
Count of Participants [Participants] |
1
12.5%
|
Title | Incidence of in Vivo Expansion ≥100 of Donor Derived NK Cells Per /μl Blood |
---|---|
Description | Number of patients with successful in vivo NK-cell expansion which is defined by measuring an absolute circulating donor-derived NK cell count of ≥100 cells/μl in patient's peripheral blood. |
Time Frame | Day 14 post NK cell infusion |
Outcome Measure Data
Analysis Population Description |
---|
One patient died after receiving 2 days of chemotherapy and never received any elements of research, NK cells or ALT-803. So only 7 participants' data were analyzed |
Arm/Group Title | Cy, FLU, Haplo NK and ALT-803 |
---|---|
Arm/Group Description | Fludarabine 25 mg/m2 x 5 days start Day -6 ; Cyclophosphamide 60 mg/kg x 2 days on Day -5 and -4 ; The Alt-803 stimulated NK cell enriched product on Day 0 followed by ALT-803 at 10 mcg/kg subcutaneously on Day 0, Day 5 and Day 10 |
Measure Participants | 7 |
Count of Participants [Participants] |
0
0%
|
Title | Number of Participants Experiencing ALT-803 Associated Toxicity |
---|---|
Description | Toxicity will be classified and graded according to NCI's Common Terminology Criteria for Adverse Events V 4.0 (CTCAE) |
Time Frame | Day 0 |
Outcome Measure Data
Analysis Population Description |
---|
One patient died after receiving 2 days of chemotherapy and never received any elements of research, NK cells or ALT-803. So only 7 participants' data were analyzed |
Arm/Group Title | Cy, FLU, Haplo NK and ALT-803 |
---|---|
Arm/Group Description | Fludarabine 25 mg/m2 x 5 days start Day -6 ; Cyclophosphamide 60 mg/kg x 2 days on Day -5 and -4 ; The Alt-803 stimulated NK cell enriched product on Day 0 followed by ALT-803 at 10 mcg/kg subcutaneously on Day 0, Day 5 and Day 10 |
Measure Participants | 7 |
Count of Participants [Participants] |
2
25%
|
Title | Number of Participants Experiencing ALT-803 Associated Toxicity |
---|---|
Description | Toxicity will be classified and graded according to NCI's Common Terminology Criteria for Adverse Events V 4.0 (CTCAE) |
Time Frame | Day 5 |
Outcome Measure Data
Analysis Population Description |
---|
One patient died after receiving 2 days of chemotherapy and never received any elements of research, NK cells or ALT-803. So only 7 participants' data were analyzed |
Arm/Group Title | Cy, FLU, Haplo NK and ALT-803 |
---|---|
Arm/Group Description | Fludarabine 25 mg/m2 x 5 days start Day -6 ; Cyclophosphamide 60 mg/kg x 2 days on Day -5 and -4 ; The Alt-803 stimulated NK cell enriched product on Day 0 followed by ALT-803 at 10 mcg/kg subcutaneously on Day 0, Day 5 and Day 10 |
Measure Participants | 7 |
Count of Participants [Participants] |
1
12.5%
|
Title | Number of Participants Experiencing ALT-803 Associated Toxicity |
---|---|
Description | Toxicity will be classified and graded according to NCI's Common Terminology Criteria for Adverse Events V 4.0 (CTCAE) |
Time Frame | Day 7 |
Outcome Measure Data
Analysis Population Description |
---|
One patient died after receiving 2 days of chemotherapy and never received any elements of research, NK cells or ALT-803. So only 7 participants' data were analyzed |
Arm/Group Title | Cy, FLU, Haplo NK and ALT-803 |
---|---|
Arm/Group Description | Fludarabine 25 mg/m2 x 5 days start Day -6 ; Cyclophosphamide 60 mg/kg x 2 days on Day -5 and -4 ; The Alt-803 stimulated NK cell enriched product on Day 0 followed by ALT-803 at 10 mcg/kg subcutaneously on Day 0, Day 5 and Day 10 |
Measure Participants | 7 |
Count of Participants [Participants] |
3
37.5%
|
Title | Number of Participants Experiencing ALT-803 Associated Toxicity |
---|---|
Description | Toxicity will be classified and graded according to NCI's Common Terminology Criteria for Adverse Events V 4.0 (CTCAE) |
Time Frame | Day 10 |
Outcome Measure Data
Analysis Population Description |
---|
One patient died after receiving 2 days of chemotherapy and never received any elements of research, NK cells or ALT-803. So only 7 participants' data were analyzed |
Arm/Group Title | Cy, FLU, Haplo NK and ALT-803 |
---|---|
Arm/Group Description | Fludarabine 25 mg/m2 x 5 days start Day -6 ; Cyclophosphamide 60 mg/kg x 2 days on Day -5 and -4 ; The Alt-803 stimulated NK cell enriched product on Day 0 followed by ALT-803 at 10 mcg/kg subcutaneously on Day 0, Day 5 and Day 10 |
Measure Participants | 7 |
Count of Participants [Participants] |
3
37.5%
|
Title | Number of Participants With Treatment Related Mortality |
---|---|
Description | To evaluate the safety of the therapy as measured by rate of treatment related mortality (TRM) at 6 months |
Time Frame | 6 months post-therapy |
Outcome Measure Data
Analysis Population Description |
---|
One patient died after receiving 2 days of chemotherapy and never received any elements of research, NK cells or ALT-803. So only 7 participants' data were analyzed |
Arm/Group Title | Cy, FLU, Haplo NK and ALT-803 |
---|---|
Arm/Group Description | Fludarabine 25 mg/m2 x 5 days start Day -6 ; Cyclophosphamide 60 mg/kg x 2 days on Day -5 and -4 ; The Alt-803 stimulated NK cell enriched product on Day 0 followed by ALT-803 at 10 mcg/kg subcutaneously on Day 0, Day 5 and Day 10 |
Measure Participants | 7 |
Count of Participants [Participants] |
6
75%
|
Adverse Events
Time Frame | 1 year | |
---|---|---|
Adverse Event Reporting Description | ||
Arm/Group Title | Cy, FLU, Haplo NK and ALT-803 | |
Arm/Group Description | Fludarabine 25 mg/m2 x 5 days start Day -6 ; Cyclophosphamide 60 mg/kg x 2 days on Day -5 and -4 ; The Alt-803 stimulated NK cell enriched product on Day 0 followed by ALT-803 at 10 mcg/kg subcutaneously on Day 0, Day 5 and Day 10 | |
All Cause Mortality |
||
Cy, FLU, Haplo NK and ALT-803 | ||
Affected / at Risk (%) | # Events | |
Total | 8/8 (100%) | |
Serious Adverse Events |
||
Cy, FLU, Haplo NK and ALT-803 | ||
Affected / at Risk (%) | # Events | |
Total | 7/8 (87.5%) | |
Blood and lymphatic system disorders | ||
Febrile neutropenia | 2/8 (25%) | 2 |
Febrile neutropenia - Changed to levaquin and micafungin | 1/8 (12.5%) | 1 |
Cardiac disorders | ||
Heart failure | 1/8 (12.5%) | 1 |
Infections and infestations | ||
Lung infection | 1/8 (12.5%) | 1 |
Metabolism and nutrition disorders | ||
Tumor lysis syndrome | 1/8 (12.5%) | 1 |
Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other | 5/8 (62.5%) | 5 |
Renal and urinary disorders | ||
Acute kidney injury | 1/8 (12.5%) | 1 |
Respiratory, thoracic and mediastinal disorders | ||
Adult respiratory distress syndrome | 1/8 (12.5%) | 1 |
Other (Not Including Serious) Adverse Events |
||
Cy, FLU, Haplo NK and ALT-803 | ||
Affected / at Risk (%) | # Events | |
Total | 8/8 (100%) | |
Blood and lymphatic system disorders | ||
Disseminated intravascular coagulation | 1/8 (12.5%) | 1 |
Febrile neutropenia | 4/8 (50%) | 6 |
Cardiac disorders | ||
Atrial fibrillation | 1/8 (12.5%) | 1 |
Gastrointestinal disorders | ||
Constipation | 1/8 (12.5%) | 1 |
Diarrhea | 1/8 (12.5%) | 1 |
Oral pain | 1/8 (12.5%) | 1 |
Vomiting | 1/8 (12.5%) | 2 |
Gastroesophageal reflux disease | 1/8 (12.5%) | 1 |
General disorders | ||
Chills | 7/8 (87.5%) | 11 |
Fatigue | 4/8 (50%) | 7 |
Fever | 5/8 (62.5%) | 17 |
Injection site reaction | 7/8 (87.5%) | 24 |
Pain | 2/8 (25%) | 4 |
Infusion related reaction | 3/8 (37.5%) | 3 |
Infections and infestations | ||
Clostridium Difficile Infection | 1/8 (12.5%) | 1 |
Sepsis | 1/8 (12.5%) | 1 |
Investigations | ||
Alanine aminotransferase increased | 1/8 (12.5%) | 1 |
Aspartate aminotransferase increased | 1/8 (12.5%) | 1 |
Blood bilirubin increased | 1/8 (12.5%) | 3 |
Urine output decreased | 1/8 (12.5%) | 1 |
Metabolism and nutrition disorders | ||
Anorexia | 1/8 (12.5%) | 1 |
Hypoalbuminemia | 1/8 (12.5%) | 1 |
Hypocalcemia | 1/8 (12.5%) | 2 |
Hypophosphatemia | 1/8 (12.5%) | 1 |
Musculoskeletal and connective tissue disorders | ||
Myalgia | 1/8 (12.5%) | 1 |
Generalized muscle weakness | 1/8 (12.5%) | 1 |
Nervous system disorders | ||
Dizziness | 2/8 (25%) | 2 |
Headache | 6/8 (75%) | 12 |
Nervous system disorders - Other | 1/8 (12.5%) | 1 |
Psychiatric disorders | ||
Anxiety | 1/8 (12.5%) | 1 |
Respiratory, thoracic and mediastinal disorders | ||
Adult respiratory distress syndrome | 1/8 (12.5%) | 1 |
Cough | 1/8 (12.5%) | 1 |
Dyspnea | 1/8 (12.5%) | 3 |
Hypoxia | 2/8 (25%) | 3 |
Skin and subcutaneous tissue disorders | ||
Rash maculo-papular | 1/8 (12.5%) | 1 |
Skin and subcutaneous tissue disorders - Other | 2/8 (25%) | 2 |
Vascular disorders | ||
Hypertension | 4/8 (50%) | 14 |
Hypotension | 4/8 (50%) | 6 |
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title | Dr.Claudio G. Brunstein MD, PhD |
---|---|
Organization | Masonic Cancer Center, University of Minnesota |
Phone | 612 625 3918 |
bruns072@umn.edu |
- 2016LS056
- MT2016-05