Description:
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%).
Title
- Brief Title: Cytokine Induced Memory-like NK Cell Adoptive Therapy After Haploidentical Donor Hematopoietic Cell Transplantation
- Official Title: A Phase II Study of Cytokine Induced Memory-like NK Cell Adoptive Therapy After Haploidentical Donor Hematopoietic Cell Transplantation
Clinical Trial IDs
- ORG STUDY ID:
201610088
- NCT ID:
NCT02782546
Conditions
Interventions
Drug | Synonyms | Arms |
---|
Fludarabine | Fludara, 2-Fluoro-ara-A Monophosphate, 2-Fluoro-ara AMP, FAMP | Recipient |
Cyclophosphamide | Cytoxan, Neosar, CPM, CTX, CYT | Recipient |
Tacrolimus | Prograf | Recipient |
Mycophenolate mofetil | CellCept, Myfortic | Recipient |
G-CSF | Granulocyte-colony stimulating factor | Recipient |
ALT-803 | | Recipient |
Purpose
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%).
Trial Arms
Name | Type | Description | Interventions |
---|
Recipient | Experimental | 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. | - Fludarabine
- Cyclophosphamide
- Tacrolimus
- Mycophenolate mofetil
- G-CSF
- ALT-803
|
Donor | Experimental | Donors will receive 10mg/kg-BW of subcutaneous G-CSF from Day -5 till Day -1 and then 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. | |
Eligibility 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 cycle 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
>2000 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 on donor viral screen
- Pregnant and/or breastfeeding
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Leukemia free survival rate (LFS) |
Time Frame: | Day 100 after transplantation |
Safety Issue: | |
Description: | -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
Measure: | Leukemia free survival rate (LFS) |
Time Frame: | 1 year post transplantation |
Safety Issue: | |
Description: | -LFS is defined as the time from achievement of CR to the time of relapse, death in remission, or last follow-up. |
Measure: | Rate of overall survival (OS) |
Time Frame: | 1 year post transplantation |
Safety Issue: | |
Description: | -OS is defined as the time from the date of Day 0 until death from any cause. |
Measure: | Incidence of relapse in patients who are found to be CR (complete remission) |
Time Frame: | Day 28 post transplantation |
Safety Issue: | |
Description: | -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 |
Measure: | Incidence of post transplant-related mortality (TRM) |
Time Frame: | Day 100 after transplantation |
Safety Issue: | |
Description: | -Death that results from a transplant procedure related complication (e.g. infection, organ failure, hemorrhage, GVHD) rather than from relapse of the underlying disease or an unrelated cause. |
Measure: | Incidence of TRM |
Time Frame: | 6 months post transplantation |
Safety Issue: | |
Description: | -Death that results from a transplant procedure related complication (e.g. infection, organ failure, hemorrhage, GVHD) rather than from relapse of the underlying disease or an unrelated cause. |
Measure: | Incidence of TRM |
Time Frame: | 1 year post transplantation |
Safety Issue: | |
Description: | -Death that results from a transplant procedure related complication (e.g. infection, organ failure, hemorrhage, GVHD) rather than from relapse of the underlying disease or an unrelated cause. |
Measure: | Time to neutrophil engraftment |
Time Frame: | Day 35 post transplantation |
Safety Issue: | |
Description: | -Time to neutrophil engraftment is measured by determining the first of 3 consecutive measurements of neutrophil count ≥ 500/ul following conditioning regimen-induced nadir. |
Measure: | Time to platelet engraftment |
Time Frame: | Day 100 post transplantation |
Safety Issue: | |
Description: | -Time to platelet engraftment is measured by determining the first of 3 consecutive measurements of platelet count ≥ 20,000/ul without platelet transfusion support for 7 days. |
Measure: | Engraftment rates |
Time Frame: | Day 100 post transplantation |
Safety Issue: | |
Description: | -Engraftment rate by donor/recipient chimerism |
Measure: | Incidence and severity of acute graft-versus host disease (GvHD) rates |
Time Frame: | First 100 days after PBSC infusion |
Safety Issue: | |
Description: | -Acute GVHD rate and severity for the first 100 days after PBSC infusion will be assessed based on the Minnesota-Center for International Blood and Marrow Transplant Research (CIBMTR) GVHD grading system (Appendix D). All grades of severity of acute GVHD will be collected. |
Measure: | Incidence and severity of chronic graft-versus host disease (GvHD) rates |
Time Frame: | Day 100 through 1 year post transplantation |
Safety Issue: | |
Description: | -Incidence and severity of chronic GVHD will be assessed based on the NIH consensus criteria and global severity scoring system. Attempts should be made to confirm the diagnosis pathologically by biopsy of target organ(s). |
Details
Phase: | Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | Washington University School of Medicine |
Last Updated
April 11, 2017