ALT-801-activated Natural Killer Cells After FLAG Induction for Acute Myeloid Leukemia
This is a single-center open-label phase I clinical trial of delivering haploidentical natural killer (NK) cells matured ex vivo with ALT-801 followed by intravenous infusions of ALT-801 in patients with relapsed/refractory Acute Myeloid Leukemia (AML). The study will be conducted at M.D. Anderson Cancer Center (MDACC) and MDACC Children's Cancer Hospital in Houston, Texas.
Acute Myeloid Leukemia
Biological: Donor Natural Killer (NK) cells
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Single-center Open-label Phase I Study of ALT-801 for ex Vivo Maturation and in Vivo Retargeting of Haploidentical Natural Killer Cells Delivered Following Fludarabine, Cytarabine, and G-CSF in Patients With Relapsed/Refractory Acute Myeloid Leukemia|
- Maximum tolerated dose of NK cells [ Time Frame: 18 months ] [ Designated as safety issue: Yes ]Determined by the maximum tolerated dose of NK cells that can be given in combination with ALT-801 with less than 1/3 of patients experience dose-limiting toxicities related to the NK cells or ALT-801.
- Safety of delivering NK cells and ALT-801 in combination with FLAG [ Time Frame: 6 months after study completes accrual ] [ Designated as safety issue: Yes ]Determined by whether the maximum tolerated dose of NK cells can be given in combination with ALT-801 and FLAG chemotherapy without exceeding a rate of 0.28 for >= Grade 3 toxicities (10% above that of FLAG therapy alone) during the treatment period.
- Activation status of NK cells following activation with ALT-801 [ Time Frame: 6 months after study completes accrual ] [ Designated as safety issue: No ]Activation status of ALT-801-activated NK cells will be determined by measuring NK cell degranulation against standardized targets and comparing with freshly-obtained NK cells.
- In vivo persistence and function of haploidentical NK cells activated with ALT-801. [ Time Frame: 6 months after study completes accrual ] [ Designated as safety issue: No ]Determined by measuring levels of donor NK cells in the blood and their degranulation against standardized targets.
- Overall response to this regimen [ Time Frame: 6 months after study completes accrual ] [ Designated as safety issue: No ]Determined according to AML Response Criteria in NCCN Practice Guidelines for Oncology v.1.2008.
- Rate of stem cell transplantation and the time-to-transplantation [ Time Frame: 6 months after study completes accrual ] [ Designated as safety issue: No ]Determined by reporting how often and at what time patients achieve sufficient remission and health status to receive hematopoietic stem cell transplantation as definitive therapy after receiving this combination of chemotherapy, cellular therapy, and immune therapy.
- ALT-801 immunogenicity [ Time Frame: 6 months after study completes accrual ] [ Designated as safety issue: No ]Determined by measuring levels of anti-ALT-801 antibodies in serum before treatment and at the end of treatment.
|Study Start Date:||November 2011|
|Study Completion Date:||November 2013|
|Estimated Primary Completion Date:||October 2013 (Final data collection date for primary outcome measure)|
|Experimental: FLAG + NK Cells + ALT-801||
5 mcg/kg daily from day -7 until post-nadir ANC > 1000Drug: Cytarabine
2 g/m2 daily from day -6 through -2Drug: Fludarabine
30 mg/m2 daily from day -6 through -2Biological: Donor Natural Killer (NK) cells
Infused once on day 0. Four cohorts of escalating doses receiving 0, 1, 10, or 20 x 10^6 cells/KgBiological: ALT-801
0.04 mg/kg IV thrice weekly for 8 doses beginning day +2
Hematopoietic stem cell transplantation (SCT) is an effective treatment for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). For patients transplanted in first remission or with low risk MDS, approximately 60% of patients have achieved long-term disease free survival. Patients with relapsed leukemia have a poorer outcome; the long-term disease free survival rate for relapsed AML is 5-10% without hematopoietic stem cell transplantation (HSCT). With HSCT, survival after relapse approaches 40%, but success depends greatly on whether patients are in remission at the time of transplant. Many relapsed patients have refractory chemoresistant disease and never attain remission to be eligible for potentially curative HSCT, or develop significant complicating comorbidities during the prolonged intensive reinduction of their disease. Thus, improved strategies for achieving remission in relapsed patients prior to transplantation are critical to improving the survival of these patients. Relapsed/refractory AML requires remission prior to allogeneic HSCT for optimal survival, but responds poorly to chemotherapy. Human leukocyte antigen (HLA)-haploidentical, NK-enriched peripheral blood cell infusions may augment induction chemotherapy in patients with poor prognosis AML, but there are significant toxicities related to the IL-2 infusions given for optimal NK cell activity. The purpose of this trial is to estimate the toxicity and feasibility of treating relapsed/refractory AML with FLAG chemotherapy followed by haploidentical donor-derived natural killer (NK) cells using ALT-801 for ex vivo and in vivo NK cell activation as an alternative to interleukin-2 (IL-2).
ALT-801 is a genetically engineered fusion protein, that is, a single protein made by combining the DNA of two or more different genes. ALT-801 is a combination of IL-2 (an important protein for stimulating immune cells) and a binding portion that recognizes tumor cells.
The primary objective of this study is to evaluate the safety and feasibility of an infused allogeneic donor NK cell product and ALT-801 following a FLAG preparative regimen to treat relapsed/refractory acute myelogenous leukemia. The primary endpoint for toxicity is the absence of NK cell Product or ALT-801-related grade 2 toxicity, excluding grade 2 fever, rigor/chills, fatigue, vomiting/nausea, pruritus/itching, electrolyte imbalance, hypoalbuminemia or lymphopenia within 21 days of the ALT-801 or NK cell product infusion. The primary endpoint of feasibility is defined as being able to infuse NK-cells at the maximum tolerated cell dose or the highest dose level on day 0 and complete all 8 planned doses of ALT-801, with a safety that does not exceed toxicity limits, in greater than or equal to 7 of 10 subjects.
|United States, Texas|
|MD Anderson Cancer Center|
|Houston, Texas, United States, 77030|
|Study Director:||Hing C Wong, PhD||Altor Bioscience Corporation|