ALT-801-activated Natural Killer Cells After FLAG Induction for Acute Myeloid Leukemia

Sponsor

Altor BioScience (Industry)

Overall Status

Withdrawn

CT.gov ID

NCT01478074

Collaborator

M.D. Anderson Cancer Center (Other)

Enrollment

Location

Arm

Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia	Drug: G-CSF Drug: Cytarabine Drug: Fludarabine Biological: Donor Natural Killer (NK) cells Biological: ALT-801	Phase 1

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (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

Study Start Date :

Nov 1, 2011

Anticipated Primary Completion Date :

Oct 1, 2013

Actual Study Completion Date :

Nov 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: FLAG + NK Cells + ALT-801	Drug: G-CSF 5 mcg/kg daily from day -7 until post-nadir ANC > 1000 Drug: Cytarabine 2 g/m2 daily from day -6 through -2 Drug: Fludarabine 30 mg/m2 daily from day -6 through -2 Biological: 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/Kg Biological: ALT-801 0.04 mg/kg IV thrice weekly for 8 doses beginning day +2

Arm

Intervention/Treatment

Experimental: FLAG + NK Cells + ALT-801

Drug: G-CSF

5 mcg/kg daily from day -7 until post-nadir ANC > 1000

Drug: Cytarabine

2 g/m2 daily from day -6 through -2

Drug: Fludarabine

30 mg/m2 daily from day -6 through -2

Biological: 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/Kg

Biological: ALT-801

0.04 mg/kg IV thrice weekly for 8 doses beginning day +2

Outcome Measures

Primary Outcome Measures

Maximum tolerated dose of NK cells [18 months]
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 [6 months after study completes accrual]
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.

Secondary Outcome Measures

Activation status of NK cells following activation with ALT-801 [6 months after study completes accrual]
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. [6 months after study completes accrual]
Determined by measuring levels of donor NK cells in the blood and their degranulation against standardized targets.
Overall response to this regimen [6 months after study completes accrual]
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 [6 months after study completes accrual]
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 [6 months after study completes accrual]
Determined by measuring levels of anti-ALT-801 antibodies in serum before treatment and at the end of treatment.

Eligibility Criteria

Criteria

Ages Eligible for Study:

2 Years to 59 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Recipient Inclusion Criteria:

Patients with relapsed AML, including those with CNS disease or previous hematopoietic stem cell transplantation, or primary refractory AML (primary AML that has failed remission to at least two cycles of induction therapy)
For patients of Cohorts 2 to 4, availability of a haploidentical family peripheral blood stem cell donor selected for best possible KIR reactivity
Patient is between 2 and 59 years of age, inclusive
Patient must have recovered from the treatment-related toxicities of prior cytotoxic agents received in the 4 weeks prior to beginning treatment on this protocol, with the exception of cytopenias resulting from persistent disease, and alopecia
Zubrod performance scale (Refer to Appendix C) ≤ 2 or Lansky (Refer to Appendix D) > 60
Adequate renal function defined as:

For adults serum creatinine < 2 mg/dL
For children serum creatinine < 2 mg/dL or < 2 times upper limit of normal (ULN) for age (which ever is less) If abnormal creatinine level, 24h creatinine clearance > 60 mL/min/1.73m^2

Adequate liver function, defined as: Total bilirubin ≤ 2 mg/dL and SGPT (ALT) ≤ 2.5 x ULN for age (unless Gilbert's disease or abnormal liver function due to primary disease)
Pulmonary symptoms controlled by medication and pulse oximetry> 92% room air
New York Heart Association classification < III
Negative serum test to rule out pregnancy within 2 weeks prior to registration in females of childbearing potential (non childbearing potential defined as premenarchal, greater than one year post-menopausal, or surgically sterilized)
Sexually active males and females of childbearing potential must agree to use a form of contraception considered effective and medically acceptable by the Investigator
Negative serology for human immunodeficiency virus (HIV)

Recipient Exclusion Criteria:

Investigational therapies in the 4 weeks prior to beginning treatment on this protocol
Congestive heart failure < 6 months prior to screening
Unstable angina pectoris < 6 months prior to screening
Myocardial infarction < 6 months prior to screening

Donor Inclusion Criteria:

Related to recipient (sibling, parent, offspring, offspring of a sibling)
HLA-haploidentical to recipient (need not be re-tested if already performed previously, provided copies of the original results are available)
Able and willing to undergo apheresis
Willing to donate blood for baseline chimerism assessment
Negative serum test to rule out pregnancy within two weeks prior to registration in females of childbearing potential (non childbearing potential defined as premenarchal, greater than one year post-menopausal, or surgically sterilized)
Donor must meet institutional eligibility criteria for allogeneic blood stem cell donation including infectious disease screening panel (Hepatitis B, Hepatitis C, HIV, CMV, and West Nile Virus) and CBC, differential and platelet studies
Donor must meet stem cell donor eligibility criteria as set forth in 21 CFR 1271 subpart C
The preferred Donor will be selected as the most alloreactive of the available haploidentical related donors on the basis of predicted NK cell alloreactivity using Recipient and Donor HLA type. If necessary, the best of equally alloreactive donors will be determined by Donor KIR type. NK alloreactivity is defined as o A KIR gene is present on the Donor NK cells for which

the HLA haplotype (KIR ligand) for the KIR receptor in question is absent in the Recipient, and
the HLA haplotype (KIR ligand) for the KIR receptor in question is present in the Donor