Clofarabine, Cytarabine, and Filgrastim Followed by Infusion of Non-HLA Matched Ex Vivo Expanded Cord Blood Progenitors in Treating Patients With Acute Myeloid Leukemia

Sponsor

Nohla Therapeutics, Inc. (Industry)

Overall Status

Completed

CT.gov ID

NCT01031368

Collaborator

National Cancer Institute (NCI) (NIH), Fred Hutchinson Cancer Center (Other)

Enrollment

Location

Arm

34.8

Duration (Months)

0.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This phase I trial is studying the safety and potential efficacy of infusing non-human leukocyte antigen (HLA) matched ex vivo expanded cord blood progenitors following treatment with clofarabine and cytarabine for patients with acute myeloid leukemia (AML). The combination of clofarabine, cytarabine (Ara-C) and granulocyte colony-stimulating factor (G-CSF) has been tested in earlier studies for the treatment of acute myeloid leukemia. In these previous clinical trials, this combination of drugs has been shown to have an anti-leukemia effect. However, the combination of clofarabine and Ara-C is profoundly myelosuppressive and immunosuppressive causing periods of neutropenia potentially lasting more than three weeks. During this period, patients are at increased risk of infections that can result in an increased risk of death. G-CSF is a growth factor that is used to help the white blood cells recover more quickly, but even with G-CSF, the use of clofarabine and Ara-C is often limited by the need to take long breaks between treatments to allow blood counts to recover. In our lab we have developed a method of growing or "expanding" blood stem cells (cells that give rise to the blood system) from umbilical cord blood. We are doing this study to find out if giving these expanded cells after chemotherapy is safe, helps the blood system recover more quickly from chemotherapy to allow shorter breaks between treatments, and decreases the risk of infection

Condition or Disease	Intervention/Treatment	Phase
Adult Acute Megakaryoblastic Leukemia (M7) Adult Acute Minimally Differentiated Myeloid Leukemia (M0) Adult Acute Monoblastic Leukemia (M5a) Adult Acute Monocytic Leukemia (M5b) Adult Acute Myeloblastic Leukemia With Maturation (M2) Adult Acute Myeloblastic Leukemia Without Maturation (M1) Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities Adult Acute Myeloid Leukemia With Del(5q) Adult Acute Myeloid Leukemia With Inv(16)(p13;q22) Adult Acute Myeloid Leukemia With t(15;17)(q22;q12) Adult Acute Myeloid Leukemia With t(16;16)(p13;q22) Adult Acute Myeloid Leukemia With t(8;21)(q22;q22) Adult Acute Myelomonocytic Leukemia (M4) Adult Acute Promyelocytic Leukemia (M3) Adult Erythroleukemia (M6a) Adult Pure Erythroid Leukemia (M6b) Recurrent Adult Acute Myeloid Leukemia Untreated Adult Acute Myeloid Leukemia	Drug: cytarabine Drug: clofarabine Drug: filgrastim Biological: Ex-vivo expanded cord blood progenitor cell infusion Other: laboratory biomarker analysis	Phase 1

Detailed Description

PRIMARY OBJECTIVES:

Assess the safety of infusing off-the-shelf non-HLA matched expanded cord blood cells following administration of cytarabine hydrochloride (GCLAC) for patients with AML.

SECONDARY OBJECTIVES:

Assess the ability of the product to provide temporary myeloid engraftment.
Assess the kinetics/persistence of potential engraftment.
Assess the kinetics of autologous recovery when compared to historical cohorts.
Assess the development of alloimmunization.

OUTLINE:

INDUCTION THERAPY: Patients receive clofarabine intravenously (IV) over 1 hour and cytarabine hydrochloride IV over 2 hours on days 1-5. Patients receive an infusion of non-HLA matched ex vivo expanded cord blood progenitors on day 6. Filgrastim (G-CSF) is administered subcutaneously (SC) on days 0-5 and from day 7 until blood counts recover. Treatment modifications may apply according to response.

CONSOLIDATION THERAPY: Patients receive clofarabine IV over 1 hour and cytarabine hydrochloride IV over 2 hours on days 1-5. Patients also receive G-CSF SC beginning on day 0 and continuing until blood counts recover.

Patients may receive treatment for 1-4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3-6 months for 2 years and then annually for 3 years.

Study Design

Study Type:

Interventional

Actual Enrollment :

29 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Clofarabine in Combination With Cytarabine (Ara-C) and G-CSF Priming Followed by Infusion of Ex Vivo Expanded Cord Blood Progenitors for Patients With AML

Study Start Date :

Dec 1, 2009

Actual Primary Completion Date :

Sep 1, 2012

Actual Study Completion Date :

Oct 24, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (chemotherapy, G-CSF, cord blood infusion) INDUCTION THERAPY: Patients receive clofarabine IV over 1 hour and cytarabine hydrochloride IV over 2 hours on days 1-5. Patients receive an infusion of non-HLA matched ex vivo expanded cord blood progenitors on day 6. G-CSF is administered SC on days 0-5 and from day 7 until blood counts recover. Treatment modifications may apply according to response. CONSOLIDATION THERAPY: Patients receive clofarabine IV over 1 hour and cytarabine hydrochloride IV over 2 hours on days 1-5. Patients also receive G-CSF SC beginning on day 0 and continuing until blood counts recover.	Drug: cytarabine Given IV Other Names: ARA-C arabinofuranosylcytosine arabinosylcytosine Cytosar-U cytosine arabinoside Drug: clofarabine Given IV Other Names: CAFdA Clofarex Clolar Drug: filgrastim Given SC Other Names: G-CSF Neupogen Biological: Ex-vivo expanded cord blood progenitor cell infusion Undergo ex vivo-expanded cord blood progenitor cell infusion Other Names: Dilanubicel NLA101 Other: laboratory biomarker analysis Correlative studies

Arm

Intervention/Treatment

Experimental: Treatment (chemotherapy, G-CSF, cord blood infusion)

INDUCTION THERAPY: Patients receive clofarabine IV over 1 hour and cytarabine hydrochloride IV over 2 hours on days 1-5. Patients receive an infusion of non-HLA matched ex vivo expanded cord blood progenitors on day 6. G-CSF is administered SC on days 0-5 and from day 7 until blood counts recover. Treatment modifications may apply according to response. CONSOLIDATION THERAPY: Patients receive clofarabine IV over 1 hour and cytarabine hydrochloride IV over 2 hours on days 1-5. Patients also receive G-CSF SC beginning on day 0 and continuing until blood counts recover.

Drug: cytarabine

Given IV

Other Names:

ARA-C

arabinofuranosylcytosine

arabinosylcytosine

Cytosar-U

cytosine arabinoside

Drug: clofarabine

Given IV

Other Names:

CAFdA

Clofarex

Clolar

Drug: filgrastim

Given SC

Other Names:

G-CSF

Neupogen

Biological: Ex-vivo expanded cord blood progenitor cell infusion

Undergo ex vivo-expanded cord blood progenitor cell infusion

Other Names:

Dilanubicel

NLA101

Other: laboratory biomarker analysis

Correlative studies

Outcome Measures

Primary Outcome Measures

Grade 3 or greater infusion toxicity, as defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 [Up to 24 hours after expanded progenitor cell infusion]
Treatment-related mortality [Up to 5 years]
Platelet refractoriness in the presence of alloimmunization [Up to 6 months post-treatment]
Exacerbation of chemotherapy-related toxicity, as defined by NCI CTCAE version 3.0 [Up to 21 days after initiation of clofarabine/cytarabine administration]
Delayed marrow recovery (in the absence of relapse) when expanded cord blood progenitors are infused, defined as failure to achieve neutrophil recovery (ANC less than 500) post treatment with marrow cellularity and marrow blast count less than 5% [Up to day 35]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Cohort A: Diagnosis of AML by World Health Organization (WHO) criteria, either relapsed or refractory; acute promyelocytic leukemia [Acute promyelocytic leukemia with t(15;17)(q22;q12) and variants] will be eligible only after failure of a regimen containing arsenic trioxide; patients in this cohort must have had an initial remission duration of < 1 year and cannot have received any prior salvage chemotherapy
Cohort B: Untreated AML patients, excluding those with favorable cytogenetic or molecular abnormalities per the European LeukemiaNet recommendations
Cohort C: Untreated AML patients, including those with favorable cytogenetic or molecular abnormalities per the European LeukemiaNet recommendations
The first three patients enrolled in cohorts A and B must be less than 60 years old; thereafter, patients aged >= 18 and =< 70 are eligible
The first three patients enrolled in cohorts A and B must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 -1; thereafter, ECOG performance status of 0-2 is required
Serum creatinine =< 1.0 mg/dL; if serum creatinine > 1.0 mg/dl, then the estimated glomerular filtration rate (GFR) must be > 60 mL/min/1.73 m^{2 as calculated by the
Modification of Diet in Renal Disease equation where predicted GFR (ml/min/1.73 m}2) = 186 X (Serum Creatinine)^{-1.154 X (age in years)}-0.203 X (0.742 if patient is female) X (1.212 if patient is black)
Serum total bilirubin =< 1.5 x upper limit of normal (ULN) unless elevation is thought to be due to Gilbert's syndrome, hemolysis, or hepatic infiltration by the hematologic malignancy
Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 X ULN, unless elevation is thought to be due to hepatic infiltration by the hematologic malignancy
Alkaline phosphatase =< 2.5 x ULN
Capable of understanding the investigational nature, potential risks and benefits of the study, and able to provide valid informed consent
Female patients of childbearing potential must have a negative serum pregnancy test within 2 weeks prior to enrollment
Male and female patients must be willing to use an effective contraceptive method during the study and for a minimum of 90 days after study treatment

Exclusion Criteria:

Allogeneic transplant recipients
Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol with the exception of intrathecal chemotherapy administered on days that are not concurrent with clofarabine and cytarabine
Have any other severe concurrent disease, or have a history of serious organ dysfunction or disease involving the heart, kidney, liver (including symptomatic hepatitis, veno-occlusive disease), or other organ system dysfunction
Patients with a systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment)
Pregnant or lactating patients
Any significant concurrent disease, illness, or psychiatric disorder that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results