Allogeneic Stem Cell Transplant With Clofarabine, Ara-C and TBI for AML and ALL

March 23, 2016 updated by: Mitchell Cairo, New York Medical College

Clofarabine in Combination With Cytarabine and Total Body Irradiation Followed by Allogeneic Stem Cell Transplantation in Children With Acute Lymphoblastic Leukemia and Acute Non-Lymphoblastic Leukemia

Hypothesis: Myeloablative conditioning using a dose escalation of clofarabine in combination with cytarabine (ARA-C) and total body irradiation (TBI) will lead to improved survival for previously untransplanted children and adolescents with acute lymphoblastic leukemia (ALL) and acute non-lymphoblastic leukemia (ANLL)followed by allogeneic stem cell transplantation (AlloSCT).

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Pediatric patients with ALL who have multiple relapses show a declining reinduction rate with each successive relapse. Chessels et al reported the results in 235 pediatric patients with ALL in CR3 treated between 1972 and 1998. Only 18 of the 235 patients remained alive, with multiple early treatment failures implying significant instability of the third remission state. Factors that were found to be of significant influence on survival for these patients in CR3 were length of CR2, type of second event, immunophenotype, type of third treatment, type of first relapse, presenting leukocyte count, and length of CR1. The 3-year leukemia-free survival for patients with ALL in CR3 treated with hematopoietic progenitor cell transplantation (HPCT) was reported as 20% in a single-institution report on patients transplanted with unrelated donors between 1987 and 1999. This report found a 20% relapse rate in ALL patients in CR3 and reported that patients transplanted after 1992 had a higher rate of relapse, implying that as improved chemotherapy regimens become more successful in curing patients, those who develop relapse may have disease more resistant to treatment. Clofarabine ([2-chloro-9-(2-deoxy-2-fluoro-D-arabinofuranosyl)adenine]; Cl-F-ara-A; CAFdA) is a rationally designed, second-generation purine nucleoside antimetabolite. Clofarabine was designed as a hybrid molecule to overcome the limitations and incorporate the best qualities of fludarabine (F-ara-A) and cladribine (2-CdA, CdA), all three molecules are currently approved by the FDA for treatment of hematologic malignancies. In an open-label Phase II, pediatric patients with refractory or relapsed ALL received clofarabine 52 mg/m2 by IVI over 2 hours for 5 consecutive days repeated every 2 to 6 weeks depending on toxicity and response. Among the 49 patients evaluated for efficacy, the overall remission rate was 20%. The median duration of remission could not be calculated for the 6 patients who achieved a CR because 3 patients were still in remission at the time of data cutoff. The median duration for the 4 patients who achieved a CRp was 20 weeks (Range: 4.6 to 28.6 weeks). Eight (16%) patients went on to receive a transplant with 7 (14%) experiencing clinical benefit. In an open-label Phase II study, pediatric patients with refractory or relapsed AML received clofarabine 52 mg/m2 by IVI over 2 hours for 5 consecutive days repeated every 2 to 6 weeks depending on toxicity and response. The overall remission rate (CR + CRp) was 3%; 23% of patients achieved a PR. The median duration of remission for patients who achieved at least a PR was 16.2 weeks. Twelve (34%) patients went on to receive a transplant, 7 of whom were still alive at the time of data cutoff with survival ranging from 16.4 weeks to 93.6 weeks.

Patients enrolling must have undergone an extensive pre-transplant evaluation to assess remission status, assure adequate organ system function, and document freedom from active viral, bacterial, and fungal infection. Patients should proceed to transplant as soon as possible following their reinduction chemotherapy. Patients with delays in therapy due to toxicity or donor procurement delays should receive maintenance chemotherapy if possible. Patients must be scheduled to begin their preparative regimen within 10 days of enrolling on the study. This will be a 2 part study. Part A will be the dose escalation phase. Once the MTD and/or safe/tolerated dose of clofarabine has been established, Part B will accrue patients to further define the event free, disease free and overall survival at the MTD or safe/tolerated dose of clofarabine. At study entry during Part A, a clofarabine dose level will be assigned to each patient. During Part B, the established MTD or safe/tolerated dose of clofarabine will be used.

In Part A this study will enroll patients with ALL and ANLL in relapse, induction failure, CR3 or CR3P and without prior AlloSCT. These patients will receive a conditioning regimen of clofarabine, ARA-C and TBI followed by AlloSCT. Patients will start their pre-conditioning regimen on Day -10. Patients will receive ARA-C (3000 mg/m2 [total ARA-C dose of 18g/m2]) daily on Days -10, -9, -8, -7, -6, and -5 and clofarabine (Dose assigned at enrollment, see section 8.2.2 for dose escalation table for Part A) on Days -9, -8, -7, -6, and -5. On days when clofarabine and ARA-C are both given, clofarabine will be given as a 2 hr infusion followed by 4 hr rest and then ARA-C given as a 3 hr infusion. Fractionated TBI (200 cGy) will be administered twice daily for 3 days on Day -4, -3 and -2. The AlloSCT will be performed on Day 0. GVHD prophylaxis will consist of tacrolimus and MMF. In Part B, this study will enroll patients with ALL or ANLL in CR3 or CR3P and without prior AlloSCT. The pre-conditioning regimen will be the same as in Part A EXCEPT the established MTD or safe/tolerated dose of clofarabine from Part A will be utilized.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
32

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • New York
      • Vallhala, New York, United States, 10595
        • New York Medical College

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

No older than 30 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Age: Patients must be <30 years of age.
  • Disease Status: ALL in relapse, induction failure, CR3, or CR3P (Part A ONLY); AML in relapse, induction failure, CR3, or CR3P (Part A ONLY); ALL in CR3 or CR3P (Part A and Part B); AML in CR3 or CR3P (Part A and BONLY); CR3/CR3P must be documented by bone marrow and CNS assessment within 14 days of initiation of the pre-transplant conditioning regimen.
  • Creatinine clearance >40 ml/min/m2 or >60 ml/min/1.73 m2 or an equivalent radioisotope glomerular filtration rate (GFR) as determined by the institutional normal range or serum creatinine based on age
  • Adequate liver function defined as: Total bilirubin <2.5 mg/dl l, or SGOT (AST) or SGPT (ALT) <5 x upper limit of normal
  • Adequate cardiac function defined as: Shortening fraction >27% by echocardiogram, or Ejection fraction of >50% by radionuclide angiogram or echocardiogram.
  • Adequate pulmonary function defined as: Corrected DLCO >60% by pulmonary function test; For children who are uncooperative, no evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry >94% on room air.
  • Performance Status: For patients age 1-16 years, Lansky score of >60; For patients > 16 years, Karnofsky score of >60.
  • Patients must have received a minimum of one round of re-induction and one round of consolidation chemotherapy after relapse #2

Exclusion Criteria:

  • Patients with prior myeloablative allogeneic stem cell transplantation and /or TBI.
  • Females who are pregnant (positive HCG) or lactating.
  • Karnofsky <60% or Lansky <60% if less than 16 years of age
  • Age >30 years of age
  • Any patient with uncontrolled infection prior to study entry
  • Patients with evidence of active disease.
  • Patients with Down syndrome are excluded

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Part A
Part A will be the dose escalation phase to determine the MTD and/or safe/tolerated dose of clofarabine.
Drug: Clofarabine
Dose escalation of clofarabine on Days -9, -8, -7, -6, -5: 1 - 30 mg/m2; 2 - 40 mg/m2; 2 - 46 mg/m2; 3 - 52 mg/m2
Other Names:
  • Clolar®
Drug: Clofarabine
Use dose of clofarabine established in Part A to further define event free, disease free and overall survival.
Other Names:
  • Clolar®
Experimental: Part B
Part B will accrue patients to further define the event free, disease free and overall survival at the MTD or safe/tolerated dose of clofarabine.
Drug: Clofarabine
Dose escalation of clofarabine on Days -9, -8, -7, -6, -5: 1 - 30 mg/m2; 2 - 40 mg/m2; 2 - 46 mg/m2; 3 - 52 mg/m2
Other Names:
  • Clolar®
Drug: Clofarabine
Use dose of clofarabine established in Part A to further define event free, disease free and overall survival.
Other Names:
  • Clolar®

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Time Frame
To determine the maximum tolerated dose (MTD) and/or the safe, tolerated dose of clofarabine in combination with ARA-C and TBI followed by AlloSCT in children with ALL and ANLL.
Time Frame: 2.5 years
2.5 years
To define the toxicity and safety of the conditioning regimen of clofarabine, ARA-C, TBI followed by AlloSCT in children with ALL and ANLL.
Time Frame: 2.5 years
2.5 years
To define the pharmacokinetics of clofarabine given in combination with ARA-C and TBI followed by AlloSCT in children with ALL and ANLL.
Time Frame: 2.5 years
2.5 years

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Time Frame
To determine the event-free, disease-free and overall survival of the conditioning regimen of clofarabine, ARA-C and TBI followed by AlloSCT in children with ALL and AML.
Time Frame: 5 years
5 years
To estimate the time to hematopoietic reconstitution, stratified by cell source, following clofarabine, ARA-C and TBI followed by AlloSCT in children with ALL and AML.
Time Frame: 2.5 years
2.5 years
To measure the changes in minimal residual disease with ALL and AML following clofarabine, ARA-C and TBI followed by AlloSCT
Time Frame: 5 years
5 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
New York Medical College

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Genzyme, a Sanofi Company

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Mitchell S Cairo, New York Medical College

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
June 1, 2007

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
January 1, 2016

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
March 1, 2016

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
September 11, 2007

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
September 12, 2007

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
September 14, 2007

Study Record Updates

Last Update Posted (Estimate)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
March 24, 2016

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 23, 2016

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
March 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • L 9471

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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