A Study of Clofarabine in Combination With Etoposide and Cyclophosphamide in Children With Acute Leukemias.

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Sanofi ( Genzyme, a Sanofi Company )
ClinicalTrials.gov Identifier:
NCT00315705
First received: April 18, 2006
Last updated: March 17, 2014
Last verified: March 2014
  Purpose

Clofarabine (injection) is approved by the Food and Drug Administration (FDA) for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia (ALL) who have had at least 2 prior treatment regimens. This use is based on the induction of complete responses. Randomized trials demonstrating increased survival or other clinical benefit have not been conducted.

The purpose of the phase 1 portion of this study was to determine if clofarabine added to a combination of etoposide and cyclophosphamide is safe in children with relapsed or refractory acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML). The purpose of the phase 2 portion of the study was to measure the effectiveness of the combination therapy in children with ALL.


Condition Intervention Phase
Acute Lymphoblastic Leukemia
Acute Myelogenous Leukemia
Relapsed Leukemia
Drug: clofarabine
Drug: Etoposide
Drug: Cyclophosphamide
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1/2 Dose-Escalation Study of Clofarabine in Combination With Etoposide and Cyclophosphamide in Pediatric Patients With Refractory or Relapsed Acute Leukemias.

Resource links provided by NLM:


Further study details as provided by Sanofi:

Primary Outcome Measures:
  • Maximum Tolerated Dose (MTD) in Phase 1 [ Time Frame: Up to Day 42 (Phase 1 portion of study) ] [ Designated as safety issue: Yes ]

    The MTD was to be the highest dose level of clofarabine in combination with etoposide and cyclophosphamide that caused <= 1 of 6 participants to experience a dose limiting toxicity (DLT) with the next higher dose level having at least 2 of 3 or 2 of 6 participants experiencing a DLT. The MTD would be used as the recommended phase 2 dose (RP2D). If the MTD could not be determined, then the target dose of clofarabine 40 mg/m^2, etoposide 100 mg/m^2 and cyclophosphamide 440 mg/m^2 as taken by Cohort 5 was to become the RP2D.

    The rating scale used is 0 = not the MTD, 1 = the MTD.


  • Participants With Dose Limiting Toxicity in Phase 1 [ Time Frame: Up to Day 42 (Phase 1 portion of study) ] [ Designated as safety issue: Yes ]
    The number of participants in each cohort that had dose limiting toxicity is summarized. Toxicities were reviewed by an independent Data Safety Monitoring Board (DSMB) who determined if additional participants should be added to the cohort and the criteria for escalating to the next cohort.

  • Percentage of Participants Achieving A Response Over the First Two Treatment Cycles in Phase 2 [ Time Frame: Approximately 28-56 days (Phase 2 portion of study) ] [ Designated as safety issue: No ]
    Response categories 1) complete remission (CR): without circulating blasts or extramedullary disease, bone marrow (BM) with <5% blasts, and platelet (plt)/ANC recovery: ≥75/ ≥0.75 [x 10^9/L] 2) CR in absence of plt recovery (CRp): plt ≥20 to <75 x 10^9/L 3) partial remission (PR): no circulating blasts, appearance of normal hematopoietic progenitors, and either a BM with ≥5% and ≤25% blasts with recovery of plts/ANC or a BM with <5% blasts not meeting CR/CRp definition 4) Overall remission (OR): CR+CRp 5) Any response: CR+CRp+PR.


Secondary Outcome Measures:
  • Summary of Participants With Adverse Events (AEs) in Phase 1 [ Time Frame: Up to 9.5 months (Phase 1 portion of study) ] [ Designated as safety issue: Yes ]

    Number of participants with AEs that occurred during treatment and follow-up period (45 days after last cycle). Drug-related AEs and SAEs were followed until resolved or mutually agreed by the investigator and Genzyme to discontinue reporting. AEs were classified by the investigator according to severity (graded using National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version 3.0) and relationship to study drug. The severity scale is:

    > Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death related to AE


  • Percentage of Participants Achieving A Response Over the First Two Treatment Cycles in Phase 1 [ Time Frame: Approximately 2 months (Phase 1 portion of study) ] [ Designated as safety issue: No ]
    Response categories 1) complete remission (CR): without circulating blasts or extramedullary disease, bone marrow (BM) with <5% blasts, and platelet (plt)/ANC recovery: ALL ≥75/ ≥0.75 [x 10^9/L]; AML ≥100/ ≥1.0 [x 10^9/L] 2) CR in absence of plt recovery (CRp): ALL plt ≥20 to <75 x 10^9/L; AML plt ≥20 to <100 x 10^9/L 3) partial remission (PR): no circulating blasts, appearance of normal hematopoietic progenitors, and either a BM with ≥5% and ≤25% blasts with recovery of plts/ANC or a BM with <5% blasts not meeting CR/CRp definition 4) Overall remission (OR): CR+CRp 5) Any response: CR+CRp+PR.

  • Time to Remission for Participants Who Had a Response in Phase 1 [ Time Frame: up to 8 weeks (Phase 1 portion of study) ] [ Designated as safety issue: No ]
    The weeks between start of intervention and remission as assessed by the investigator in Phase 1. Participants who had a complete remission (CR) or complete remission with the absence of total platelet recovery (CRp) are included.

  • Kaplan Meier Estimate of Duration of Remission (DOR) for Participants Who Achieved Overall Remission (OR) in Phase 1 [ Time Frame: Up to 2 years (Phase 1 portion of study) ] [ Designated as safety issue: No ]
    Duration of response is the time from the first objective measurement of complete response (CR) or complete response with the absence of total platelet recovery (CRp) to the date of first objective documentation of disease relapse or death due to any cause, plus one day. For summary purposes, results are presented as weeks.

  • Kaplan Meier Estimates of Event-free Survival (EFS) for Participants in Phase 1 [ Time Frame: Up to 2 years (Phase 1 portion of study) ] [ Designated as safety issue: No ]
    Event-free survival (EFS) is defined as the time from date of first administration of study interventions until the earliest of the following: date of death or date of first response assessment confirming relapse or date of final response assessment which fails to confirm response, plus one day. For summary purposes, results are presented as weeks.

  • Number of Participants With 4-month Event Free Survival in Phase 1 [ Time Frame: 4 months (Phase I portion of study) ] [ Designated as safety issue: No ]
    Number of participants with event-free survival at four months post first dose of therapy. A participant is considered event-free if at month 4 they have not died or had a response assessment confirming a relapse.

  • Kaplan Meier Estimates of Overall Survival (OS) for Participants in Phase 1 [ Time Frame: Up to 2 years (Phase 1 portion of study) ] [ Designated as safety issue: No ]
    Overall survival is defined as the time from date of first administration of study interventions until date of death, plus one day. For summary purposes, results are presented as weeks.

  • Summary of Participants With Adverse Events (AEs) in Phase 2 [ Time Frame: Up to 9.5 months (Phase 2 portion of study) ] [ Designated as safety issue: Yes ]

    Number of participants with AEs that occurred during treatment and follow-up period (45 days after last cycle). Drug-related AEs and SAEs were followed until resolved or mutually agreed by the investigator and Genzyme to discontinue reporting. AEs were classified by the investigator according to severity (graded using National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version 3.0) and relationship to study drug. The severity scale is:

    > Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death related to AE


  • Time to Remission for Participants Who Had a Response in Phase 2 [ Time Frame: up to 8 weeks (Phase 2 portion of study) ] [ Designated as safety issue: No ]
    The weeks between start of intervention and remission as assessed by the investigator in Phase 2. Participants who had a complete remission (CR) or complete remission with the absence of total platelet recovery (CRp) are included.

  • Kaplan Meier Estimate of Duration of Remission (DOR) for Participants Who Achieved Overall Remission (OR) in Phase 2 [ Time Frame: Up to 2 years (Phase 2 portion of study) ] [ Designated as safety issue: No ]
    Duration of response is the time from the first objective measurement of complete response (CR) or complete response with the absence of total platelet recovery (CRp) to the date of first objective documentation of disease relapse or death due to any cause, plus one day. For summary purposes, results are presented as weeks.

  • Kaplan Meier Estimates of Event-free Survival (EFS) for Participants in Phase 2 [ Time Frame: Up to 2 years (Phase 2 portion of study) ] [ Designated as safety issue: No ]
    Event-free survival (EFS) is defined as the time from date of first administration of study interventions until the earliest of the following: date of death or date of first response assessment confirming relapse or date of final response assessment which fails to confirm response, plus one day. For summary purposes, results are presented as weeks.

  • Number of Participants With 4-month Event Free Survival in Phase 2 [ Time Frame: 4 months (Phase 2 portion of study) ] [ Designated as safety issue: No ]
    Number of participants with event-free survival at four months post first dose of therapy. A participant is considered event-free if at month 4 they have not died or had a response assessment confirming a relapse.

  • Kaplan Meier Estimates of Overall Survival (OS) for Participants in Phase 2 [ Time Frame: Up to 2 years (Phase 2 portion of study) ] [ Designated as safety issue: No ]
    Overall survival is defined as the time from date of first administration of study interventions until date of death, plus one day. For summary purposes, results are presented as weeks.


Enrollment: 50
Study Start Date: March 2006
Study Completion Date: May 2010
Primary Completion Date: May 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: clofarabine, etoposide, cyclophosphamide

Phase 1: escalating dosage of the three drugs delivered intravenously. Clofarabine dosage from 20-40 mg/m^2, etoposide dosage from 75-100 mg/m^2, cyclophosphamide dosage from 340-440 mg/m^2.

Phase 2: The recommended phase 2 doses (RP2D) were clofarabine 40 mg/m^2, etoposide 100 mg/m^2 and cyclophosphamide 440 mg/m^2 delivered intravenously

Drug: clofarabine
Clofarabine 20‑40 mg/m²/day 2 hour intravenous (IV) infusion daily for 5 days of a 28 day cycle as the first of the three IV interventions administered. Maximum of 8 cycles given in both the phase 1 and phase 2 study periods.
Other Names:
  • Clolar
  • Evoltra
Drug: Etoposide
Etoposide 75-100 mg/m²/day 2 hour intravenous (IV) infusion daily for 5 days of a 28 day cycle following clofarabine therapy. Maximum of 8 cycles given in both the phase 1 and phase 2 study periods.
Other Name: Eposin
Drug: Cyclophosphamide
Cyclophosphamide 340‑440 mg/m²/day as 30-60 minute intravenous (IV) infusion daily for 5 days of a 28 day cycle following the other two interventions. Maximum of 8 cycles given in both the phase 1 and phase 2 study periods.
Other Names:
  • Endoxan
  • Revimmune
  • Cytoxan

  Eligibility

Ages Eligible for Study:   1 Year to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • NOTE: the following eligibility criteria were applicable to acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML) patients for the Phase 1 portion of this study, and to ALL patients for the Phase 2 portion of the study (only ALL patients were allowed in the Phase 2 portion of the study).
  • ALL with > 25% blasts in bone marrow; AML with ≥ 5% blasts in bone marrow; ALL and AML patients may have extramedullary disease
  • Karnofsky Performance Status ≥ 50 for patients > 10 years old; Lansky Performance Status ≥ 50 for patients ≤ 10 years old
  • Prior therapy: AML: 1-2 prior induction regimens and ≤ 1 hematopoietic stem cell transplant (HSCT); ALL: 1-3 prior induction regimens
  • Adequate liver, renal, pancreatic, and cardiac function
  • Have received no prior HSCT (study amended in Phase 2 to exclude patients with prior HSCT)

Exclusion Criteria:

  • NOTE: the following eligibility criteria were applicable to ALL and AML patients for the Phase 1 portion of this study, and to ALL patients for the Phase 2 portion of the study (only ALL patients were allowed in the Phase 2 portion of the study).
  • Burkitt's leukemia
  • Previous treatment with clofarabine
  • Uncontrolled systemic fungal, bacterial or other infection and 48 hrs negative blood cultures required for patients with a history of fever within 3 days of enrollment
  • Active CNS involvement (i.e., should be CNS1 or CNS2)
  • Inadequate time since last therapy: ≤ 14 days since last cytotoxic chemotherapy; ≤ 7 days since last biologic therapy; ≤ 14 days since last monoclonal antibody therapy
  • Have received prior HSCT (study amended in Phase 2 to exclude patients with prior HSCT)
  • Pregnant or lactating
  • Have tested positive for hepatitis B or hepatitis C infection or history of cirrhosis
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00315705

Locations
United States, Alabama
Children's Hospital of Alabama
Birmingham, Alabama, United States
United States, California
Children's Hospital of Los Angeles
Los Angeles, California, United States
Rady Children's Hospital
San Diego, California, United States
United States, Connecticut
Connecticut Children's Medical Center
Hartford, Connecticut, United States
United States, Illinois
Children's Memorial Hospital
Chicago, Illinois, United States
United States, Indiana
St. Vincent Children's Hospital
Indianapolis, Indiana, United States
United States, Massachusetts
Dana Farber Cancer Institute
Boston, Massachusetts, United States
United States, Michigan
Children's Hospital of Michigan
Detroit, Michigan, United States
United States, New York
New York School of Medicine
New York, New York, United States
Memorial Sloan-Kettering Cancer Center
New York, New York, United States
United States, Tennessee
St. Jude Children's Research Hospital
Memphis, Tennessee, United States
United States, Texas
University of Texas MD Anderson Cancer Center
Houston, Texas, United States
United States, Washington
Seattle Children's Hospital
Seattle, Washington, United States
Sponsors and Collaborators
Genzyme, a Sanofi Company
Investigators
Study Director: Medical Monitor Genzyme, a Sanofi Company
  More Information

No publications provided by Sanofi

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Sanofi ( Genzyme, a Sanofi Company )
ClinicalTrials.gov Identifier: NCT00315705     History of Changes
Other Study ID Numbers: CLO21800205
Study First Received: April 18, 2006
Results First Received: April 27, 2011
Last Updated: March 17, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Sanofi:
clofarabine
acute leukemia
ALL
AML
clolar
CLO218

Additional relevant MeSH terms:
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Leukemia, Myeloid
Leukemia
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cyclophosphamide
Etoposide phosphate
Clofarabine
Etoposide
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antineoplastic Agents, Phytogenic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on September 29, 2014