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

NCT00315705 | Completed Phase 1 Results

• 1 other identifier: CLO21800205
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 13

Brief Summary

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.

Conditions

Acute Lymphoblastic Leukemia; Acute Myelogenous Leukemia; Relapsed Leukemia

Keywords

clofarabine; acute leukemia; ALL; AML; clolar; CLO218

Outcome Measures

Primary Outcomes (3)

• Maximum Tolerated Dose (MTD) in Phase 1

  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.

  Up to Day 42 (Phase 1 portion of study)

• Participants With Dose Limiting Toxicity in Phase 1

  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.

  Up to Day 42 (Phase 1 portion of study)

• Percentage of Participants Achieving A Response Over the First Two Treatment Cycles in Phase 2

  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.

  Approximately 28-56 days (Phase 2 portion of study)

Secondary Outcomes (13)

• Summary of Participants With Adverse Events (AEs) in Phase 1

  Up to 9.5 months (Phase 1 portion of study)

• Percentage of Participants Achieving A Response Over the First Two Treatment Cycles in Phase 1

  Approximately 2 months (Phase 1 portion of study)

• Time to Remission for Participants Who Had a Response in Phase 1

  up to 8 weeks (Phase 1 portion of study)

• Kaplan Meier Estimate of Duration of Remission (DOR) for Participants Who Achieved Overall Remission (OR) in Phase 1

  Up to 2 years (Phase 1 portion of study)

• Kaplan Meier Estimates of Event-free Survival (EFS) for Participants in Phase 1

  Up to 2 years (Phase 1 portion of study)

Study Arms (1)

clofarabine, etoposide, cyclophosphamide

EXPERIMENTAL

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; Drug: Etoposide; Drug: Cyclophosphamide

Interventions

clofarabine DRUG

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.

Also known as: Clolar, Evoltra

clofarabine, etoposide, cyclophosphamide

Etoposide DRUG

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.

Also known as: Eposin

clofarabine, etoposide, cyclophosphamide

Cyclophosphamide DRUG

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.

Also known as: Endoxan, Revimmune, Cytoxan

clofarabine, etoposide, cyclophosphamide

Eligibility Criteria

• Age: 1 Year - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Genzyme, a Sanofi Company: lead

Study Sites (13)

Children's Hospital of Alabama

Birmingham, Alabama, United States

Location

Children's Hospital of Los Angeles

Los Angeles, California, United States

Location

Rady Children's Hospital

San Diego, California, United States

Location

Connecticut Children's Medical Center

Hartford, Connecticut, United States

Location

Children's Memorial Hospital

Chicago, Illinois, United States

Location

St. Vincent Children's Hospital

Indianapolis, Indiana, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, United States

Location

Children's Hospital of Michigan

Detroit, Michigan, United States

Location

Memorial Sloan-Kettering Cancer Center

New York, New York, United States

Location

New York School of Medicine

New York, New York, United States

Location

St. Jude Children's Research Hospital

Memphis, Tennessee, United States

Location

University of Texas MD Anderson Cancer Center

Houston, Texas, United States

Location

Seattle Children's Hospital

Seattle, Washington, United States

Location

Related Publications (1)

• Hijiya N, Thomson B, Isakoff MS, Silverman LB, Steinherz PG, Borowitz MJ, Kadota R, Cooper T, Shen V, Dahl G, Thottassery JV, Jeha S, Maloney K, Paul JA, Barry E, Carroll WL, Gaynon PS. Phase 2 trial of clofarabine in combination with etoposide and cyclophosphamide in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. Blood. 2011 Dec 1;118(23):6043-9. doi: 10.1182/blood-2011-08-374710. Epub 2011 Oct 3.

  PMID: 21967976 DERIVED

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid, Acute; Leukemia

Interventions

Clofarabine; Etoposide; Cyclophosphamide

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, Myeloid

Intervention Hierarchy (Ancestors)

Adenine Nucleotides; Purine Nucleotides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Nucleotides; Ribonucleotides; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Glucosides; Glycosides; Carbohydrates; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds

Results Point of Contact

• Title: Genzyme Medical Information
• Organization: Genzyme Corporation

1-800-745-4447

Study Officials

• Medical Monitor

  Genzyme, a Sanofi Company

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 18, 2006
• First Posted: April 19, 2006
• Study Start: March 1, 2006
• Primary Completion: May 1, 2010
• Study Completion: May 1, 2010
• Last Updated: April 14, 2014
• Results First Posted: June 30, 2011

Record last verified: 2014-03

Locations

US (13)