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

• ClinicalTrials.gov Identifier: NCT00315705
• Recruitment Status: Completed
• First Posted: April 19, 2006
• Results First Posted: June 30, 2011
• Last Update Posted: April 14, 2014
• Sponsor: Genzyme, a Sanofi Company
• Information provided by (Responsible Party): Sanofi ( Genzyme, a Sanofi Company )

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Acute Lymphoblastic Leukemia; Acute Myelogenous Leukemia; Relapsed Leukemia	Drug: clofarabine; Drug: Etoposide; Drug: Cyclophosphamide	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 50 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (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.
• Study Start Date: March 2006
• Actual Primary Completion Date: May 2010
• Actual Study Completion Date: May 2010

Arms and Interventions

Arm

Intervention/treatment

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

Outcome Measures

Primary Outcome Measures :

1. Maximum Tolerated Dose (MTD) in Phase 1 [ Time Frame: Up to Day 42 (Phase 1 portion of study) ]

   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.

2. Participants With Dose Limiting Toxicity in Phase 1 [ Time Frame: Up to Day 42 (Phase 1 portion of study) ]
   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.
3. 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) ]
   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 :

1. Summary of Participants With Adverse Events (AEs) in Phase 1 [ Time Frame: Up to 9.5 months (Phase 1 portion of study) ]
   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
2. 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) ]
   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.
3. Time to Remission for Participants Who Had a Response in Phase 1 [ Time Frame: up to 8 weeks (Phase 1 portion of study) ]
   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.
4. 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) ]
   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.
5. Kaplan Meier Estimates of Event-free Survival (EFS) for Participants in Phase 1 [ Time Frame: Up to 2 years (Phase 1 portion of study) ]
   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.
6. Number of Participants With 4-month Event Free Survival in Phase 1 [ Time Frame: 4 months (Phase I portion of study) ]
   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.
7. Kaplan Meier Estimates of Overall Survival (OS) for Participants in Phase 1 [ Time Frame: Up to 2 years (Phase 1 portion of study) ]
   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.
8. Summary of Participants With Adverse Events (AEs) in Phase 2 [ Time Frame: Up to 9.5 months (Phase 2 portion of study) ]
   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
9. Time to Remission for Participants Who Had a Response in Phase 2 [ Time Frame: up to 8 weeks (Phase 2 portion of study) ]
   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.
10. 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) ]
    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.
11. Kaplan Meier Estimates of Event-free Survival (EFS) for Participants in Phase 2 [ Time Frame: Up to 2 years (Phase 2 portion of study) ]
    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.
12. Number of Participants With 4-month Event Free Survival in Phase 2 [ Time Frame: 4 months (Phase 2 portion of study) ]
    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.
13. Kaplan Meier Estimates of Overall Survival (OS) for Participants in Phase 2 [ Time Frame: Up to 2 years (Phase 2 portion of study) ]
    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.

Eligibility Criteria

• Ages Eligible for Study: 1 Year to 21 Years (Child, Adult)
• Sexes Eligible for Study: All
• 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

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

Memorial Sloan-Kettering Cancer Center

New York, New York, United States

New York School of Medicine

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

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Genzyme, a Sanofi Company
• ClinicalTrials.gov Identifier: NCT00315705
• Other Study ID Numbers: CLO21800205
• First Posted: April 19, 2006
• Results First Posted: June 30, 2011
• Last Update Posted: April 14, 2014
• Last Verified: March 2014

Keywords provided by Sanofi ( Genzyme, a Sanofi Company ):

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

Additional relevant MeSH terms:

Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Neoplasms by Histologic Type; Neoplasms; Leukemia, Lymphoid; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Cyclophosphamide; Etoposide; Clofarabine; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites