A Study of Clofarabine in Combination With Etoposide and Cyclophosphamide in Children With Acute Leukemias.
- Conditions
- Acute Lymphoblastic LeukemiaAcute Myelogenous LeukemiaRelapsed Leukemia
- Interventions
- Registration Number
- NCT00315705
- Lead Sponsor
- Genzyme, a Sanofi Company
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 50
- 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)
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description clofarabine, etoposide, cyclophosphamide 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 clofarabine, etoposide, cyclophosphamide clofarabine 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 clofarabine, etoposide, cyclophosphamide Etoposide 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
- Primary Outcome Measures
Name Time Method Maximum Tolerated Dose (MTD) in Phase 1 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.Participants With Dose Limiting Toxicity in Phase 1 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.
Percentage of Participants Achieving A Response Over the First Two Treatment Cycles in Phase 2 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
Name Time Method Summary of Participants With Adverse Events (AEs) in Phase 1 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
Percentage of Participants Achieving A Response Over the First Two Treatment Cycles in Phase 1 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.
Time to Remission for Participants Who Had a Response in Phase 1 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.
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) 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 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.
Number of Participants With 4-month Event Free Survival in Phase 1 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.
Kaplan Meier Estimates of Overall Survival (OS) for Participants in Phase 1 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.
Summary of Participants With Adverse Events (AEs) in Phase 2 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
Time to Remission for Participants Who Had a Response in Phase 2 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.
Kaplan Meier Estimate of Duration of Remission (DOR) for Participants Who Achieved Overall Remission (OR) in Phase 2 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.
Kaplan Meier Estimates of Event-free Survival (EFS) for Participants in Phase 2 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.
Number of Participants With 4-month Event Free Survival in Phase 2 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.
Kaplan Meier Estimates of Overall Survival (OS) for Participants in Phase 2 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.
Trial Locations
- Locations (13)
Dana Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Memorial Sloan-Kettering Cancer Center
🇺🇸New York, New York, United States
University of Texas MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
Rady Children's Hospital
🇺🇸San Diego, California, United States
Children's Hospital of Los Angeles
🇺🇸Los Angeles, California, United States
Connecticut Children's Medical Center
🇺🇸Hartford, Connecticut, United States
St. Jude Children's Research Hospital
🇺🇸Memphis, Tennessee, United States
Seattle Children's Hospital
🇺🇸Seattle, Washington, United States
Children's Hospital of Alabama
🇺🇸Birmingham, Alabama, United States
Children's Memorial Hospital
🇺🇸Chicago, Illinois, United States
St. Vincent Children's Hospital
🇺🇸Indianapolis, Indiana, United States
Children's Hospital of Michigan
🇺🇸Detroit, Michigan, United States
New York School of Medicine
🇺🇸New York, New York, United States