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

Acute Lymphoblastic Leukemia Clinical Trial

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00315705
• Other study ID #: CLO21800205
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: April 18, 2006
• Last updated: March 17, 2014
• Start date: March 2006
• Est. completion date: May 2010

Study information

• Verified date: March 2014
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 50
• Est. completion date: May 2010
• Est. primary completion date: May 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 1 Year to 21 Years

Eligibility

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

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acute Lymphoblastic Leukemia
• Acute Myelogenous Leukemia
• Leukemia
• Leukemia, Lymphoid
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Relapsed Leukemia

Intervention

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.
• 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.
• 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.

Locations

Country	Name	City	State
United States	Children's Hospital of Alabama	Birmingham	Alabama
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Children's Memorial Hospital	Chicago	Illinois
United States	Children's Hospital of Michigan	Detroit	Michigan
United States	Connecticut Children's Medical Center	Hartford	Connecticut
United States	University of Texas MD Anderson Cancer Center	Houston	Texas
United States	St. Vincent Children's Hospital	Indianapolis	Indiana
United States	Children's Hospital of Los Angeles	Los Angeles	California
United States	St. Jude Children's Research Hospital	Memphis	Tennessee
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	New York School of Medicine	New York	New York
United States	Rady Children's Hospital	San Diego	California
United States	Seattle Children's Hospital	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Genzyme, a Sanofi Company

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)	Yes
Primary	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)	Yes
Primary	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)	No
Secondary	Summary of Participants With Adverse Events (AEs) in Phase 1	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	Up to 9.5 months (Phase 1 portion of study)	Yes
Secondary	Percentage of Participants Achieving A Response Over the First Two Treatment Cycles in Phase 1	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.	Approximately 2 months (Phase 1 portion of study)	No
Secondary	Time to Remission for Participants Who Had a Response in Phase 1	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.	up to 8 weeks (Phase 1 portion of study)	No
Secondary	Kaplan Meier Estimate of Duration of Remission (DOR) for Participants Who Achieved Overall Remission (OR) in Phase 1	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.	Up to 2 years (Phase 1 portion of study)	No
Secondary	Kaplan Meier Estimates of Event-free Survival (EFS) for Participants in Phase 1	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.	Up to 2 years (Phase 1 portion of study)	No
Secondary	Number of Participants With 4-month Event Free Survival in Phase 1	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.	4 months (Phase I portion of study)	No
Secondary	Kaplan Meier Estimates of Overall Survival (OS) for Participants in Phase 1	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.	Up to 2 years (Phase 1 portion of study)	No
Secondary	Summary of Participants With Adverse Events (AEs) in Phase 2	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	Up to 9.5 months (Phase 2 portion of study)	Yes
Secondary	Time to Remission for Participants Who Had a Response in Phase 2	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.	up to 8 weeks (Phase 2 portion of study)	No
Secondary	Kaplan Meier Estimate of Duration of Remission (DOR) for Participants Who Achieved Overall Remission (OR) in Phase 2	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.	Up to 2 years (Phase 2 portion of study)	No
Secondary	Kaplan Meier Estimates of Event-free Survival (EFS) for Participants in Phase 2	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.	Up to 2 years (Phase 2 portion of study)	No
Secondary	Number of Participants With 4-month Event Free Survival in Phase 2	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.	4 months (Phase 2 portion of study)	No
Secondary	Kaplan Meier Estimates of Overall Survival (OS) for Participants in Phase 2	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.	Up to 2 years (Phase 2 portion of study)	No