Clofarabine and Cytarabine in Treating Young Patients With Refractory or Relapsed Acute Myeloid Leukemia or Acute Lymphoblastic Leukemia

Leukemia Clinical Trial

Official title:

A Phase I/II Study of CLOLAR® (Clofarabine, IND# 73, 789) in Combination With Cytarabine in Pediatric Patients With Refractory/Relapsed Leukemia

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00372619
• Other study ID #: AAML0523
• Secondary ID: CDR0000494654NCI
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• First received: September 6, 2006
• Last updated: October 5, 2015
• Start date: March 2007

Study information

• Verified date: October 2015
• Source: Children's Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

RATIONALE: Drugs used in chemotherapy, such as clofarabine and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of clofarabine when given together with cytarabine and to see how well they work in treating young patients with refractory or relapsed acute myeloid leukemia or acute lymphoblastic leukemia. (Phase I closed to enrollment as of 09/16/09)

Description:

OBJECTIVES:

Primary

• To define the overall response rate (complete remission or remission without platelet recovery) in young patients with relapsed or refractory acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) treated with clofarabine in combination with cytarabine.

Secondary

• To determine the safety profile and tolerability of clofarabine when given in combination with cytarabine in patients with and without prior stem cell transplantation.

• To identify apoptosis specific genes that are important in mediating response to clofarabine and cytarabine.

• To quantitate the level of human equilibrative nucleoside transporter proteins (hENT1 and hENT2) and human concentrative nucleoside transporter proteins (hCNT2 and hCNT3) in blasts of these patients.

• To determine gene expression profiles at study entry and at time of relapse in order to isolate profiles that may predict response and also to complement apoptosis specific protein arrays.

• To perform serial measurements of minimal residual disease (MRD) to provide an objective determination of the effectiveness of this treatment regimen and to correlate with post remission events (relapse, death).

• To perform FLT3/ITD analysis to help determine the prevalence and clinical significance of this somatic mutation in patients with relapsed AML.

OUTLINE: This is a multicenter, phase I, dose-escalation study of clofarabine followed by a phase II study. Patients are stratified according to disease (acute lymphoblastic leukemia [ALL] vs acute myeloid leukemia [AML]). (Phase I closed to accrual as of 09/16/09)

• Intrathecal CNS prophylaxis (all patients with ALL and at physician's discretion for patients with AML or acute leukemia of ambiguous lineage): Patients receive intrathecal (IT) cytarabine on day 0 of the first course of induction therapy. Patients also receive IT methotrexate on day 1 of the second course of induction therapy and on day 1 of all courses of maintenance therapy.

• Induction therapy:

• Course 1: Patients receive cytarabine IV over 2 hours and clofarabine IV over 2 hours on days 1-5. Patients with ≥ 5% blasts (i.e., M2 or M3 bone marrow) at days 14-21 proceed immediately to course 2 of induction therapy. Patients with < 5% blasts (i.e., M1 bone marrow) may proceed to course 2 of induction therapy at blood count recovery or at day 42.

• Course 2: Patients receive clofarabine IV over 2 hours followed by cytarabine IV over 2 hours on days 1-5. After the second course of induction therapy, patients with M2 or M3 bone marrow at days 14-21 are removed from the study. Patients with M1 bone marrow proceed to maintenance therapy 14-42 days after the initiation of course 2.

• Maintenance therapy: Patients receive clofarabine and cytarabine as in induction therapy. Treatment repeats every 14-42 days for up to 10 courses in the absence of disease progression or unacceptable toxicity.

Patients may undergo blood and bone marrow sample collection periodically for correlative laboratory studies.

After completion of study therapy, patients are followed periodically for up to 5 years.

PROJECTED ACCRUAL: A total of 87 patients will be accrued for this study.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 74
• Est. primary completion date: August 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 1 Year to 30 Years

Eligibility

DISEASE CHARACTERISTICS:

• Histologically confirmed diagnosis of 1 of the following:

• Acute myeloid leukemia (AML) with = 5% blasts in the bone marrow (M2/M3 bone marrow) with or without extramedullary disease

• Acute lymphoblastic leukemia (ALL) with > 25% blasts in the bone marrow (M3 bone marrow) with or without extramedullary disease

• Acute leukemia of ambiguous lineage with = 5% blasts in the bone marrow (M2/M3 bone marrow) with or without extramedullary disease

• Disease must have relapsed after or be refractory to prior induction therapy

• Patients with AML or acute leukemia of ambiguous lineage must be in first relapse OR refractory to first induction therapy with = 1 attempt at remission induction

• Patients with AML who enroll on the phase I portion of the study must have received prior mitoxantrone hydrochloride and cytarabine for newly diagnosed AML (phase I closed to accrual as of 09/16/09)

• Patients with ALL must be in second or third relapse (= 3 prior induction regimens) OR refractory to reinduction in first relapse

• Patients with ALL refractory to first induction therapy are not eligible

• No acute promyelocytic leukemia

• No CNS 3 involvement (i.e., WBC = 5/µL in the cerebrospinal fluid with blasts present on cytospin)

PATIENT CHARACTERISTICS:

• Karnofsky performance status (PS) 50-100% (> 16 years of age) OR Lansky PS 50-100% (= 16 years of age) OR ECOG PS 0-2

• Life expectancy = 8 weeks

• Creatinine clearance or radioisotope glomerular filtration rate = 70 mL/min

• Direct bilirubin = 1.5 times upper limit of normal (ULN)

• ALT < 2.5 times ULN (unless it is related to leukemic involvement)

• Shortening fraction = 27% by echocardiogram OR ejection fraction = 45% by gated radionuclide study

• No evidence of dyspnea at rest or exercise intolerance

• Pulse oximetry > 94% at room air

• Amylase = 1.5 times ULN

• Lipase < 1.5 times ULN

• No active, uncontrolled grade 3 or 4 infection

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception during and for = 3 months after completion of study treatment

• No known hepatitis B or C infection or history of cirrhosis

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• Recovered from all prior therapy*

• At least 14 days since prior cytotoxic therapy (except hydroxyurea and intrathecal chemotherapy)*

• At least 7 days since prior biologic agent*

• At least 14 days since prior monoclonal antibody therapy*

• No more than 1 prior autologous or allogeneic hematopoietic stem cell transplantation

• No evidence of active graft-vs-host disease

• At least 4 months since transplantation

• No other concurrent chemotherapy or immunomodulating agents

• No other concurrent investigational therapy NOTE: *Patients who relapse during ALL maintenance therapy do not require a waiting period.

Study Design

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

Related Conditions & MeSH terms

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

Intervention

Drug:
• clofarabine
Given IV for 5 days
• cytarabine
Given IV
• methotrexate
Given intrathecally or IT age based dosage

Other:
• laboratory biomarker analysis

Locations

Country	Name	City	State
Canada	IWK Health Centre	Halifax	Nova Scotia
Canada	Hopital Sainte Justine	Montreal	Quebec
Canada	Allan Blair Cancer Centre at Pasqua Hospital	Regina	Saskatchewan
Canada	Hospital for Sick Children	Toronto	Ontario
Canada	CancerCare Manitoba	Winnipeg	Manitoba
United States	Tulane Cancer Center Office of Clinical Research	Alexandria	Louisiana
United States	C.S. Mott Children's Hospital at University of Michigan Medical Center	Ann Arbor	Michigan
United States	AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus	Atlanta	Georgia
United States	Children's Hospital Colorado Center for Cancer and Blood Disorders	Aurora	Colorado
United States	Alvin and Lois Lapidus Cancer Institute at Sinai Hospital	Baltimore	Maryland
United States	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland
United States	CancerCare of Maine at Eastern Maine Medical Center	Bangor	Maine
United States	UAB Comprehensive Cancer Center	Birmingham	Alabama
United States	Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill	Chapel Hill	North Carolina
United States	Blumenthal Cancer Center at Carolinas Medical Center	Charlotte	North Carolina
United States	Presbyterian Cancer Center at Presbyterian Hospital	Charlotte	North Carolina
United States	Children's Memorial Hospital - Chicago	Chicago	Illinois
United States	University of Illinois Cancer Center	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio
United States	Rainbow Babies and Children's Hospital	Cleveland	Ohio
United States	Ellis Fischel Cancer Center at University of Missouri - Columbia	Columbia	Missouri
United States	Palmetto Health South Carolina Cancer Center	Columbia	South Carolina
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Driscoll Children's Hospital	Corpus Christi	Texas
United States	Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas	Dallas	Texas
United States	Dayton Children's - Dayton	Dayton	Ohio
United States	Southern California Permanente Medical Group	Downey	California
United States	Lee Cancer Care of Lee Memorial Health System	Fort Myers	Florida
United States	Cook Children's Medical Center - Fort Worth	Fort Worth	Texas
United States	Helen DeVos Children's Hospital at Spectrum Health	Grand Rapids	Michigan
United States	Greenville Hospital Cancer Center	Greenville	South Carolina
United States	Hackensack University Medical Center Cancer Center	Hackensack	New Jersey
United States	Penn State Children's Hospital	Hershey	Pennsylvania
United States	Cancer Research Center of Hawaii	Honolulu	Hawaii
United States	Baylor University Medical Center - Houston	Houston	Texas
United States	Indiana University Melvin and Bren Simon Cancer Center	Indianapolis	Indiana
United States	St. Vincent Indianapolis Hospital	Indianapolis	Indiana
United States	University of Mississippi Cancer Clinic	Jackson	Mississippi
United States	Nemours Children's Clinic	Jacksonville	Florida
United States	Children's Mercy Hospital	Kansas City	Missouri
United States	CCOP - Nevada Cancer Research Foundation	Las Vegas	Nevada
United States	Jonathan Jaques Children's Cancer Center at Miller Children's Hospital	Long Beach	California
United States	Kosair Children's Hospital	Louisville	Kentucky
United States	Children's Hospital Central California	Madera	California
United States	Marshfield Clinic - Marshfield Center	Marshfield	Wisconsin
United States	Midwest Children's Cancer Center at Children's Hospital of Wisconsin	Milwaukee	Wisconsin
United States	Masonic Cancer Center at University of Minnesota	Minneapolis	Minnesota
United States	Overlook Hospital	Morristown	New Jersey
United States	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee
United States	Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School	New Brunswick	New Jersey
United States	Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center	New York	New York
United States	Newark Beth Israel Medical Center	Newark	New Jersey
United States	Children's Hospital of The King's Daughters	Norfolk	Virginia
United States	Children's Hospital of Orange County	Orange	California
United States	Nemours Children's Clinic - Orlando	Orlando	Florida
United States	St. Joseph's Hospital and Medical Center	Paterson	New Jersey
United States	Nemours Children's Clinic - Pensacola	Pensacola	Florida
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	Legacy Emanuel Hospital and Health Center and Children's Hospital	Portland	Oregon
United States	Carilion Medical Center for Children at Roanoke Community Hospital	Roanoke	Virginia
United States	James P. Wilmot Cancer Center at University of Rochester Medical Center	Rochester	New York
United States	Mayo Clinic Cancer Center	Rochester	Minnesota
United States	Primary Children's Medical Center	Salt Lake City	Utah
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	Rady Children's Hospital - San Diego	San Diego	California
United States	UCSF Helen Diller Family Comprehensive Cancer Center	San Francisco	California
United States	Curtis and Elizabeth Anderson Cancer Institute at Memorial Health University Medical Center	Savannah	Georgia
United States	Children's Hospital and Regional Medical Center - Seattle	Seattle	Washington
United States	Providence Cancer Center at Sacred Heart Medical Center	Spokane	Washington
United States	Simmons Cooper Cancer Institute	Springfield	Illinois
United States	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis	St. Louis	Missouri
United States	SUNY Upstate Medical University Hospital	Syracuse	New York
United States	St. Joseph's Cancer Institute at St. Joseph's Hospital	Tampa	Florida
United States	Children's National Medical Center	Washington	District of Columbia
United States	Lombardi Comprehensive Cancer Center at Georgetown University Medical Center	Washington	District of Columbia
United States	Alfred I. duPont Hospital for Children	Wilmington	Delaware
United States	UMASS Memorial Cancer Center - University Campus	Worcester	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
Children's Oncology Group	National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Response (CR for ALL Patients), (CR + CRp for AML Patients)	Overall response for ALL patients: CR - complete remission (attainment of an M1 bone marrow (< 5% blasts) with no evidence of circulating blasts or extramedullary disease and with recovery of peripheral counts (absolute neutrophil count (ANC) > 750/µL and platelet count > 75,000/µL).; Overall response for AML patients: (CR + CRp), defined as: CR - complete remission (attainment of an M1 bone marrow (<5% blasts) with no evidence of circulating blasts or extramedullary disease and with recovery of peripheral blood counts (absolute neutrophil count (ANC) > 1000/uL and platelet count > 100,000/uL)) or CRp - remission without platelet recovery (Attainment of an M1 bone marrow (<5% blasts) with no evidence of circulating blasts or extramedullary disease and with recovery of absolute neutrophil count (ANC) > 1000/uL and platelet transfusion independence (defined as: no platelet transfusions x 1 week)).	2 cycles or up to 84 days	No
Secondary	Safety and Tolerability as Measured by CTCAE v3.0		End of therapy	Yes
Secondary	Correlate the Expression of Apoptosis Specific Genes	Correlate the expression of apoptosis specific genes with chemoresistance and determine whether therapy with clofarabine is able to overcome blocks in apoptosis through modulation of gene expression. Gene expression analysis will be performed on specimens obtained during therapy. Apoptosis specific microarray data will be analyzed using GeneTraffic software (Iobion Informatics, La Jolla CA).	End of therapy	No