Clinical trial NCT00022451: Tipifarnib in Treating Young Patients With Refractory Leukemia
Official title: A Phase I Trial and Pharmacokinetic Study of R115777 in Pediatric Patients With Refractory Leukemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Leukemia
Keywords: recurrent childhood acute lymphoblastic leukemia
recurrent childhood acute myeloid leukemia
relapsing chronic myelogenous leukemia
blastic phase chronic myelogenous leukemia
chronic myelogenous leukemia, BCR-ABL1 positive
childhood acute promyelocytic leukemia (M3)
acute undifferentiated leukemia
juvenile myelomonocytic leukemia
childhood chronic myelogenous leukemia
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
Collaborators: name: National Cancer Institute (NCI)
name: Children's Oncology Group
First posted: 2003-01-27
Sex: ALL
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

Brief summary: RATIONALE: Tipifarnib may stop the growth of cancer cells by blocking the enzymes necessary for cancer cell growth.

PURPOSE: Phase I trial to study the effectiveness of tipifarnib in treating young patients who have refractory leukemia.

Detailed description: OBJECTIVES:

Primary

* Determine the maximum tolerated dose and toxicity profile of tipifarnib in pediatric patients with refractory leukemia.
* Determine the pharmacokinetics of this drug in these patients.
* Determine the toxicity profile of this drug in these patients.

Secondary

* Analyze the gene expression profile of leukemic blasts from these patients before and after treatment with this drug.
* Determine circulating levels of nerve growth factor and correlate these levels with clinical neurotoxicity from this drug in these patients.

OUTLINE: This is an open-label, dose-escalation study.

Patients receive oral tipifarnib every 12 hours on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of tipifarnib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 of 6 patients experience dose-limiting toxicity. At least 9 additional patients are treated at the MTD.

PROJECTED ACCRUAL: A total of 12-34 patients will be accrued for this study within 1-2 years.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically confirmed acute lymphoblastic leukemia, acute nonlymphoblastic leukemia, juvenile myelomonocytic leukemia (JMML), or chronic myelogenous leukemia (CML) in blast crisis

  * Refractory to standard curative therapy
  * Acute promyelocytic leukemia refractory to tretinoin and arsenic trioxide
  * Philadelphia chromosome-positive CML refractory to imatinib mesylate
* Greater than 25% blasts in bone marrow (M3 bone marrow) except for patients with JMML
* Active extramedullary disease allowed
* No active leptomeningeal leukemia

PATIENT CHARACTERISTICS:

Age:

* 21 and under

Performance status:

* Karnofsky 50-100% (over 10 years of age)
* Lansky 50-100% (10 years of age and under)

Life expectancy:

* Not specified

Hematopoietic:

* Not required to be normal

Hepatic:

* Bilirubin normal
* SGPT and SGOT normal
* No significant hepatic dysfunction
* No grade 3 or 4 liver function test results within the past month

Renal:

* Creatinine normal OR
* Creatinine clearance at least 60 mL/min
* No significant renal dysfunction

Cardiovascular:

* No significant cardiac dysfunction

Pulmonary:

* No significant pulmonary dysfunction

Neurologic:

* No history of grand mal seizures grade 3 or greater except febrile seizures
* No persistent sensory or motor neuropathy greater than grade 2

Other:

* No clinically significant unrelated systemic illness
* No serious infection
* No organ dysfunction that would preclude study participation
* No requirement for total parenteral nutrition
* No known allergy to azoles (e.g., clotrimazole, fluconazole, ketoconazole, voriconazole)
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

* At least 1 week since prior colony-stimulating factor therapy (e.g., filgrastim \[G-CSF\] or sargramostim \[GM-CSF\]) except epoetin alfa
* At least 3 months since prior myeloablative therapy followed by bone marrow or stem cell transplantation
* No concurrent immunotherapy
* No concurrent GM-CSF or interleukin-11

Chemotherapy:

* At least 2 weeks since prior chemotherapy
* No concurrent intrathecal chemotherapy
* No other concurrent chemotherapy

Endocrine therapy:

* At least 1 week since prior corticosteroids
* No concurrent corticosteroids (except for acute allergic reaction)

Radiotherapy:

* At least 4 weeks since prior radiotherapy
* No concurrent radiotherapy

Surgery:

* Not specified

Other:

* Recovered from nonhematologic toxicity of all prior therapy
* At least 1 week since prior retinoids
* No antacids (magnesium- or aluminum-containing formulations) within 2 hours of study drug
* No other concurrent investigational agents
* No concurrent retinoids
* No concurrent anticonvulsants

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: Arkansas Cancer Research Center at University of Arkansas for Medical Sciences
state: Arkansas
city: Duarte
country: United States
facility: City of Hope Comprehensive Cancer Center
state: California
city: La Jolla
country: United States
facility: Rebecca and John Moores UCSD Cancer Center
state: California
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Los Angeles
country: United States
facility: Jonsson Comprehensive Cancer Center, UCLA
state: California
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: San Francisco
country: United States
facility: UCSF Comprehensive Cancer Center
state: California
city: Stanford
country: United States
facility: Stanford Cancer Center at Stanford University Medical Center
state: California
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Gainesville
country: United States
facility: Shands Cancer Center at the University of Florida Health Science Center
state: Florida
city: Atlanta
country: United States
facility: AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Scottish Rite Campus
state: Georgia
city: Augusta
country: United States
facility: MBCCOP-Medical College of Georgia Cancer Center
state: Georgia
city: Chicago
country: United States
facility: Children's Memorial Hospital - Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Riley Children Cancer Center at Riley Hospital for Children
state: Indiana
city: Kansas City
country: United States
facility: Kansas Masonic Cancer Research Institute at the University of Kansas Medical Center
state: Kansas
city: New Orleans
country: United States
facility: MBCCOP - LSU Health Sciences Center
state: Louisiana
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
state: Maryland
city: Bethesda
country: United States
facility: Warren Grant Magnuson Clinical Center - NCI Clinical Studies Support
state: Maryland
city: Boston
country: United States
facility: Floating Hospital for Children
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: Detroit
country: United States
facility: Children's Hospital of Michigan
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota Cancer Center
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic Cancer Center
state: Minnesota
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Kansas City
country: United States
facility: Children's Mercy Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Cardinal Glennon Children's Hospital
state: Missouri
city: Saint Louis
country: United States
facility: St. Louis Children's Hospital
state: Missouri
city: Hackensack
country: United States
facility: Cancer Center at Hackensack University Medical Center
state: New Jersey
city: New Brunswick
country: United States
facility: Cancer Institute of New Jersey at Robert Wood Johnson University Hospital
state: New Jersey
city: New York
country: United States
facility: NYU School of Medicine's Kaplan Comprehensive Cancer Center
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: New York
country: United States
facility: Herbert Irving Comprehensive Cancer Center at Columbia University
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical University Hospital
state: New York
city: Durham
country: United States
facility: Duke Comprehensive Cancer Center
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Columbus
country: United States
facility: Columbus Children's Hospital
state: Ohio
city: Oklahoma City
country: United States
facility: Oklahoma University Medical Center
state: Oklahoma
city: Portland
country: United States
facility: CCOP - Columbia River Oncology Program
state: Oregon
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh
state: Pennsylvania
city: Charleston
country: United States
facility: Hollings Cancer Center at Medical University of South Carolina
state: South Carolina
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt Children's Hospital
state: Tennessee
city: Dallas
country: United States
facility: Simmons Cancer Center at University of Texas Southwestern Medical Center - Dallas
state: Texas
city: Fort Worth
country: United States
facility: Cook Children's Medical Center - Fort Worth
state: Texas
city: Houston
country: United States
facility: Texas Children's Cancer Center
state: Texas
city: Houston
country: United States
facility: University of Texas - MD Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio
state: Texas
city: San Antonio
country: United States
facility: MBCCOP - South Texas Pediatrics
state: Texas
city: Temple
country: United States
facility: CCOP - Scott and White Hospital
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute
state: Utah
city: Seattle
country: United States
facility: Children's Hospital and Regional Medical Center - Seattle
state: Washington
city: Madison
country: United States
facility: University of Wisconsin Comprehensive Cancer Center
state: Wisconsin
city: Marshfield
country: United States
facility: CCOP - Marshfield Clinic Research Foundation
state: Wisconsin
city: Milwaukee
country: United States
facility: Midwest Children's Cancer Center
state: Wisconsin
city: Parkville
country: Australia
facility: Royal Children's Hospital
state: Victoria
city: Perth
country: Australia
facility: Princess Margaret Hospital for Children
state: Western Australia
city: Toronto
country: Canada
facility: Hospital for Sick Children
state: Ontario
city: Montreal
country: Canada
facility: Montreal Children's Hospital at McGill University Health Center
state: Quebec
city: Montreal
country: Canada
facility: Hopital Sainte Justine
state: Quebec
Study officials:
affiliation: National Cancer Institute (NCI)
name: Brigitte C. Widemann, MD
role: STUDY_CHAIR
References:
citation: de Nigris F, Balestrieri ML, Napoli C. Targeting c-Myc, Ras and IGF cascade to treat cancer and vascular disorders. Cell Cycle. 2006 Aug;5(15):1621-8. doi: 10.4161/cc.5.15.3138. Epub 2006 Aug 1.
citation: Widemann BC, Arceci RJ, Jayaprakash N, Fox E, Zannikos P, Goodspeed W, Goodwin A, Wright JJ, Blaney SM, Adamson PC, Balis FM. Phase 1 trial and pharmacokinetic study of the farnesyl transferase inhibitor tipifarnib in children and adolescents with refractory leukemias: a report from the Children's Oncology Group. Pediatr Blood Cancer. 2011 Feb;56(2):226-33. doi: 10.1002/pbc.22775. Epub 2010 Sep 21.