Ixabepilone in Treating Young Patients With Solid Tumors or Leukemia That Haven't Responded to Therapy

This study has been completed.
Sponsor:
Collaborator:
Information provided by:
National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT00030108
First received: January 30, 2002
Last updated: March 14, 2012
Last verified: March 2012
  Purpose

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die.

PURPOSE: This phase I trial is studying the side effects and best dose of ixabepilone in treating young patients with relapsed or refractory solid tumors or leukemia.


Condition Intervention Phase
Brain and Central Nervous System Tumors
Childhood Germ Cell Tumor
Extragonadal Germ Cell Tumor
Kidney Cancer
Leukemia
Liver Cancer
Neuroblastoma
Ovarian Cancer
Sarcoma
Unspecified Childhood Solid Tumor, Protocol Specific
Drug: ixabepilone
Phase 1

Study Type: Interventional
Study Design: Primary Purpose: Treatment
Official Title: Phase I Trial and Pharmacokinetic Study of BMS-247550 (NSC 710428, Ixabepilone), an Epothilone B Analog, in Pediatric Patients With Refractory Solid Tumors and Leukemias

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Maximum tolerated dose and dose-limiting toxicity of ixabepilone [ Designated as safety issue: Yes ]
  • Toxicity spectrum [ Designated as safety issue: Yes ]
  • Plasma pharmacokinetics [ Designated as safety issue: No ]
  • Pharmacodynamics [ Designated as safety issue: No ]
  • Nerve growth factor levels before and after drug administration [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Objective tumor response [ Designated as safety issue: No ]
  • Tubulin polymerization in PBMCs prior to the start of the infusion, just before the end of the infusion, 5 hours after the end of the infusion and before the start of the infusion on day 2 of the ixabepilone on course 1 [ Designated as safety issue: No ]

Estimated Enrollment: 30
Study Start Date: November 2001
Study Completion Date: April 2010
Primary Completion Date: March 2010 (Final data collection date for primary outcome measure)
Detailed Description:

OBJECTIVES:

Primary

  • Determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of ixabepilone in young patients with refractory solid tumors (closed to accrual as of 10/4/2007) or relapsed or refractory leukemia.
  • Determine the toxicity spectrum of this drug in these patients.
  • Determine the plasma pharmacokinetics of this drug in these patients.
  • Determine the pharmacodynamics of this drug in these patients.
  • Assess the nerve growth factor levels, before and after the initiation of this drug, as a potential surrogate marker for the development of peripheral neuropathy in these patients.

Secondary

  • Determine the response of patients treated with this drug.
  • Compare the tolerability, toxicity profile, MTD, DLT, pharmacokinetics, and pharmacodynamics of this drug in young patients treated on this study vs adults with solid tumors (closed to accrual as of 10/4/2007) treated on the ongoing Medicine Branch, NCI, phase I study.
  • Assess the safety and tolerability of ixabepilone at the solid tumor MTD (expanded leukemia cohort).
  • Evaluate the plasma pharmacokinetics of in young patients with refractory or relapsed leukemia.
  • Evaluate the extent of tubulin polymerization in leukemic blasts at baseline after treatment with ixabepilone ex-vivo.
  • Compare the effects of tubulin polymerization in leukemic blasts with ixabepilone versus paclitaxel ex-vivo with an without the presence of a potent P-glycoprotein inhibitor.
  • Evaluate the activity known drug transporters in drug-resistant leukemias in leukemic blasts.

OUTLINE: This is a multicenter, dose-escalation study.

Patients receive ixabepilone IV over 1 hour on days 1-5. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of ixabepilone until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 or more of 6 patients experience dose-limiting toxicity. Intrapatient dose escalation to one dose level above the enrollment dose level is allowed in patients who have stable or responding disease or are experiencing other benefits from therapy (e.g., decrease in tumor-related pain symptoms) and who have no grade 2 or greater non-hematologic toxicity and no grade 3 or greater hematologic toxicity. Additional patients are treated at the MTD. Patients treated at the MTD may not undergo intrapatient dose escalation.

PROJECTED ACCRUAL: A maximum of 30 patients will be accrued for this study within 1-2 years.

  Eligibility

Ages Eligible for Study:   2 Years to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Meets 1 of the following criteria:

    • Histologically confirmed solid tumor (closed to accrual as of 10/4/2007) that relapsed after or failed to respond to front-line curative therapy and for which no other potentially curative treatment options exist

      • Curative therapy may include surgery, radiotherapy, chemotherapy, or any combination of these modalities
      • Eligible tumor types include, but are not limited to, the following:

        • Rhabdomyosarcoma
        • Other soft tissue sarcomas
        • Ewing's sarcoma family of tumors
        • Osteosarcoma
        • Neuroblastoma
        • Wilms' tumor
        • Hepatic tumors
        • Germ cell tumors
        • Primary brain tumors

          • Histologic confirmation may be waived for brain stem or optic glioma
    • Diagnosis of relapsed or refractory leukemia

      • Patients with refractory or second or greater relapsed leukemia must have > 25% blasts in the bone marrow (M3 bone marrow) with or without active extramedullary disease (except for leptomeningeal disease)
      • Relapsed after or failed to respond to frontline curative therapy and no other potentially curative therapy (e.g., radiotherapy, chemotherapy, or any combination of these modalities) exists
    • Patients with acute promyelocytic leukemia must be refractory to treatment with retinoic acid and arsenic trioxide
    • Patients with Philadelphia chromosome positive chronic myelogenous leukemia must be refractory to imatinib
  • No active CNS leukemia (CNS3)

PATIENT CHARACTERISTICS:

Age:

  • 2 to 18 (solid tumor patients [closed to accrual as of 10/4/2007])
  • 1 to 21 (leukemia patients)

Performance status:

  • For patients age 11 to 21:

    • Karnofsky 50-100%
  • For patients age 1 to 10:

    • Lansky 50-100%

Life expectancy:

  • Not specified

Hematopoietic:

  • Platelet count at least 100,000/mm^3 (20,000/mm^3 for leukemia patients)
  • Hemoglobin ≥ 8.0 g/dL

Hepatic:

  • Bilirubin less than 1.5 times upper limit of normal (ULN)
  • SGOT and SGPT less than 2.5 times ULN
  • No hepatic dysfunction that would preclude study

Renal:

  • Creatinine normal for age OR
  • Creatinine clearance at least 60 mL/min
  • No renal dysfunction that would preclude study

Other:

  • No known severe prior hypersensitivity reaction to agents containing Cremophor EL
  • No clinically significant unrelated systemic illness (e.g., serious infections or other organ dysfunction) that would preclude study
  • No grade 2 or greater preexisting sensory neuropathy
  • More than 2 month since prior and no concurrent evidence of graft vs host disease
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

  • Recovered from all therapy-related acute toxic effects (leukemia patients only)
  • Prior epoetin alfa allowed
  • At least 3 days since other prior colony-stimulating factors (e.g., filgrastim (G-CSF), sargramostim (GM-CSF), or interleukin-11 (IL-11))
  • At least 6 months since prior bone marrow transplantation
  • At least 2 months since prior stem cell transplantation or rescue (leukemia patients)
  • At least 7 days since prior therapy with a biological agent and hematopoietic growth factor with the exception of erythropoietin
  • More than 3 weeks since prior monoclonal antibody therapy (leukemia patients only)
  • No concurrent GM-CSF or IL-11
  • No concurrent immunotherapy

Chemotherapy:

  • See Disease Characteristics
  • Recovered from all therapy-related acute toxic effects (leukemia patients only)
  • At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas)
  • No other concurrent anticancer chemotherapy

Endocrine therapy:

  • Concurrent corticosteroids allowed for the control of symptoms related to tumor-associated edema in patients with brain tumors
  • Patients with brain tumors must be on a stable or tapering dose of corticosteroids for 7 days before baseline scan is performed for the purpose of assessing response to study therapy
  • Must be on a stable or tapering dose of corticosteroids for 7 days prior to study entry (leukemia patients only)

Radiotherapy:

  • See Disease Characteristics
  • Recovered from all therapy-related acute toxic effects (leukemia patients only)
  • At least 4 weeks since prior radiotherapy
  • More than 2 weeks since prior local palliative radiotherapy (leukemia patients only)
  • More than 3 months since prior total-body irradiation, craniospinal radiotherapy, or radiotherapy to ≥50% of the pelvis (leukemia patients only)
  • More than 6 weeks since prior other substantial bone marrow radiotherapy (leukemia patients only)
  • No prior extensive radiotherapy (e.g., craniospinal irradiation, total body irradiation, or radiotherapy to more than half of the pelvis)
  • No concurrent anticancer radiotherapy

Surgery:

  • See Disease Characteristics

Other:

  • Recovered from prior therapy
  • At least 30 days since any prior investigational anticancer therapy
  • At least 1 week since prior known inhibitors of CYP3A4, including any of the following:

    • Antibiotics (i.e., clarithromycin, erythromycin, or troleandomycin)
    • Anti-HIV agents (i.e, delaviridine, nelfinavir, amprenavir, ritonavir, idinavir, saquinavir, or lopinavir)
    • Anti-fungals (i.e., itraconazole, ketoconazole, fluconazole [doses > 3mg/kg/day], or voriconazole)
    • Anti-depressants (i.e., nefaxodone or fluovoxamine)
    • Calcium channel blockers (i.e., verapamil or diltiazem)
    • Anti-emetics (i.e., aprepitant [Emend®])
    • Miscellaneous agents (i.e., amiodarone)
    • Grapefruit juice
  • No other concurrent investigational agents
  • No concurrent St. John's Wort
  • No concurrent known inhibitors of CYP3A4, including grapefruit juice
  • Concurrent other agents inducing CYP3A4 allowed
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00030108

Locations
United States, District of Columbia
Children's National Medical Center
Washington, District of Columbia, United States, 20010-2970
United States, Maryland
Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office
Bethesda, Maryland, United States, 20892-1182
Sponsors and Collaborators
Investigators
Study Chair: AeRang Kim, MD National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
ClinicalTrials.gov Identifier: NCT00030108     History of Changes
Obsolete Identifiers: NCT00025961
Other Study ID Numbers: 020031, 02-C-0031, NCI-5425, CDR0000069133
Study First Received: January 30, 2002
Last Updated: March 14, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by National Institutes of Health Clinical Center (CC):
recurrent childhood rhabdomyosarcoma
childhood craniopharyngioma
recurrent neuroblastoma
recurrent childhood liver cancer
recurrent Wilms tumor and other childhood kidney tumors
childhood central nervous system germ cell tumor
recurrent osteosarcoma
unspecified childhood solid tumor, protocol specific
childhood germ cell tumor
recurrent childhood soft tissue sarcoma
childhood oligodendroglioma
childhood choroid plexus tumor
childhood grade I meningioma
childhood grade II meningioma
childhood grade III meningioma
recurrent childhood cerebellar astrocytoma
recurrent childhood cerebral astrocytoma
recurrent childhood medulloblastoma
recurrent childhood visual pathway and hypothalamic glioma
previously treated childhood rhabdomyosarcoma
recurrent Ewing sarcoma/peripheral primitive neuroectodermal tumor
recurrent childhood ependymoma
childhood teratoma
childhood malignant testicular germ cell tumor
childhood malignant ovarian germ cell tumor
childhood extragonadal germ cell tumor
recurrent childhood malignant germ cell tumor
B-cell childhood acute lymphoblastic leukemia
childhood acute basophilic leukemia
childhood acute eosinophilic leukemia

Additional relevant MeSH terms:
Neoplasms
Ovarian Neoplasms
Sarcoma
Neuroblastoma
Neoplasms, Germ Cell and Embryonal
Liver Neoplasms
Carcinoma, Renal Cell
Kidney Neoplasms
Nervous System Neoplasms
Central Nervous System Neoplasms
Leukemia
Endocrine Gland Neoplasms
Neoplasms by Site
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neuroectodermal Tumors, Primitive, Peripheral
Neuroectodermal Tumors, Primitive
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Digestive System Neoplasms
Digestive System Diseases

ClinicalTrials.gov processed this record on October 19, 2014