Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Published Results
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Objectives

Primary

1. 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.
2. Determine the toxicity spectrum of this drug in these patients.
3. Determine the plasma pharmacokinetics of this drug in these patients.
4. Determine the pharmacodynamics of this drug in these patients.
5. 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

1. Determine the response of patients treated with this drug.
2. 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.
3. Assess the safety and tolerability of ixabepilone at the solid tumor MTD (expanded leukemia cohort).
4. Evaluate the plasma pharmacokinetics of in young patients with refractory or relapsed leukemia.
5. Evaluate the extent of tubulin polymerization in leukemic blasts at baseline after treatment with ixabepilone ex-vivo.
6. 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.
7. Evaluate the activity known drug transporters in drug-resistant leukemias in leukemic blasts.

Entry 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)

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

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/mm³ (20,000/mm³ 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

Expected Enrollment

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

Outcomes

Maximum tolerated dose and dose-limiting toxicity of ixabepilone
Toxicity spectrum
Plasma pharmacokinetics
Pharmacodynamics
Nerve growth factor levels before and after drug administration

Objective tumor response
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

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.

Widemann BC, Goodspeed W, Goodwin A, et al.: Phase I trial and pharmacokinetic study of ixabepilone administered daily for 5 days in children and adolescents with refractory solid tumors. J Clin Oncol 27 (4): 550-6, 2009.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

NCI - Center for Cancer Research

AeRang Kim, MD, Protocol chair		Ph: 301-451-7025

Registry Information
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
Trial Start Date		2001-11-02
Trial Completion Date		2010-03-30
Registered in ClinicalTrials.gov		NCT00030108
Date Submitted to PDQ		2001-11-02
Information Last Verified		2009-01-13

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