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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


Phase 1
2 Years
21 Years
Not Enrolling
Both
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

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Trial Information

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


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.

Inclusion 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

Type of Study:

Interventional

Study Design:

Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose and dose-limiting toxicity of ixabepilone

Safety Issue:

Yes

Principal Investigator

AeRang Kim, MD

Investigator Role:

Study Chair

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Food and Drug Administration

Study ID:

020031

NCT ID:

NCT00030108

Start Date:

November 2001

Completion Date:

April 2010

Related Keywords:

  • 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
  • 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
  • childhood acute lymphoblastic leukemia
  • childhood acute myeloid leukemia in remission
  • childhood acute promyelocytic leukemia (M3)
  • L1 childhood acute lymphoblastic leukemia
  • L2 childhood acute lymphoblastic leukemia
  • L3 childhood acute lymphoblastic leukemia
  • non-T, non-B, cALLa negative childhood acute lymphoblastic leukemia
  • non-T, non-B, cALLa positive childhood acute lymphoblastic leukemia
  • non-T, non-B, cALLa positive, pre-B childhood acute lymphoblastic leukemia
  • recurrent childhood acute lymphoblastic leukemia
  • recurrent childhood acute myeloid leukemia
  • TdT negative childhood acute lymphoblastic leukemia
  • TdT positive childhood acute lymphoblastic leukemia
  • chronic myelogenous leukemia, BCR-ABL1 positive
  • childhood chronic myelogenous leukemia
  • Carcinoma, Renal Cell
  • Kidney Neoplasms
  • Leukemia
  • Liver Neoplasms
  • Nervous System Neoplasms
  • Neuroblastoma
  • Ovarian Neoplasms
  • Central Nervous System Neoplasms
  • Neoplasms, Germ Cell and Embryonal
  • Neoplasms
  • Sarcoma

Name

Location

Children's National Medical CenterWashington, District of Columbia  20010-2970
Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral OfficeBethesda, Maryland  20892-1182