Clinical trial NCT00036959: ABT-751 in Treating Young Patients With Refractory Solid Tumors
Official title: Phase I Trial and Pharmacokinetic Study of ABT-751, an Orally Bioavailable Tubulin Binding Agent, on a 7 Day and 21 Day Dosing Schedule in Pediatric Patients With Refractory Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Brain and Central Nervous System Tumors
Childhood Germ Cell Tumor
Extragonadal Germ Cell Tumor
Kidney Cancer
Liver Cancer
Neuroblastoma
Ovarian Cancer
Sarcoma
Unspecified Childhood Solid Tumor, Protocol Specific
Keywords: metastatic osteosarcoma
childhood infratentorial ependymoma
recurrent childhood rhabdomyosarcoma
childhood supratentorial ependymoma
childhood craniopharyngioma
disseminated neuroblastoma
recurrent neuroblastoma
recurrent childhood liver cancer
stage IV childhood liver cancer
recurrent Wilms tumor and other childhood kidney tumors
stage IV Wilms tumor
childhood central nervous system germ cell tumor
recurrent osteosarcoma
unspecified childhood solid tumor, protocol specific
childhood germ cell tumor
metastatic childhood soft tissue sarcoma
recurrent childhood soft tissue sarcoma
childhood high-grade cerebral astrocytoma
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
metastatic Ewing sarcoma/peripheral primitive neuroectodermal tumor
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
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
Collaborators: name: National Cancer Institute (NCI)
First posted: 2003-01-27
Enrollment: 90
Sex: ALL
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

Brief summary: RATIONALE: Drugs used in chemotherapy, such as ABT-751, work in different ways to stop tumor cells from dividing so they stop growing or die.

PURPOSE: This phase I trial is studying the side effects of ABT-751 in treating young patients with refractory solid tumors.

Detailed description: OBJECTIVES:

Primary

* Determine the maximum tolerated dose and dose-limiting toxic effects of ABT-751 administered daily for 7 days every 21 days or daily for 21 days every 28 days in children with refractory solid tumors.
* Determine the toxicity spectrum of these regimens in these patients.
* Determine the pharmacokinetics of these regimens in these patients.
* Evaluate the pharmacodynamics of this drug by measuring the fraction of tubulin that is polymerized in the peripheral blood mononuclear cells of these patients before and after receiving this drug.

Secondary

* Quantify responses in patients treated with these regimens.
* Assess the effect of this drug on tumor vascularity and tumor blood flow using dynamic enhanced MRI in these patients.

OUTLINE: This is an open-label, multicenter, dose-escalation study of 2 different schedules of ABT-751. Patients are assigned to 1 of 2 dosing schedules.

* Schedule 1 (closed to accrual as of 5/25/2009): Patients receive oral ABT-751 once daily on days 1-7. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
* Schedule 2 (closed to accrual as of 5/25/2009): Patients receive oral ABT-751 once daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

On each schedule, cohorts of 3-6 patients receive escalating doses of ABT-751 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. Once the MTD is determined, up to 9 patients (a minimum of 3 patients age 11 and under and 3 patients age 12 to 18) are treated at the MTD.

PROJECTED ACCRUAL: A maximum of 90 patients will be accrued for this study within 8 months.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically confirmed solid tumor\*, including, but 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
  * Brain stem or optic gliomas (histological confirmation may be waived if a biopsy has not been performed) NOTE: \*Closed to accrual for all diagnoses except neuroblastoma as of 4/16/05
* Relapsed after or failed to respond to frontline standard therapy and no other standard treatment options (e.g., surgery, radiotherapy, chemotherapy, or any combination of these modalities) exist
* Measurable or evaluable disease\* NOTE: \*Not required for patients with neuroblastoma
* No CNS tumor with motor or sensory deficits that would obscure the study assessment of sensory neuropathy

PATIENT CHARACTERISTICS:

Age:

* 18 and under

Performance status:

* Lansky 60-100% (age 10 and under)
* Karnofsky 60-100% (age 11 to 18)

Life expectancy:

* Not specified

Hematopoietic:

* Absolute neutrophil count at least 1,500/mm\^3
* Platelet count at least 100,000/mm\^3

Hepatic:

* Bilirubin no greater than 1.5 times upper limit of normal (ULN)
* ALT and AST no greater than 2.5 times ULN (5 times ULN for patients treated after the maximum tolerated dose is determined)
* No clinically significant hepatic dysfunction

Renal:

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

Cardiovascular:

* LVEF normal by echocardiogram

Other:

* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception
* No allergy to sulfa-containing medications
* No clinically significant unrelated systemic illness (e.g., other organ dysfunction) that would preclude study participation
* No serious infection
* No preexisting grade 2 or greater sensory or motor neuropathy
* HIV negative

PRIOR CONCURRENT THERAPY:

Biologic therapy:

* At least 4 months since prior bone marrow transplantation
* At least 72 hours since prior interleukin-11
* At least 72 hours since prior colony-stimulating factors (e.g., filgrastim \[G-CSF\] or sargramostim \[GM-CSF\]) except epoetin alfa
* No concurrent growth factors (e.g., GM-CSF) except epoetin alfa

  * Concurrent G-CSF allowed if neutropenia lasts longer than 5 days OR if the patient experiences confirmed septicemia associated with neutropenia
* No concurrent immunotherapy
* No concurrent interleukin-11

Chemotherapy:

* See Disease Characteristics
* At least 30 days since prior chemotherapy (42 days for nitrosoureas)
* No other concurrent anticancer chemotherapy

Endocrine therapy:

* Patients with brain tumors:

  * Must be on a stable or tapering dose of corticosteroids for 7 days before baseline scan performed for the purpose of assessing response to study therapy
  * Concurrent corticosteroids allowed for control of symptoms of tumor-associated edema

Radiotherapy:

* See Disease Characteristics
* At least 4 weeks since prior radiotherapy
* At least 4 months since prior extensive radiotherapy (craniospinal radiotherapy, total body irradiation, or radiotherapy to more than 50% of the pelvis)
* No concurrent radiotherapy

Surgery:

* See Disease Characteristics

Other:

* Recovered from prior therapy
* At least 30 days since prior investigational anticancer therapy
* No other concurrent investigational agents

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Chicago
country: United States
facility: Children's Memorial Hospital - Chicago
state: Illinois
city: Bethesda
country: United States
facility: Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office
state: Maryland
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
Study officials:
affiliation: National Cancer Institute (NCI)
name: Elizabeth Fox, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Fox E, Maris JM, Cohn SL, Goodspeed W, Goodwin A, Kromplewski M, Medina D, Xiong H, Krivoshik A, Widemann B, Adamson PC, Balis FM. Pharmacokinetics of orally administered ABT-751 in children with neuroblastoma and other solid tumors. Cancer Chemother Pharmacol. 2010 Sep;66(4):737-43. doi: 10.1007/s00280-009-1218-z. Epub 2010 Jan 1.
citation: Fox E, Maris JM, Widemann BC, Goodspeed W, Goodwin A, Kromplewski M, Fouts ME, Medina D, Cohn SL, Krivoshik A, Hagey AE, Adamson PC, Balis FM. A phase I study of ABT-751, an orally bioavailable tubulin inhibitor, administered daily for 21 days every 28 days in pediatric patients with solid tumors. Clin Cancer Res. 2008 Feb 15;14(4):1111-5. doi: 10.1158/1078-0432.CCR-07-4097.
citation: Fox E, Maris JM, Widemann BC, Meek K, Goodwin A, Goodspeed W, Kromplewski M, Fouts ME, Medina D, Cho SY, Cohn SL, Krivoshik A, Hagey AE, Adamson PC, Balis FM. A phase 1 study of ABT-751, an orally bioavailable tubulin inhibitor, administered daily for 7 days every 21 days in pediatric patients with solid tumors. Clin Cancer Res. 2006 Aug 15;12(16):4882-7. doi: 10.1158/1078-0432.CCR-06-0534.