Protocol Number: 02-C-0031

Title:

Phase I Trial and Pharmacokinetic Study of BMS-247550 (NSC 710428), an Epothilone B Analog, in Pediatric Patients with Refractory Solid Tumors

Number:

02-C-0031

Summary:

This study will determine the highest dose of the experimental anticancer drug BMS-247550 that can be given safely to children. It will examine how the body handles the drug, its side effects and its effect on tumors. BMS-247550 belongs to a class of drugs called epothilones. These drugs are similar to another class called taxanes, which includes paclitaxel (Taxol) and docetaxel (Taxotere). The epothilones are able to kill cancer cells that are resistant to Taxol.

Children 2 to 18 years of age and older with solid tumor cancers that do not respond to standard therapy may be eligible for this study. Cancers may include rhabdomyosarcoma and other soft tissue sarcomas, Ewing's sarcoma tumors, osteosarcoma, neuroblastoma, Wilms' tumor, liver tumors, germ cell tumors, brain tumors, and others. Candidates will be screened with a medical history and physical and neurological examinations; height, weight, and body surface area measurements; blood and urine tests; and X-ray studies to determine the extent of disease.

Participants will receive BMS-247550 intravenously (through a vein) over a 60-minute period for 5 consecutive days in 21- to 28-day cycles (i.e., 5 days of drug treatment followed by 15 to 22 days without drug, depending on the amount of time needed to recover from the drug side effects). The drug dose will be increased in successive small groups of patients, if the side effects at the previous dose are acceptable, until the optimum dose is achieved. Patients may continue treatment indefinitely unless their cancer worsens or they develop side effects that persist for more than 2 weeks.

Patients will be followed with a physical examination every week and routine blood tests twice a week. They will have computed tomography (CT) or magnetic resonance imaging (MRI) scans after the first treatment cycle and then after every other treatment cycle to evaluate the size of their tumor. In addition, they will have the following blood studies:

- Pharmacology studies: During the first treatment cycle, blood samples will be drawn frequently to examine how the body absorbs and uses the drug. For this study, 12 blood samples of 1.5 teaspoons each will be drawn after the first dose of BMS-247550; two samples each will be drawn on treatment days 2 through 5; and, if possible, one sample will be drawn at 24 and 48 hours after the fifth dose of drug. To avoid multiple needle sticks for the first day's samples, the blood will be collected through the child's permanent venous catheter (Hickman line or port-a-cath) or through an IV heparin lock (a small plastic catheter inserted into the vein).

- Drug effects on normal cells: To determine the effect of the drug on normal cells circulating in the blood, samples will be collected before, and 1 hour, 6 hours, and 24 hours after the first dose of drug in the first treatment cycle.

- Measurement of nerve growth factor: Blood will be collected to measure the effect of BMS-247550 on a substance called nerve growth factor to determine which patients may be at risk for developing nervous system side effects. Blood samples will be collected before the first and third treatment cycles, and in the event that the child develops signs of nerve damage, such as pain, tingling, or changes in sensation in the hands and feet.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): None

Eligibility Criteria:

INCLUSION CRITERIA:

AGE: Patients must be greater than or equal to 2 years and less than or equal to 18 years of age.

DIAGNOSIS: Histologically confirmed solid tumors, which may include but are not limited to rhabdomyosarcoma and other soft tissue sarcomas, Ewing's sarcoma family of tumors, osteosarcoma, neuroblastoma, Wilms' tumor, hepatic tumors, germ cell tumors, and primary brain tumors. In patients with brain stem or optic gliomas the requirement for histological confirmation may be waived.

MEASURABLE/EVALUABLE DISEASE: Patients must have measurable or evaluable tumors.

PRIOR THERAPY:

- The patient's cancer must have relapsed after or failed to respond to frontline curative therapy and there must not be other potentially curative treatment options available. Curative therapy may include surgery, radiation therapy, chemotherapy, or any combination of these modalities.

- Patients must have had their last dose of radiation therapy at least four weeks prior to study entry, their last dose of chemotherapy at least 28 days prior to study entry (6 weeks for nitrosoureas), and their last dose of any investigational cancer therapy at least 30 days prior to study entry.

- Patients must have recovered from the toxic effects of all prior therapy before entry onto this trial.

- Patients with brain tumors must be on a stable or tapering dose of corticosteroids for 7 days prior to the baseline scan performed for the purpose of assessing response to therapy on this study.

- Patients should be off colony stimulating factors such as Filgrastim (G-CSF), sargramostim (GM-CSF), and IL-11 (with the exception of erythropoietin) for at least 72 hours prior to study entry.

PERFORMANCE STATUS: Patients greater than 10 years must have a Karnofsky performance level greater than or equal to 50, and children less than or equal to 10 years must have a Lansky performance level greater than or equal to 50. Patients who are unable to walk because of paralysis or weakness, but who are up in a wheelchair will be considered ambulatory for the purpose of calculating the performance score.

HEMATOLOGIC FUNCTION: Patients must have adequate bone marrow function, defined as a peripheral absolute neutrophil count of greater than or equal to 1,500/micro liter, and a platelet count of greater than or equal to 100,000/micro liter.

HEPATIC FUNCTION: Patients must have adequate liver function, defined as bilirubin less than 1.5 times the upper limit of normal, SGPT (ALT) and SGOT (AST) less than 2.5 times the upper limit of normal.

RENAL FUNCTION: Patients must have an age-adjusted normal serum creatinine OR a creatinine clearance greater than or equal to 60 mL/min/1.73 m2.

INFORMED CONSENT: All patients or their legal guardians (if the patient is less than 18 years old) must sign a document of informed consent (screening protocol) prior to performing studies to determine patient eligibility. After confirmation of patient eligibility all patients or their legal guardians must sign the protocol specific informed consent to document their understanding of the investigational nature and the risks of this study before any protocol related studies are performed (other than the studies which were performed to determine patient eligibility).

DURABLE POWER OF ATTORNEY (DPA): Patients who have brain tumors and who are 18 years of age will be offered the opportunity to assign a DPA so that another person can make decisions about their medical care if they become incapacitated or cognitively impaired.

BIRTH CONTROL: Subjects of childbearing or child-fathering potential must be willing to use a medically acceptable form of birth control, which includes abstinence, while they are being treated on this study.

EXCLUSION CRITERIA:

Clinically significant unrelated systemic illness, such as serious infections, hepatic, renal or other organ dysfunction, which in the judgment of the Principal or Associate Investigators of this protocol would compromise the patient's ability to tolerate the investigational agent or are likely to interfere with the study procedures or results.

Patients with a history of bone marrow transplantation within the previous 6 months or extensive radiotherapy (craniospinal radiation, total body radiation, or radiation to more than half of the pelvis).

Pregnant or breast feeding females are excluded because BMS-247550 may be harmful to the developing fetus or nursing child.

Patients currently receiving other investigational agents.

Patients currently receiving St. John Wort. The intake of other agents inducing CYP3A4 is not prohibited.

Patients receiving known inhibitors of CYP3A4 including grapefruit juice within 1 week prior to and following the administration of BMS-247550.

Patients with preexisting grade 2 or greater sensory neuropathy.

Patients with known severe prior hypersensitivity reaction to agents containing Cremophor EL.

Special Instructions: Currently Not Provided

Keywords:

Childhood Cancers

Tubulin

Pharmacodynamics

Maximum Tolerated Dose

Dose Escalation

Recruitment Keywords:

Cancer

Childhood Cancer

Pediatrics

Solid Tumors

Pediatric Tumors

Conditions:

Neoplasms

Neoplasm by Histologic Type

Optic Glioma

Brainstem Tumor

Investigational Drug(s):

BMS-247550 (ixabepilone)

Investigational Device(s):

None

Contacts:

CSSC
Clinical Studies Support Center/NCI
164 Rollins Avenue
2nd FLoor
Rockville, MD 20852
Phone: (888) 624-1937
Fax: (301) 881-8239

Electronic Address: ncicssc@mail.nih.gov

Citations:

Desoxyepothilone B is curative against human tumor xenografts that are refractory to paclitaxel

Epothilones, a new class of microtubule-stabilizing agents with a taxol-like mechanism of actionboll

Phase I trial of docetaxel administered as a 1-hour infusion in children with refractory solid tumors: a collaborative pediatric branch, National Cancer Institute and Children's Cancer Group trial

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