NANT 2001-03: A Phase I study of CEP-701 in Patients with Refractory Neuroblastoma
Date First Published: 08-11-2003
Date Modified: 03-15-2005
Basic Study Information
| Type | Status | Age Range (yrs.) | Sponsor | Protocol IDs |
|---|
| Treatment | Active | No greater than 21 years at diagnosis | NANT | N2001-03 |
Objectives
- To determine the maximum tolerated dose (MTD) of CEP-701 given on a twice daily chronic administration schedule (five days on, two days off) to children with high-risk neuroblastoma with residual or refractory disease.
- To determine the dose limiting toxicities (DLTs) of CEP-701 given on this schedule.
- To characterize the pharmacokinetic behavior of CEP-701 in children with residual or refractory high-risk neuroblastoma.
- To determine the degree of TrkB tyrosine kinase inhibition activity present in the serum of patients treated with CEP-701, and correlate these findings with dose level, pharmacokinetic, and anti-tumor activity data.
- To determine the degree of TrkB tyrosine kinase inhibition in neuroblastoma cells metastatic to the bone marrow following five days of CEP-701 therapy.
- To define the antitumor activity of CEP-701, within the confines of a Phase I study.
Entry Criteria
Disease Characteristics:
- Diagnosis of neuroblastoma (ICD-O morphology 9500/3) verified by histology and/or demonstration of clumps of tumor cells in the bone marrow with elevated urinary catecholamine metabolites. Patients must have high-risk neuroblastoma classified as either recurrent disease or resistant/refractory disease.
Prior/Concurrent Therapy:
Biologic therapy:
- One of the following must be true:
- Measurable tumor on CT or MRI scan or X-ray. Measurable is defined as minimum of 20 mm in at least one dimension; for spiral CT defined as minimum of 10 mm in at least one dimension. For patients who are in first response (recurrent, refractory, or resistant disease), biopsy of lesion must demonstrate viable neuroblastoma. If lesion was radiated, biopsy must be done at least 4 weeks after radiation is completed.
–OR-
MIBG scan with positive uptake at a minimum of one site. For patients who are in first response (recurrent, refractory, or resistant disease), biopsy of lesion must demonstrate viable neuroblastoma. If lesion was radiated, biopsy must be done at least 4 weeks after radiation is completed.
–OR-
Bone marrow with tumor cells seen on routine morphology (not NSE staining only) of bilateral aspirate and/or biopsy; and/or greater than or equal to the equivalent of 5 tumor cells/106 mononuclear cells in the bone marrow by immunocytologic analysis on two successive bone marrows done from one day to four weeks apart. Patients in first response (recurrent, refractory, or resistant disease) are eligible ONLY if they have morphologic evidence of tumor in bone marrow.
Patients in first response with persistent tumor based on CT/MRI/MIBG scan following completion of an accepted frontline myeloablative regimen OR who are medically ineligible to receive such a regimen, must have histologic confirmation of active neuroblastoma to be eligible for study entry. Patients in second or greater response will be eligible without histologic confirmation. At least 7 days since the completion of therapy with a biologic (anti-neoplastic) agent.Chemotherapy:
- Must not have received myelosuppressive chemotherapy within 3 weeks of entry onto this study (4 weeks if prior therapy with nitrosourea containing agents).
Endocrine therapy:
Radiotherapy:
- Greater than 2 weeks must have elapsed since the last dose for local palliative XRT (small port); greater than 4 weeks must have elapsed since the last dose of radiation to any site biopsied to document study eligibility; greater than 6 weeks must have elapsed since the last dose of craniospinal or other XRT involving significant bone marrow irradiation (i.e. – total pelvis or total abdomen).
Surgery:
Other:
- Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy in addition to the therapy guidelines discussed above.
- Must be at least 3 months post autologous stem cell transplant.
Patient Characteristics:
Age:
- Not greater than 21 years of age at time of original neuroblastoma diagnosis.
Performance status:
- Karnofsky score > 50% for patients > 16 years of age
- Lansky > 50 for children < 16 years of age.
- Patients who are unable to walk because of paralysis, but who are up in a wheelchair will be considered ambulatory for the purpose of assessing the performance score.
Life expectancy:
Hematopoietic:
- Must not have received growth factors within 7 days of entry onto this study.
- Patients must have adequate bone marrow function defined as:
- Peripheral absolute neutrophils count (ANC) = 1000/µl
- Platelet count = 50,000/µl (transfusion independent)
- Hemoglobin = 8.0 gm/dl (may receive RBC transfusions)
Patients with neuroblastoma metastatic to bone marrow who have granulocytopenia, anemia, and/or thrombocytopenia are eligible provided they meet all other eligible criteria, but will not be evaluable for hematological toxicity.Hepatic:
Patients must have normal liver function, defined as:
- Total bilirubin within normal limits for age, AND
- ALT (SGPT) and AST (SGOT) within normal limits for age.
Renal:
- Serum creatinine < 1.5 x normal for age, OR
Age Range Serum Creatinine
< 5 years < 0.8 mg/dl
5 years to < 10 years < 1.0 mg/dl
10 years to < 15 years < 1.2 mg/dl
> 15 years < 1.5 mg/dl - Creatinine clearance or radioisotope GFR > 60 ml/min/1.73 m2.
Cardiovascular:
- Patients must have a normal ejection fraction (>50%) documented by echocardiogram or radionuclide MUGA evaluation OR normal fractional shortening (> 28% or above lower limit of institutional normal range) documented by echocardiogram.
Pulmonary:
- Normal lung function as manifested by no dyspnea at rest or exercise intolerance and no supplemental oxygen requirement.
Neurologic:
Other:
- No patients with uncontrolled infections.
- No patients who have previously received CEP-701.
- Patients with a history of prior allogeneic stem cell transplantation AND active graft versus host disease of > Grade 2.
- Agreement to obtain a pregnancy test in girls who are post-menarchal.
- Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method.
- Pregnancy tests must be repeated for post-menarchal females prior to each drug cycle.
- Ability to obtain a signed informed consent from patient and/or their parents or legal representative.
Projected Accrual
A total of 12-24 patients will be accrued for this study.
Outline
The goal of this research project is to evaluate the safety and efficacy of CEP-701 (also known as Cephalon) as a therapy for children with poor prognosis relapsed or refractory neuroblastoma who have failed conventional treatment.
