Colony-Stimulating Factors in Treating Children With Recurrent or Refractory Solid Tumors

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Colony-stimulating factors such as thrombopoietin and G-CSF may increase the number of immune cells found in bone marrow or peripheral blood and may help a person's immune system recover from the side effects of chemotherapy. PURPOSE: Phase I trial to study the effectiveness of colony-stimulating factors in treating children who have recurrent or refractory solid tumors and who are receiving chemotherapy.

Detailed Description
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OBJECTIVES: Determine the pharmacokinetics and toxicities associated with the administration of recombinant human thrombopoietin in children with solid tumors receiving myelosuppressive chemotherapy with ifosfamide, carboplatin, and etoposide (ICE). Determine a safe dose of recombinant human thrombopoietin with filgrastim (G-CSF) in this patient population. Evaluate the time to platelet count recovery following chemotherapy in this patient population. Evaluate the depth and duration of neutropenia and thrombocytopenia and the number of platelet transfusion events in this patient population. OUTLINE: This is a dose escalation study of recombinant human thrombopoietin. All patients receive chemotherapy consisting of carboplatin IV over 60 minutes on days 0 and 1 and etoposide and ifosfamide IV over 60 minutes on days 0-4. Chemotherapy is continued in the absence of disease progression or unacceptable toxicity for a maximum of 6 courses every 21 days. Cohorts of 3-6 patients each receive escalating doses of recombinant human thrombopoietin IV on days 4, 6, 8, 10, and 12 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which fewer than 2 patients experience dose limiting toxicity. After the MTD is determined an additional cohort of patients are treated at this dose level every other day on days 4-20. Patients receive filgrastim (G-CSF) subcutaneously beginning on day 5 and continuing until absolute neutrophil count is greater than 1000/mm3 for 2 consecutive days or day 33. PROJECTED ACCRUAL: A total of 24 evaluable patients will be accrued for this study.

Official Title
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A Phase I Study of Thrombopoietin (rhTPO) Plus G-CSF in Children Receiving Ifosfamide, Carboplatin, and Etoposide (I.C.E.) Chemotherapy for Recurrent or Refractory Solid Tumors

Conditions
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Cancer

Intervention / Treatment
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* Biological: recombinant human thrombopoietin
* Drug: carboplatin
* Drug: etoposide
* Drug: ifosfamide
* Biological: G-CSF


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically proven (except for brain stem tumors) malignancy that has failed or relapsed after standard first-line antineoplastic therapy Sarcoma (soft tissue and bone) Kidney tumors Brain tumors Other solid tumors (gonadal and germ cell tumors, malignant melanoma, retinoblastoma, liver tumors, and miscellaneous tumors) Must have had recurrence within the past 4 weeks No bone marrow involvement No prior or concurrent myelogenous leukemia PATIENT CHARACTERISTICS: Age: 1 to 21 Performance status: Lansky or Karnofsky 60-100% Life expectancy: At least 12 weeks Hematopoietic: Absolute neutrophil count greater than 1000/mm3 Platelet count greater than 100,000/mm3 No grade III or IV thrombosis Hepatic: Bilirubin less than 1.5 times upper limit of normal (ULN) SGOT or SGPT less than 2.5 times ULN Renal: Creatinine clearance or glomerular filtration rate at least 70 mL/min Cardiovascular: Ejection fraction normal No evidence of arrhythmias requiring therapy Fractional shortening greater than 28% Other: Not pregnant or nursing PRIOR CONCURRENT THERAPY: Biologic therapy: At least 10 days since prior colony-stimulating factor therapy and recovered At least 30 days since prior epoetin alfa No other concurrent cytokines, including epoetin alfa Chemotherapy: At least 3 weeks since prior chemotherapy (6 weeks for nitrosoureas) and recovered At least 3 months since therapy with etoposide, carboplatin, or ifosfamide that is identical to study treatment Endocrine therapy: Not specified Radiotherapy: Concurrent radiotherapy allowed after third course of therapy No prior cranial/spinal radiotherapy No prior radiotherapy to greater than 50% of bone marrow Surgery: Concurrent surgery allowed after the second course of therapy Other: No concurrent investigational agents No concurrent lithium, aspirin, coumadin, or heparin

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Chemotherapy days 0-4, G-CSF (5 μg/kg/d) as a daily subcutaneous injection beginning on Day 5. All patients receive recombinant human thrombopoietin (rhTPO). rhTPO began on the last day of ICE (Ifosfamide, Carboplatin and Etoposide) chemotherapy (Day 4) and subsequent doses will be administered on Days 6, 8, 10 and 12 (5 doses total). The initial dose of rhTPO was 1.2 μg/kg/dose and was subsequently escalated to 2.4 and 3.6 μg/kg/dose as tolerated. Therapy will continue for maximum six courses. Pharmacokinetic data will be obtained (during course one only). | Biological: recombinant human thrombopoietin<br> <br> * Other names: BB-IND # 7431);Drug: carboplatin<br> <br> * Other names: NSC #241240;Drug: etoposide<br> <br> * Other names: NSC #141540;Drug: ifosfamide<br> <br> * Other names: IND #7887;Biological: G-CSF<br> <br> * Other names: NSC #614629;|
| Experimental: Cohort 2<br>Chemotherapy days 0-4, G-CSF (5 μg/kg/d) as a daily subcutaneous injection beginning on Day 5. All patients receive recombinant human thrombopoietin (rhTPO). The dose of rhTPO 1.2 μg/kg/dose and subsequently escalated to 2.4 and 3.6 μg/kg/dose as tolerated. Patients assigned to Cohort II will receive pre-chemotherapy rhTPO at 3.6 μg/kg/dose on Days -5, -3, -1, and post-chemotherapy rhTPO on Days +4, +6, and +8 (6 doses total. Subsequent courses of chemotherapy will begin as soon as the ANC recovers to ≥ 1,000/μL and the platelet count to ≥ 100,000/μL between days 21 and 35. Therapy will continue for maximum six courses. Pharmacokinetic data will be obtained (during course one nly). For the second cohort, full data collection will occur for cycles one and two and limited data collection for cycles 3, 4, 5, and 6. | Biological: recombinant human thrombopoietin<br> <br> * Other names: BB-IND # 7431);Drug: carboplatin<br> <br> * Other names: NSC #241240;Drug: etoposide<br> <br> * Other names: NSC #141540;Drug: ifosfamide<br> <br> * Other names: IND #7887;Biological: G-CSF<br> <br> * Other names: NSC #614629;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the pharmacokinetics and toxicities associated with the administration of recombinant human thrombopoietin (rhTPO) | To determine the pharmacokinetics and toxicities associated with the administration of recombinant human thrombopoietin (rhTPO) in children receiving I.C.E. myelosuppressive chemotherapy. | length of study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the time for patients to demonstrate platelet recovery | To evaluate the time for patients to demonstrate platelet recovery following I.C.E. chemotherapy with rhTPO + G-CSF. | Length of study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent childhood rhabdomyosarcoma, recurrent renal cell cancer, recurrent neuroblastoma, recurrent childhood liver cancer, recurrent Wilms tumor and other childhood kidney tumors, recurrent retinoblastoma, childhood central nervous system germ cell tumor, recurrent osteosarcoma, recurrent gestational trophoblastic tumor, recurrent malignant testicular germ cell tumor, recurrent intraocular melanoma, recurrent melanoma, unspecified childhood solid tumor, protocol specific, childhood germ cell tumor, recurrent childhood soft tissue sarcoma, recurrent ovarian germ cell tumor, extragonadal germ cell tumor, recurrent uterine sarcoma, neutropenia, thrombocytopenia, recurrent childhood brain stem glioma, recurrent childhood supratentorial primitive neuroectodermal tumor, recurrent childhood visual pathway glioma, recurrent childhood cerebellar astrocytoma, recurrent childhood cerebral astrocytoma, recurrent childhood medulloblastoma, recurrent Ewing sarcoma/peripheral primitive neuroectodermal tumor