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

Children's Oncology Group

Status and phase: Completed; Phase 1

Conditions: Cancer

Treatments: Biological: G-CSF; Biological: recombinant human thrombopoietin; Drug: carboplatin; Drug: etoposide; Drug: ifosfamide

Study type: Interventional

Funder types: NETWORK; NIH

Identifiers

NCT00003597

CDR0000066668

09717

CCG-09717

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 16 patients

Sex: All

Ages: 1 to 21 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Supportive Care

Allocation: Non-Randomized

Interventional model: Single Group Assignment

Masking: None (Open label)

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16 participants in 2 patient groups

Cohort 1

Experimental group

Description:

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).

Treatment:

Drug: ifosfamide

Drug: etoposide

Drug: carboplatin

Biological: recombinant human thrombopoietin

Biological: G-CSF

Cohort 2

Experimental group

Description:

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.

Treatment:

Drug: ifosfamide

Drug: etoposide

Drug: carboplatin

Biological: recombinant human thrombopoietin

Biological: G-CSF