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

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

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.

Study Overview

• Status: Completed
• Conditions: Cancer
• Intervention / Treatment: Drug: carboplatin; Drug: etoposide; Drug: ifosfamide; Biological: recombinant human thrombopoietin; Biological: G-CSF

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • Western Australia
    • Perth, Western Australia, Australia, 6001
      • Princess Margaret Hospital for Children
• United States
  • California
    • Long Beach, California, United States, 90806
      • Long Beach Memorial Medical Center
    • Los Angeles, California, United States, 90095-1781
      • Jonsson Comprehensive Cancer Center, UCLA
    • Los Angeles, California, United States, 91010
      • Beckman Research Institute, City of Hope
    • Los Angeles, California, United States, 90027-0700
      • Children's Hospital Los Angeles
    • Orange, California, United States, 92668
      • Children's Hospital of Orange County
    • San Francisco, California, United States, 94115-0128
      • UCSF Cancer Center and Cancer Research Institute
  • District of Columbia
    • Washington, District of Columbia, United States, 20010-2970
      • Children's National Medical Center
  • Indiana
    • Indianapolis, Indiana, United States, 46202-5265
      • Indiana University Cancer Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0752
      • University of Michigan Comprehensive Cancer Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota Cancer Center
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Cancer Center
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital - Kansas City
  • New York
    • New York, New York, United States, 10021
      • Memorial Sloan-Kettering Cancer Center
    • New York, New York, United States, 10016
      • Kaplan Cancer Center
    • New York, New York, United States, 10032
      • Herbert Irving Comprehensive Cancer Center
  • Ohio
    • Cincinnati, Ohio, United States, 45229-3039
      • Children's Hospital Medical Center - Cincinnati
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15213
      • Children's Hospital of Pittsburgh
  • Tennessee
    • Nashville, Tennessee, United States, 37232-6838
      • Vanderbilt Cancer Center
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas - MD Anderson Cancer Center
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • Huntsman Cancer Institute
  • Washington
    • Seattle, Washington, United States, 98105
      • Children's Hospital and Regional Medical Center - Seattle
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1; 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).	Drug: carboplatin; Other Names: CBDCA; Paraplatin; NSC #241240; Drug: etoposide; Other Names: VP-16; VePesid; NSC #141540; Drug: ifosfamide; Other Names: IFX; NSC #109724; IFOS; IND #7887; Biological: recombinant human thrombopoietin; Other Names: RhTPO; BB-IND # 7431); Biological: G-CSF; Other Names: Filgrastim; r-metHuG-CSF; NSC #614629; Neupogen®; GRANULOCYTE COLONY-STIMULATING FACTOR
Experimental: Cohort 2; 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.	Drug: carboplatin; Other Names: CBDCA; Paraplatin; NSC #241240; Drug: etoposide; Other Names: VP-16; VePesid; NSC #141540; Drug: ifosfamide; Other Names: IFX; NSC #109724; IFOS; IND #7887; Biological: recombinant human thrombopoietin; Other Names: RhTPO; BB-IND # 7431); Biological: G-CSF; Other Names: Filgrastim; r-metHuG-CSF; NSC #614629; Neupogen®; GRANULOCYTE COLONY-STIMULATING FACTOR

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Children's Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Mitchell S. Cairo, MD, Herbert Irving Comprehensive Cancer Center

Publications and helpful links

General Publications

• Angiolillo AL, Davenport V, Bonilla MA, van de Ven C, Ayello J, Militano O, Miller LL, Krailo M, Reaman G, Cairo MS; Children's Oncology Group. A phase I clinical, pharmacologic, and biologic study of thrombopoietin and granulocyte colony-stimulating factor in children receiving ifosfamide, carboplatin, and etoposide chemotherapy for recurrent or refractory solid tumors: a Children's Oncology Group experience. Clin Cancer Res. 2005 Apr 1;11(7):2644-50. doi: 10.1158/1078-0432.CCR-04-1959.

Study record dates

Study Major Dates

• Study Start: November 1, 1998
• Primary Completion (Actual): October 1, 2004
• Study Completion (Actual): September 1, 2005

Study Registration Dates

• First Submitted: November 1, 1999
• First Submitted That Met QC Criteria: April 17, 2003
• First Posted (Estimate): April 18, 2003

Study Record Updates

• Last Update Posted (Estimate): July 24, 2014
• Last Update Submitted That Met QC Criteria: July 23, 2014
• Last Verified: July 1, 2014

More Information

Terms related to this study

• Keywords: recurrent renal cell cancer; unspecified childhood solid tumor, protocol specific; neutropenia; recurrent melanoma; recurrent intraocular melanoma; thrombocytopenia; recurrent childhood rhabdomyosarcoma; recurrent neuroblastoma; recurrent uterine sarcoma; recurrent ovarian germ cell tumor; recurrent malignant testicular germ cell tumor; recurrent Ewing sarcoma/peripheral primitive neuroectodermal tumor; recurrent osteosarcoma; recurrent Wilms tumor and other childhood kidney tumors; recurrent childhood supratentorial primitive neuroectodermal tumor; recurrent childhood cerebellar astrocytoma; recurrent childhood cerebral astrocytoma; extragonadal germ cell tumor; recurrent childhood liver cancer; recurrent childhood soft tissue sarcoma; recurrent childhood brain stem glioma; recurrent childhood medulloblastoma; childhood central nervous system germ cell tumor; childhood germ cell tumor; recurrent retinoblastoma; recurrent gestational trophoblastic tumor; recurrent childhood visual pathway glioma
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Recurrence; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Adjuvants, Immunologic; Carboplatin; Etoposide; Ifosfamide; Lenograstim
• Other Study ID Numbers: 09717; CCG-09717; CDR0000066668