Study of Fixed vs. Flexible Filgrastim to Accelerate Bone Marrow Recovery After Chemotherapy in Children With Cancer

• Sponsor: Barbara Ann Karmanos Cancer Institute (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01987596
• Collaborator: National Cancer Institute (NCI) (NIH), Children's Hospital of Michigan (Other)
• Enrollment: 23
• Location: 1
• Arms: 2
• Duration (Months): 58
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This randomized phase III trial studies flexible administration of filgrastim after combination chemotherapy to see how well it works compared to fixed administration of filgrastim in decreasing side effects of chemotherapy in younger patients with cancer. Cancer chemotherapy frequently results in neutropenia (low blood counts) when patients are susceptible to severe infections. A medicine called G-CSF (filgrastim) stimulates bone marrow and daily filgrastim shots are commonly used to shorten neutropenic periods and decrease infections after chemotherapy. Since filgrastim is customarily used on a fixed schedule starting early after chemotherapy and there are data that early doses may not be needed, this study tests new flexible schedule of filgrastim to optimize its use by reducing the number of painful shots, cost of treatment, and filgrastim side effects in children with cancer receiving chemotherapy.

Condition or Disease	Intervention/Treatment	Phase
Childhood Choroid Plexus Tumor; Childhood Medulloblastoma; Childhood Pineoblastoma; Childhood Soft Tissue Sarcoma; Childhood Supratentorial Primitive Neuroectodermal Tumor; Neuroblastoma; Osteosarcoma; Retinoblastoma; Wilms Tumor and Other Childhood Kidney Tumors; Recurrent/Refractory Childhood Hodgkin Lymphoma; Unspecified Childhood Solid Tumor, Protocol Specific	Biological: filgrastim	Phase 3

Detailed Description

PRIMARY OBJECTIVES:

1. To compare the effect of flexible vs. fixed administration of G-CSF (filgrastim) on the parameters of hematological recovery including duration of absolute neutrophil count (ANC) < 500/uL; time to ANC recovery >= 1,000/uL and time to platelet recovery >= 75,000/uL in children receiving myelotoxic chemotherapy.

SECONDARY OBJECTIVES:

1. To compare the effect of flexible vs. fixed administration of G-CSF on the incidence of febrile neutropenia and number of hospital days on antibiotics following myelotoxic chemotherapy.

2. To evaluate the number of days of platelet transfusion events after chemotherapy cycles with flexible vs. fixed administration of G-CSF.

3. To evaluate on the incidence and duration of G-CSF-related side effects including extremities/back pain and headaches after chemotherapy courses followed by flexible vs. fixed administration of G-CSF.

4. To evaluate the peripheral blood progenitor responses and subsets of progenitor cells (cluster of differentiation [CD]34/41/61/117/10/19/11b/33) to chemotherapy followed by flexible vs. fixed administration of G-CSF.

OUTLINE:

CHEMOTHERAPY: Depending on their diagnosis patients are assigned to 1 of 3 chemotherapy regimens.

ICE: Patients receive etoposide intravenously (IV) over 1 hour on days 1-3, ifosfamide IV over 3 hours on days 1-3, and carboplatin IV over 1 hour on day 4. Patients with recurrent Hodgkin lymphoma receive etoposide and ifosfamide on days 1-3 and carboplatin on day 3.

ICT: Patients receive topotecan hydrochloride IV over 30 minutes on days 1-3, and ifosfamide and carboplatin as in ICE.

OPEC: Patients receive vincristine sulfate on days 1, 8, and 15; etoposide IV over 1 hour on days 1-3; cyclophosphamide IV over 1 hour on days 1-2; and cisplatin IV over 6 hours on day 4.

For all chemotherapy regimens, treatment repeats every 21 days for 2 courses. Patients are then randomized to 1 of 2 treatment arms.

ARM I (fixed filgrastim): Patients receive filgrastim subcutaneously (SC) once daily (QD) started at 24 hours after completion of chemotherapy and stopped when ANC reaches at least 1,000/uL post nadir.

ARM II (flexible filgrastim): Patients receive filgrastim SC QD started on the first day after chemotherapy when ANC falls below 1,000/uL and stopped when ANC reaches at least 1,000/uL post nadir.

After completion of the first filgrastim treatment, patients cross-over to the other filgrastim arm and repeat the same course of chemotherapy as before. After completion of the second filgrastim treatment, chemotherapy treatment may continue for up to 5 (OPEC) or 6 (ICE, ICT) courses in the absence of disease progression or unacceptable toxicity.

Study Design

• Study Type: Interventional
• Actual Enrollment: 23 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Supportive Care
• Official Title: Prospective and Randomized Study of Fixed Versus Flexible Prophylactic Administration of Granulocyte Colony-Stimulating Factor (G-CSF) in Children With Cancer
• Study Start Date: Aug 1, 2013
• Actual Primary Completion Date: Jun 1, 2018
• Actual Study Completion Date: Jun 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (fixed filgrastim) Patients receive filgrastim SC QD started at 24 hours after completion of chemotherapy and stopped when ANC reaches at least 1,000/uL post nadir.	Biological: filgrastim; Given SC once daily starting on day 1 after chemotherapy in Arm I (fixed) and on any day when ANC drops below 1000/mcl in Arm II (flexible); Other Names: G-CSF Neupogen
Experimental: Arm II (flexible filgrastim) Patients receive filgrastim SC QD started on the first day after chemotherapy when ANC falls below 1,000/uL and stopped when ANC reaches at least 1,000/uL post nadir.	Biological: filgrastim; Given SC once daily starting on day 1 after chemotherapy in Arm I (fixed) and on any day when ANC drops below 1000/mcl in Arm II (flexible); Other Names: G-CSF Neupogen

Outcome Measures

Primary Outcome Measures

1. Days to ANC Greater Than or Equal to 1,000/uL From the Start of Chemotherapy [From the start of the course until the first date the ANC reaches >= 1,000/uL post nadir, assessed up to 1 year]

   Time in days until absolute neutrophil count (ANC) recovery to greater than or equal to 1,000/uL from the start of chemotherapy

Secondary Outcome Measures

1. Incidence of Febrile Neutropenia [Up to 1 year]

   occurrence of febrile neutropenia

2. Cumulative GCSF Dose [up until engraftment]

   Cumulative GCSF dose - number of GCSF injections until ANC recovery greater than or equal to 1,000/uL from the start of chemotherapy

3. Days to First G-CSF Dose [time to ANC 1000]

   Time (in days) to first G-CSF dose

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Year to 25 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subjects must have or have had at initial diagnosis, histologic proof of their malignancy; young children with primary embryonal brain tumor treated according to Head Start protocol are eligible; subjects with bone marrow involvement are NOT eligible for study

• Patients will receive repeated cycles of identical chemotherapy that will likely result in grades III-IV hematological toxicity; patients will be treated outside of Children's Oncology Group (COG) protocols with specific requirements for schedule of G-CSF administration; the following categories of patients treated at Children's

Hospital of Michigan are eligible for this study:

• Patients with brain tumors treated according to Head Start II protocol with vincristine, etoposide, cyclophosphamide, and cisplatin (OPEC) chemotherapy;

• Patients with recurrent Hodgkin lymphoma treated with ICE (ifosfamide, carboplatin, etoposide) chemotherapy;

• Patients with recurrent solid tumors including sarcomas, Wilms' tumor, neuroblastomas, or brain tumors treated with high dose ICE or ICT (ifosfamide, carboplatin, topotecan) chemotherapy

• Patients with UH Wilms' tumor treated with CE (cyclophosphamide, etoposide); patients with neuroblastoma treated with CE (carboplatin, etoposide);

• Patients with soft tissue sarcomas treated with IA (ifosfamide, doxorubicin);

• Patients with osteosarcoma treated with high dose ifosfamide

• Subjects must have fully recovered from the toxic effects of any prior therapy; at least 3 weeks should have elapsed since the last dose of chemotherapy (6 weeks in the case of nitrosourea containing therapy); subjects must have recovered from previous colony-stimulating factor therapy and have been off colony-stimulating factors (G-CSF, granulocyte macrophage colony-stimulating factor [GM-CSF], interleukin [IL]-11) for more than 10 days and off erythropoietin for 30 days

• ANC > 1000/uL

• Platelet count > 100,000/uL

• Creatinine clearance or glomerular filtration rate (GFR) which is greater than or equal to 70 ml/min/1.73 m^2

• Bilirubin less than 1.5 x normal limit (NL)

• Serum glutamic oxaloacetic transaminase (SGOT) or serum glutamate pyruvate transaminase (SGPT) less than 2.5 x NL for age

• Subjects should have a normal ejection fraction (per institutional limits), no evidence of cardiac arrhythmias requiring therapy, and a fractional shortening of > 28%

• All subjects must have a life expectancy of 12 weeks or more

• Diagnostic categories

• Sarcoma (soft tissue and bone)

• Kidney tumors

• Brain tumors

• Other solid tumors (gonadal and germ cell tumors, retinoblastoma, neuroblastoma, and miscellaneous tumors)

• Hodgkin lymphoma

• Performance status must be > 60 from Lansky (age 1 to 16) or Karnofsky (age > 16)

Exclusion Criteria:

• Subjects with any of the following will NOT be eligible for study:

• Bone marrow involvement

• Active myelogenous leukemia, or history of myelogenous leukemia

• Pregnancy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan	United States	48201

Sponsors and Collaborators

• Barbara Ann Karmanos Cancer Institute
• National Cancer Institute (NCI)
• Children's Hospital of Michigan

Investigators

• Principal Investigator: Maxim Yankelevich, Barbara Ann Karmanos Cancer Institute

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 14, 2013

More Information

Publications

None provided.

• Responsible Party: Maxim Yankelevich, Principal Investigator, Barbara Ann Karmanos Cancer Institute
• ClinicalTrials.gov Identifier: NCT01987596
• Other Study ID Numbers: 2013-062; NCI-2013-02001; 2013-062; P30CA022453
• First Posted: Nov 19, 2013
• Last Update Posted: Oct 29, 2020
• Last Verified: Oct 1, 2020

• Additional relevant MeSH terms: Sarcoma; Neuroblastoma; Osteosarcoma; Medulloblastoma; Neuroectodermal Tumors; Neuroectodermal Tumors, Primitive; Wilms Tumor; Retinoblastoma; Choroid Plexus Neoplasms; Pinealoma; Lenograstim

Study Results

Participant Flow

Arm/Group Title	Arm I (Fixed Flexible Filgrastim Schedule)	Arm II (Flexible Fixed Filgrastim Schedule)
Arm/Group Description	Period 1 Fixed: Patients receive filgrastim SC QD once daily started at 24 hours after completion of chemotherapy and stopped when ANC reaches at least 1,000/uL post nadir. Period 2 Flexible: Patients receive filgrastim:SC once starting on day 1 after chemotherapy in Arm I (fixed) and on any day when ANC drops below 1000/mcl in Arm II (flexible)	Period 1 Flexible: Patients receive filgrastim SC QD started on the first day after chemotherapy and on any day when ANC falls below 1,000/uL and stopped when ANC reaches at least 1,000/uL post nadir. Period 2 Fixed: Patients receive filgrastim: given SC once daily starting on day 1 after chemotherapy in and daily thereafter until ANC reaches at least 1,000/uL post nadir.
Period Title: Overall Study
STARTED	12	11
COMPLETED	11	10
NOT COMPLETED	1	1

Baseline Characteristics

Arm/Group Title	Arm I (Fixed Flexible Filgrastim Schedule)	Arm II (Flexible Fixed Filgrastim Schedule)	Total
Arm/Group Description	Period 1 Fixed: Patients receive filgrastim SC QD once daily started at 24 hours after completion of chemotherapy and stopped when ANC reaches at least 1,000/uL post nadir. Period 2 Flexible: Patients receive filgrastim:SC once starting on day 1 after chemotherapy in Arm I (fixed) and on any day when ANC drops below 1000/mcl in Arm II (flexible)	Period 1 Flexible: Patients receive filgrastim SC QD started on the first day after chemotherapy and on any day when ANC falls below 1,000/uL and stopped when ANC reaches at least 1,000/uL post nadir. Period 2 Fixed: Patients receive filgrastim: given SC once daily starting on day 1 after chemotherapy in and daily thereafter until ANC reaches at least 1,000/uL post nadir.	Total of all reporting groups
Overall Participants	11	10	21
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	16	11	14
Sex: Female, Male (Count of Participants)
Female	2 18.2%	5 50%	7 33.3%
Male	9 81.8%	5 50%	14 66.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 9.1%	0 0%	1 4.8%
Not Hispanic or Latino	10 90.9%	10 100%	20 95.2%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	1 10%	1 4.8%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	4 36.4%	4 40%	8 38.1%
White	4 36.4%	5 50%	9 42.9%
More than one race	3 27.3%	0 0%	3 14.3%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	11 100%	10 100%	21 100%

Outcome Measures

1. Primary Outcome

Title	Days to ANC Greater Than or Equal to 1,000/uL From the Start of Chemotherapy
Description	Time in days until absolute neutrophil count (ANC) recovery to greater than or equal to 1,000/uL from the start of chemotherapy
Time Frame	From the start of the course until the first date the ANC reaches >= 1,000/uL post nadir, assessed up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fixed	Flexible
Arm/Group Description	Mean of time to ANC1000 during period participants were on fixed regimen	Mean of time to ANC1000 during period participants were on flexible regimen
Measure Participants	21	21
Mean (95% Confidence Interval) [days]	16.0	16.7

2. Secondary Outcome

Title	Incidence of Febrile Neutropenia
Description	occurrence of febrile neutropenia
Time Frame	Up to 1 year

Outcome Measure Data

Analysis Population Description

Each patient server as his/her own control

Arm/Group Title	Fixed	Flexible
Arm/Group Description	Incidence duriing time patient was on fixed schedule	Incidence duriing time patient was on flexible schedule
Measure Participants	21	21
Yes	5 45.5%	6 60%
No	16 145.5%	15 150%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fixed, Flexible
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.00
	Comments
	Method	McNemar
	Comments

3. Secondary Outcome

Title	Cumulative GCSF Dose
Description	Cumulative GCSF dose - number of GCSF injections until ANC recovery greater than or equal to 1,000/uL from the start of chemotherapy
Time Frame	up until engraftment

Outcome Measure Data

Analysis Population Description

Patients who had data for period 2

Arm/Group Title	Fixed Filgrastim	Flexible Filgrastim
Arm/Group Description	Patients receive filgrastim daily SC QD started at 24 hours after completion of chemotherapy and stopped when ANC reaches at least 1,000/uL post nadir.	Patients receive filgrastim SC QD started on the first day after chemotherapy and on any day ANC falls below 1,000/uL and stopped when ANC reaches at least 1,000/uL post nadir.
Measure Participants	19	19
Mean (95% Confidence Interval) [Doses]	10.5	6.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fixed, Flexible
	Comments	two-period crossover design analysis
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments

4. Secondary Outcome

Title	Days to First G-CSF Dose
Description	Time (in days) to first G-CSF dose
Time Frame	time to ANC 1000

Outcome Measure Data

Analysis Population Description

All participants with period 2 data

Arm/Group Title	Arm I (Fixed Filgrastim)	Arm II (Flexible Filgrastim)
Arm/Group Description	Patients receive filgrastim SC QD started at 24 hours after completion of chemotherapy and continued daily until ANC reaches at least 1,000/uL post nadir.	Patients receive filgrastim SC QD started on the first day after chemotherapy when ANC falls below 1,000/uL and stopped when ANC reaches at least 1,000/uL post nadir.
Measure Participants	19	19
Mean (95% Confidence Interval) [days]	5.1	9.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fixed, Flexible
	Comments	2 treatment, 2 periiod cross-over analysis
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments

Adverse Events

Time Frame	6 months
Adverse Event Reporting Description	Nothing to mention
Arm/Group Title	Arm I (Fixed Filgrastim)		Arm II (Flexible Filgrastim)
Arm/Group Description	Patients receive filgrastim SC QD started at 24 hours after completion of chemotherapy and stopped when ANC reaches at least 1,000/uL post nadir. filgrastim: Given SC once daily starting on day 1 after chemotherapy in Arm I (fixed) and on any day when ANC drops below 1000/mcl in Arm II (flexible)		Patients receive filgrastim SC QD started on the first day after chemotherapy when ANC falls below 1,000/uL and stopped when ANC reaches at least 1,000/uL post nadir. filgrastim: Given SC once daily starting on day 1 after chemotherapy in Arm I (fixed) and on any day when ANC drops below 1000/mcl in Arm II (flexible)
All Cause Mortality
	Arm I (Fixed Filgrastim)		Arm II (Flexible Filgrastim)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/21 (0%)		0/21 (0%)
Serious Adverse Events
	Arm I (Fixed Filgrastim)		Arm II (Flexible Filgrastim)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/21 (0%)		0/21 (0%)
Other (Not Including Serious) Adverse Events
	Arm I (Fixed Filgrastim)		Arm II (Flexible Filgrastim)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/21 (19%)		1/21 (4.8%)
Nervous system disorders
Pain	4/21 (19%)	6	1/21 (4.8%)	2
Pain	4/21 (19%)	6	1/21 (4.8%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.