NeuroblastomaPhase 1NCT00070200
Induction Chemotherapy Using Cyclophosphamide and Topotecan in Treating Patients Who Are Undergoing Autologous Peripheral Stem Cell Transplantation for Newly Diagnosed or Progressive Neuroblastoma
A Phase 1 study testing filgrastim, cisplatin and cyclophosphamide in people with Neuroblastoma, run by Children's Oncology Group at 6 sites in 2 countries.
Trial summary
RATIONALE: Drugs used in chemotherapy, such as topotecan and cyclophosphamide, use different ways to stop tumor cells from dividing so they stop growing or die. Combining chemotherapy with autologous stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells. Read more about this study
- Who is it for?
- Ages Up to 30 years
- Conditions the study is for
- Neuroblastoma
- What is being tested?
- filgrastim, cisplatin and cyclophosphamide
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 31 participants
- Where
- 6 sitesin 2 countries
- Study dates
- Mar 2004to Dec 2013
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Up to 30 years
- All sexes
- No healthy volunteers
- Child, Adult
DISEASE CHARACTERISTICS:
- Histologically or cytologically confirmed neuroblastoma or ganglioneuroblastoma meeting 1 of the following staging criteria:
- Newly diagnosed disease, at least 1 year of age, and meets criteria for 1 of the following:
- International Neuroblastoma Staging System (INSS) stage 2a/2b with MYCN amplification (greater than 10) AND unfavorable pathology
- INSS stage 3 with MYCN amplification OR unfavorable pathology
- Newly diagnosed INSS stage 4 disease meeting criteria for 1 of the following:
- Over 18 months of age
- Age 12 to 18 months with any unfavorable biologic feature (MYCN amplification, unfavorable pathology, and/or DNA index=1) or any biologic feature that is indeterminant, unsatisfactory, or unknown
- No INSS stage 4 disease and age 12 to 18 months with all 3 favorable biologic features (i.e., nonamplified MYCN, favorable pathology, and DNA index greater than 1)
- Newly diagnosed INSS stage 3, 4, or 4S disease AND under 1 year of age with MYCN amplification
- At least 1 year of age and initially diagnosed with INSS stage 1, 2, or 4S disease that progressed to stage 4 without interval chemotherapy
- Must have been enrolled on COG-ANBL00B1 at initial diagnosis
PATIENT CHARACTERISTICS:
Age
- 30 and under at initial diagnosis
Performance status
- Not specified
Life expectancy
- Not specified
Hematopoietic
- Absolute neutrophil count at least 1,000/mm^3*
- Platelet count at least 100,000/mm^3* (transfusion independent)
- Hemoglobin at least 10.0 g/dL* (red blood cell transfusions allowed) NOTE: *Granulocytopenia, anemia, and/or thrombocytopenia allowed for patients with tumor metastatic to the bone marrow
Hepatic
- Bilirubin no greater than 1.5 mg/dL
- ALT less than 300 IU/L
Renal
- Creatinine no greater than 1.5 mg/dL
- Creatinine clearance or radioisotope glomerular filtration rate at least 60 mL/min
Cardiovascular
- ECG normal
- Shortening fraction at least 27% by echocardiogram OR
- Ejection fraction at least 50% by MUGA
Other
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception
- HIV negative
PRIOR CONCURRENT THERAPY:
Biologic therapy
- Not specified
Chemotherapy
- See Disease Characteristics
- No more than 1 prior chemotherapy course on the low- or intermediate-risk neuroblastoma studies (COG-P9641, COG-A3961) prior to determination of MYCN amplification and Shimada histology
Endocrine therapy
- Not specified
Radiotherapy
- Prior localized emergency radiotherapy to sites of life-threatening or function-threatening disease allowed
Surgery
- Not specified
Other
- No other prior systemic therapy
Trial locations and contacts
6 sites in 2 countries.
6 sites in 2 countries
United States5 sites
Children's Memorial Hospital - Chicago
Chicago, Illinois, 60614
St. Jude Children's Research Hospital
Memphis, Tennessee, 38105
UCSF Comprehensive Cancer Center
San Francisco, California, 94143-0106
Children's Hospital and Regional Medical Center - Seattle
Seattle, Washington, 98105
Mary Bridge Children's Hospital and Health Center - Tacoma
Tacoma, Washington, 98405
About this study
Official title: A Pilot Induction Regimen Incorporating Topotecan for Treatment of Newly Diagnosed High Risk Neuroblastoma
RATIONALE: Drugs used in chemotherapy, such as topotecan and cyclophosphamide, use different ways to stop tumor cells from dividing so they stop growing or die. Combining chemotherapy with autologous stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells.
PURPOSE: This phase I trial is studying the side effects of induction chemotherapy using cyclophosphamide and topotecan in treating patients who are undergoing surgery and autologous stem cell transplantation followed by radiation therapy for newly diagnosed or progressive neuroblastoma.
Read the detailed description
OBJECTIVES:
Primary
- Determine the toxicity and feasibility of adding cyclophosphamide and topotecan to induction therapy in patients with newly diagnosed or progressive high-risk neuroblastoma undergoing autologous peripheral blood stem cell (PBSC) transplantation.
- Determine the feasibility of PBSC mobilization and in vivo PBSC tumor purging in these patients after treatment with this regimen.
Secondary
- Determine tumor response rate in patients treated with this regimen.
- Determine the pharmacokinetics of this regimen in these patients.
- Determine whether topotecan affects cyclophosphamide pharmacokinetics in these patients.
- Correlate host DNA with toxicity and cyclophosphamide and topotecan pharmacokinetics in patients treated with this regimen.
- Determine toxicity in patients treated with this regimen.
OUTLINE: This is a pilot, multicenter study. Patients are stratified according to diagnosis (newly diagnosed vs initially stage 1, 2, or 4S that progressed to stage 4 without interval chemotherapy).
- Induction therapy: Patients receive 6 courses of induction therapy.
- Courses 1 and 2: Patients receive cyclophosphamide IV over 30 minutes and topotecan IV over 30 minutes on days 1-5 and filgrastim (G-CSF) subcutaneously (SC) or IV beginning on day 6 and continuing until blood counts recover.
- Course 3: Patients receive etoposide IV over 2 hours on days 1-3, cisplatin IV over 1 hour on days 1-4, and G-CSF SC or IV beginning on day 5 and continuing until blood counts recover.
- Course 4: Patients receive cyclophosphamide IV over 6 hours on day 1 and doxorubicin IV and vincristine IV continuously over 24 hours on days 1-3. Patients also receive G-CSF SC or IV beginning on day 4 and continuing until blood counts recover.
- Course 5: Patients receive etoposide, cisplatin, and G-CSF as in course 3.
- Course 6: Patients receive cyclophosphamide, doxorubicin, vincristine, and G-CSF as in course 4.
Treatment repeats every 21 days for a total of 6 courses in the absence of disease progression or unacceptable toxicity.
- Consolidation therapy: Within 4-6 weeks after completing induction therapy, patients receive melphalan IV on days -7 to -5 and etoposide IV and carboplatin IV continuously over 24 hours on days -7 to -4.
- Stem cell transplantation: Peripheral blood stem cells are collected after course 2 of induction therapy and infused on day 0. Patients receive G-CSF IV beginning on day 0 and continuing until blood counts recover.
- Surgery: After course 5 of induction therapy, patients undergo surgery.
- Radiotherapy: Beginning 28-42 days after transplantation, patients receive 12 fractions of local radiotherapy to all areas of residual soft tissue disease and the primary tumor site, even if completely resected.
- Maintenance therapy: Beginning 66 days after transplantation, patients receive oral isotretinoin twice daily on days 1-14. Treatment repeats every 28 days for a total of 6 courses.
Patients are followed every 3 months for 1 year, every 6 months for 4 years, and then annually thereafter.
PROJECTED ACCRUAL: A total of 10-29 patients will be accrued for this study within 2 years.
- Conditions
- Neuroblastoma
- Being tested
- filgrastim, cisplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide
- Keywords
- recurrent neuroblastoma, stage 4S neuroblastoma, localized unresectable neuroblastoma, localized resectable neuroblastoma, regional neuroblastoma, disseminated neuroblastoma
- Medical subject headings
- Neuroblastoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
filgrastimBiological
cisplatinDrug
cyclophosphamideDrug
etoposideDrug
isotretinoinDrug
melphalanDrug
topotecan hydrochlorideDrug
conventional surgeryProcedure or surgery
peripheral blood stem cell transplantationProcedure or surgery
radiation therapyRadiation
| Study group | Role | What they receive |
|---|---|---|
| All patients | Experimental | Induction Cycles 1 and 2 (CT) (21 days each), Cyclophosphamide (Days 1 thru 5) weight based dosage (> 12 kg 400 mg/m2/day, < 12 kg 13.3 mg/kg/day, < 2 years old N/A. Topotecan (Days 1 thru 5) weight based dosage (> 12 kg 1.2 mg/m2/day, < 12 kg 0.04 mg/kg/day, < 2 years old 0.04 mg/kg/day). Filgrastim (Days 6 →) weight based dosage (> 12 kg 5 micrograms/kg, < 12 kg 5 micrograms /kg, < 2 years old 5 micrograms /kg. Receives: Biological: filgrastim; Drug: cisplatin; Drug: cyclophosphamide; Drug: doxorubicin hydrochloride; Drug: etoposide; Drug: isotretinoin; Drug: melphalan; Drug: topotecan hydrochloride; Drug: vincristine sulfate; Procedure: conventional surgery; Procedure: peripheral blood stem cell transplantation; Radiation: radiation therapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Proportion of patients who are classified as a "success"
Given that the documented delivered dose intensity of chemotherapy in current induction regimens is 75-85% of the intended dose intensity,5,78 we shall consider an individual patient as a "success" in terms of feasibility if the patient is able to receive 75% or more of the intended chemotherapy doses of known active agents.
Measured: Length of study
Secondary outcomes (5)
Number of toxic deaths
Measured: Length of study
Proportion of patients with dose limiting toxicities during induction cycle 1 and 2
Dose limiting toxicities during induction cycle 1 and 2 will be used to modify the topotecan dosage if necessary and to address Primary Aim 1 in a descriptive fashion.
Measured: Length of study
Tumor contamination of PBSCs
Tumor contamination of PBSCs as measured by immunohistochemical analysis following cycle 2 induction;
Measured: Length of study
Inability to adequately mobilize PBSCs
Inability to adequately mobilize PBSCs, defined as a harvest of < 1.5 x 10 6 CD 34 cells/kg. A patient will be designated a PBSCs "failure" if either a) or b) is the case.
Measured: Length of study
Assessment of response
After completion of induction therapy. Response will be determined using the International Response Criteria defined elsewhere in the protocol. The tumor response rate will be defined as the proportion of patients who achieve a CR, VGPR, or PR after completion of induction therapy.
Measured: Length of study
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Oct 2003 (estimated)
- Study startMar 2004
- Primary completionSep 2006
- Study completionDec 2013
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for NeuroblastomaStudies of the same condition, open and under way.
- More trials run by Children's Oncology GroupThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 31 participants (actual)
Sponsor and investigators
- Lead sponsor
- Children's Oncology Group
- Sponsor type
- Research network
- Collaborators
- National Cancer Institute (NCI)
- Responsible party
- Sponsor
- Investigators
- Julie R. Park, MD, Study chair, Seattle Children's Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00070200
- Sponsor's protocol ID
- ANBL02P1
- Other IDs
- CDR0000330140, COG-ANBL02P1
- Status last verified
- Feb 2014
- First submitted
- 3 Oct 2003
- Last updated
- 13 Feb 2014
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Park JR, Scott JR, Stewart CF, London WB, Naranjo A, Santana VM, Shaw PJ, Cohn SL, Matthay KK. Pilot induction regimen incorporating pharmacokinetically guided topotecan for treatment of newly diagnosed high-risk neuroblastoma: a Children's Oncology Group study. J Clin Oncol. 2011 Nov 20;29(33):4351-7. doi: 10.1200/JCO.2010.34.3293. Epub 2011 Oct 17.
PubMed 22010014
Study at a glance
From the registry record, last updated by the sponsor on 13 Feb 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Pilot Induction Regimen Incorporating Topotecan for Treatment of Newly Diagnosed High Risk Neuroblastoma
- ClinicalTrials.gov ID
- NCT00070200
- Acronym / sponsor ID
- ANBL02P1
- Conditions
- Neuroblastoma
- Keywords
- recurrent neuroblastoma, stage 4S neuroblastoma, localized unresectable neuroblastoma, localized resectable neuroblastoma, regional neuroblastoma, disseminated neuroblastoma
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 31 participants (actual)
- Lead sponsor
- Children's Oncology GroupResearch network
- Collaborators
- National Cancer Institute (NCI)
- Study start
- Mar 2004
- Primary completion
- Sep 2006 (actual)
- Study completion
- Dec 2013 (actual)
- First posted
- 7 Oct 2003 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
RATIONALE: Drugs used in chemotherapy, such as topotecan and cyclophosphamide, use different ways to stop tumor cells from dividing so they stop growing or die. Combining chemotherapy with autologous stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells.
PURPOSE: This phase I trial is studying the side effects of induction chemotherapy using cyclophosphamide and topotecan in treating patients who are undergoing surgery and autologous stem cell transplantation followed by radiation therapy for newly diagnosed or progressive neuroblastoma.
Detailed description
OBJECTIVES:
Primary
- Determine the toxicity and feasibility of adding cyclophosphamide and topotecan to induction therapy in patients with newly diagnosed or progressive high-risk neuroblastoma undergoing autologous peripheral blood stem cell (PBSC) transplantation.
- Determine the feasibility of PBSC mobilization and in vivo PBSC tumor purging in these patients after treatment with this regimen.
Secondary
- Determine tumor response rate in patients treated with this regimen.
- Determine the pharmacokinetics of this regimen in these patients.
- Determine whether topotecan affects cyclophosphamide pharmacokinetics in these patients.
- Correlate host DNA with toxicity and cyclophosphamide and topotecan pharmacokinetics in patients treated with this regimen.
- Determine toxicity in patients treated with this regimen.
OUTLINE: This is a pilot, multicenter study. Patients are stratified according to diagnosis (newly diagnosed vs initially stage 1, 2, or 4S that progressed to stage 4 without interval chemotherapy).
- Induction therapy: Patients receive 6 courses of induction therapy.
- Courses 1 and 2: Patients receive cyclophosphamide IV over 30 minutes and topotecan IV over 30 minutes on days 1-5 and filgrastim (G-CSF) subcutaneously (SC) or IV beginning on day 6 and continuing until blood counts recover.
- Course 3: Patients receive etoposide IV over 2 hours on days 1-3, cisplatin IV over 1 hour on days 1-4, and G-CSF SC or IV beginning on day 5 and continuing until blood counts recover.
- Course 4: Patients receive cyclophosphamide IV over 6 hours on day 1 and doxorubicin IV and vincristine IV continuously over 24 hours on days 1-3. Patients also receive G-CSF SC or IV beginning on day 4 and continuing until blood counts recover.
- Course 5: Patients receive etoposide, cisplatin, and G-CSF as in course 3.
- Course 6: Patients receive cyclophosphamide, doxorubicin, vincristine, and G-CSF as in course 4.
Treatment repeats every 21 days for a total of 6 courses in the absence of disease progression or unacceptable toxicity.
- Consolidation therapy: Within 4-6 weeks after completing induction therapy, patients receive melphalan IV on days -7 to -5 and etoposide IV and carboplatin IV continuously over 24 hours on days -7 to -4.
- Stem cell transplantation: Peripheral blood stem cells are collected after course 2 of induction therapy and infused on day 0. Patients receive G-CSF IV beginning on day 0 and continuing until blood counts recover.
- Surgery: After course 5 of induction therapy, patients undergo surgery.
- Radiotherapy: Beginning 28-42 days after transplantation, patients receive 12 fractions of local radiotherapy to all areas of residual soft tissue disease and the primary tumor site, even if completely resected.
- Maintenance therapy: Beginning 66 days after transplantation, patients receive oral isotretinoin twice daily on days 1-14. Treatment repeats every 28 days for a total of 6 courses.
Patients are followed every 3 months for 1 year, every 6 months for 4 years, and then annually thereafter.
PROJECTED ACCRUAL: A total of 10-29 patients will be accrued for this study within 2 years.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| All patients | Experimental | Biological: filgrastim, Drug: cisplatin, Drug: cyclophosphamide, Drug: doxorubicin hydrochloride, Drug: etoposide, Drug: isotretinoin, Drug: melphalan, Drug: topotecan hydrochloride, Drug: vincristine sulfate, Procedure: conventional surgery, Procedure: peripheral blood stem cell transplantation, Radiation: radiation therapyInduction Cycles 1 and 2 (CT) (21 days each), Cyclophosphamide (Days 1 thru 5) weight based dosage (> 12 kg 400 mg/m2/day, < 12 kg 13.3 mg/kg/day, < 2 years old N/A. Topotecan (Days 1 thru 5) weight based dosage (> 12 kg 1.2 mg/m2/day, < 12 kg 0.04 mg/kg/day, < 2 years old 0.04 mg/kg/day). Filgrastim (Days 6 →) weight based dosage (> 12 kg 5 micrograms/kg, < 12 kg 5 micrograms /kg, < 2 years old 5 micrograms /kg. |
Who may qualify
- Ages
- Up to 30 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| filgrastim | Biological | All patients |
| cisplatin | Drug | All patients |
| cyclophosphamide | Drug | All patients |
| doxorubicin hydrochloride | Drug | All patients |
| etoposide | Drug | All patients |
| isotretinoin | Drug | All patients |
| melphalan | Drug | All patients |
| topotecan hydrochloride | Drug | All patients |
| vincristine sulfate | Drug | All patients |
| conventional surgery | Procedure or surgery | All patients |
| peripheral blood stem cell transplantation | Procedure or surgery | All patients |
| radiation therapy | Radiation | All patients |
Primary outcome
Proportion of patients who are classified as a "success"
Time frame: Length of study
Given that the documented delivered dose intensity of chemotherapy in current induction regimens is 75-85% of the intended dose intensity,5,78 we shall consider an individual patient as a "success" in terms of feasibility if the patient is able to receive 75% or more of the intended chemotherapy doses of known active agents.
5 secondary outcomes
Number of toxic deaths
Time frame: Length of study
Proportion of patients with dose limiting toxicities during induction cycle 1 and 2
Time frame: Length of study
Tumor contamination of PBSCs
Time frame: Length of study
Inability to adequately mobilize PBSCs
Time frame: Length of study
Assessment of response
Time frame: Length of study
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Feb 2014.
- Results publication: PubMed 22010014Park JR, Scott JR, Stewart CF, London WB, Naranjo A, Santana VM, Shaw PJ, Cohn SL, Matthay KK. Pilot induction regimen incorporating pharmacokinetically guided topotecan for treatment of newly diagnosed high-risk neuroblastoma: a Children's Oncology Group study. J Clin Oncol. 2011 Nov 20;29(33):4351-7. doi: 10.1200/JCO.2010.34.3293. Epub 2011 Oct 17.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Julie R. Park, MD study chair
Seattle Children's Hospital
6 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing filgrastim, cisplatin and cyclophosphamide in people with Neuroblastoma, run by Children's Oncology Group at 6 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 13 Feb 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 6 sites in United States, Australia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Proportion of patients who are classified as a "success" (time frame: Length of study). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00070200, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Feb 2014.