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Phase III Randomized Study of Purged Versus Unpurged Peripheral Blood Stem Cell Transplantation After Dose-Intensive Induction Chemotherapy in Patients With Newly Diagnosed High Risk Neuroblastoma or Ganglioneuroblastoma
Alternate Title Basic Trial Information Objectives Entry Criteria Expected Enrollment Outcomes Outline Published Results Related Publications Trial Contact Information Registry Information
Alternate Title
Combination Chemotherapy and Peripheral Stem Cell Transplantation in Treating Patients With Neuroblastoma
Basic Trial Information
Phase | Type | Status | Age | Protocol IDs |
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Phase III | Treatment | Completed | 30 and under | COG-A3973 CCG-A3973, POG-A3973, CCG-39703, FHCRC-1631.00, NCT00004188, A3973 |
Objectives Primary - Compare the event-free survival in patients with newly diagnosed high risk neuroblastoma or ganglioneuroblastoma treated with myeloablative consolidation chemotherapy and autologous purged versus unpurged peripheral blood stem cells (PBSC).
- Compare the time to engraftment and CD34 content and tumor content by reverse transcriptase polymerase chain reaction (RT-PCR) of purged versus unpurged PBSC in patients treated with these regimens.
- Determine event-free survival of patients treated with dose intensive induction chemotherapy comprising cyclophosphamide, doxorubicin, and vincristine alternating with cisplatin and etoposide.
- Determine the toxicity of this dose-intensive induction chemotherapy regimen in these patients.
- Evaluate tumor resectability at second look or delayed surgery, response (complete response and very good partial response) at completion of induction therapy, tumor content of peripheral blood and bone marrow, and the comparison of historical data from CCG-3891 induction therapy in these patients.
Secondary - Compare the toxicity of this myeloablative consolidation regimen using purged vs unpurged PBSC in these patients.
- Determine if event-free survival is predictable by RT-PCR positivity of the stem cell, minimal residual disease in bone marrow and peripheral blood after transplantation by immunocytology, and extent of disease as measured by MIBG after transplantation in patients treated with these regimens.
- Evaluate the prognostic impact of tumor biology on event free survival in patients treated with these regimens.
- Determine the incidence of relapse in the primary site after radiotherapy and in irradiated versus unirradiated metastatic sites in these patients.
- Assess the toxicity and tolerability of maintenance therapy with topotecan and cyclophosphamide after intensive induction therapy in patients who decline or are unable to receive myeloablative therapy.
- Determine the health-related quality of life of patients treated with these regimens.
- Compare late effects of these regimens on the growth, endocrine, pulmonary, and cardiac function of these patients vs general population standards.
- Determine the incidence of second malignant neoplasms in patients treated with these regimens.
- Determine the variability of isotretinoin pharmacokinetics and relationship to pharmacogenomic parameters in these patients.
- Correlate the isotretinoin pharmacokinetics and pharmacogenomic parameters and/or genetic variations in isotretinoin metabolic enzymes with event-free survival or systemic toxicity in these patients.
Entry Criteria Disease Characteristics:
- Histologically confirmed newly diagnosed neuroblastoma OR ganglioneuroblastoma, and/or evidence of
clumps of tumor cells in bone marrow with elevated urinary catecholamine
metabolites, meeting 1 of the following criteria:
- Age greater than 18 months with stage IV disease, regardless of biologic factors
- Age 12-18 months with stage IV disease meeting one of the following criteria:
- Any unfavorable biologic feature (e.g., MYCN amplification, unfavorable pathology, and/or DNA index = 1)
- Any biologic feature that is indeterminate, unsatisfactory, or unknown
- At least 1 year old with the following:
- Stage IIa/IIb with MYCN amplification (> 10)
AND unfavorable
pathology
- Stage III with MYCN amplification (> 10) OR
unfavorable pathology
- Stage I, II, or IVS with disease progression to stage IV
without interval
chemotherapy
- No more than 3 weeks since progression
- Must have been enrolled on protocol CCG-B973, COG-ANBL00B1, or POG-9047
- Less than 1 year old with the following:
- Stage III, IV, or IVS disease with MYCN amplification
(> 10)
- Registration on protocol COG-ANBL00B1 required within 14 days of diagnosis
Prior/Concurrent Therapy:
Biologic therapy: Chemotherapy: - See Disease Characteristics
- No more than 1 prior course of chemotherapy on
the Intergroup low/intermediate risk neuroblastoma study (P9641,
A3961)
Endocrine therapy: Radiotherapy: - Prior localized emergency radiotherapy to sites of life-threatening or function-threatening disease allowed
Surgery: Other - No other prior systemic therapy
Patient Characteristics:
Age: - See Disease Characteristics
- 30 and under at time of diagnosis
Performance status: Life expectancy: Hematopoietic: - Absolute neutrophil count ≥ 1,000/mm3
- Platelet count ≥ 100,000/mm3
- Inadequate hematopoiesis secondary to bone marrow involvement
with > 10% tumor infiltration allowed
Hepatic: - Bilirubin ≤ 1.5 mg/dL
- ALT ≤ 300 units/L
Renal: - Creatinine ≤ 1.5 mg/dL
- Creatinine clearance or glomerular filtration rate ≥ 60 mL/min
Cardiovascular: - ECG normal
- Ejection fraction ≥ 55% by echocardiogram or MUGA
OR - Fractional shortening ≥ 28% by echocardiogram
Other: - Able to tolerate peripheral blood stem cell collection
- HIV negative
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception for at least 1
month prior to, during, and for 1 month after study participation
Expected Enrollment A total of 486 patients will be accrued for this study within 4 years. Outcomes Primary Outcome(s)Event-free survival rate
Secondary Outcome(s)Time to engrafment CD34 content Tumor content as measured by reverse transcriptase polymerase chain reaction
Outline This is a randomized study. Patients are randomized to one of two
treatment arms for peripheral blood stem cell (PBSC) collection. All patients receive induction chemotherapy comprising cyclophosphamide IV over 6 hours on days 0 and 1, doxorubicin IV and
vincristine IV continuously over 72 hours on days 0-2, and filgrastim (G-CSF)
subcutaneously (SC) or IV beginning on day 3 and continuing until blood counts
recover for courses 1, 2, 4, and 6. Treatment alternates with courses 3 and 5
comprising etoposide IV over 2 hours on days 0-2, cisplatin IV over 1 hour
on days 0-3, and G-CSF SC or IV beginning on day 4 and continuing until blood
counts recover. Induction chemotherapy repeats every 3 weeks or when blood
counts recover in the absence of disease progression or unacceptable
toxicity. After course 2 or 3 of induction chemotherapy, patients undergo PBSC
collection, either purged or unpurged, depending on randomization. Patients
continue on daily G-CSF until cell collection is complete. - Arm I: Patients undergo unpurged PBSC collection until the target cell
count is reached.
- Arm II: Patients undergo purged PBSC collection until the target cell
count is reached.
Patients with immunocytology positive PBSC undergo purged autologous
bone marrow collection or repeat purged or unpurged PBSC collection depending
on individual patient characteristics. All patients undergo delayed surgical resection of the residual tumor
after course 5 of induction chemotherapy. After induction therapy, patients achieving complete response, very
good partial response, or partial response receive consolidation therapy
comprising melphalan IV on days -7 to -5 followed by carboplatin IV
and etoposide IV continuously over days -7 to -4. Patients receive purged
or unpurged PBSC infusion or purged autologous bone marrow transplantation on
day 0 followed by G-CSF SC or IV beginning 4 hours after completion of
transplantation and continuing until blood counts recover. Beginning on day
66, patients receive oral isotretinoin twice daily for 14 days. Isotretinoin
therapy repeats every 4 weeks for 6 courses. After completion of consolidation (at least 28 days from stem cell
infusion), all patients receive local radiotherapy daily over 7
days. Patients not undergoing transplantation or who are ineligible for
consolidation therapy receive maintenance therapy comprising cyclophosphamide IV over 30 minutes followed by topotecan IV over 30 minutes
on days 0-4. Patients receive G-CSF SC or IV beginning on day 5 and continuing
until blood counts recover. Maintenance therapy repeats every 3 weeks for 3
courses. After completion of maintenance therapy, patients receive
radiotherapy as outlined above. Patients then receive oral isotretinoin
twice daily for 14 days. Isotretinoin therapy repeats every 4 weeks for 6
courses. Quality of life is assessed at 1* and 5 years. Patients are followed every 3 months for 1 year, every 6 months for 4
years, and then annually thereafter or until disease progression. [Note: * Patients under 5 years of age at 1 year are not assessed until 5 years.] Published ResultsKreissman SG, Villablanca JG, Diller L, et al.: Response and toxicity to a dose-intensive multi-agent chemotherapy induction regimen for high risk neuroblastoma (HR-NB): a Children's Oncology Group (COG A3973) study. [Abstract] J Clin Oncol 25 (Suppl 18): A-9505, 527s, 2007. Related PublicationsCantos MF, Gerstle JT, Irwin MS, et al.: Surgical challenges associated with intensive treatment protocols for high-risk neuroblastoma. J Pediatr Surg 41 (5): 960-5, 2006.[PUBMED Abstract] Kushner BH, Budnick A, Kramer K, et al.: Ototoxicity from high-dose use of platinum compounds in patients with neuroblastoma. Cancer 107 (2): 417-22, 2006.[PUBMED Abstract]
Trial Contact Information
Trial Lead Organizations Children's Oncology Group | | | Susan Kreissman, MD, Protocol chair | | | |
Registry Information | | Official Title | | A Randomized Study of Purged versus Unpurged Peripheral Blood Stem Cell Transplant Following Dose Intensive Induction Therapy for High Risk Neuroblastoma | | Trial Start Date | | 2001-02-09 | | Registered in ClinicalTrials.gov | | NCT00004188 | | Date Submitted to PDQ | | 1999-10-12 | | Information Last Verified | | 2006-03-28 | | NCI Grant/Contract Number | | CA13539, CA10382 |
Note: The purpose of most clinical trials listed in this database is to test new cancer treatments, or new methods of diagnosing, screening, or preventing cancer. Because all potentially harmful side effects are not known before a trial is conducted, dose and schedule modifications may be required for participants if they develop side effects from the treatment or test. The therapy or test described in this clinical trial is intended for use by clinical oncologists in carefully structured settings, and may not prove to be more effective than standard treatment. A responsible investigator associated with this clinical trial should be consulted before using this protocol. Back to Top |
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