NANT 2001-02: 131I-Metaiodobenzylguanidine (MIBG) with Intensive Chemotherapy and Autologous Stem Cell Rescue for High-Risk Neuroblastoma
| Type | Status | Age Range (yrs.) | Sponsor | Protocol ID |
|---|
| Treatment | Active | 1 to 29 | NANT | NANT 2001-02 |
Outline
First described over a century ago, neuroblastoma remains one of the most common solid tumors of childhood. Arising from neural crest tissue, the tumor shows remarkable heterogeneity in its biology, ranging from a highly undifferentiated tumor with early dissemination to forms in which spontaneous regression have been described. Despite significant advances in our knowledge of its tumor biology, the survival for patients presenting with metastatic disease remains poor (< 40%). The long term survival for patients who fail to achieve a complete remission with induction therapy, or for patients who relapse, is even less (<10%).
131I-metaiodobenzylguanidine (MIBG) was discovered in the 1970's as an agent that would concentrate within adrenomedullary tissue. The usefulness of 131I-MIBG as an imaging agent, and subsequently as a therapeutic agent for pheochromocytomas, and neuroblastomas was reported in 1980's. Response rates of 10-50% were initially reported in Phase I and II therapeutic trials targeting refractory neuroblastoma. Toxicity associated with 131I-MIBG has been primarily hematopoietic, with approximately 50% of patients receiving ≥ 15 mCi/kg requiring stem cell re-infusion. To date, non-hematopoietic toxicity has been mild. Recently, trials combining 131I-MIBG with myeloablative chemotherapy and stem cell re-infusion have been performed, with initial response rates > of approximately 50%.
The NANT (New Advances in Neuroblastoma Therapy) consortium is a cooperative group of 14 medical centers involved in neuroblastoma therapy. NANT has currently completed a phase I trial (NANT 9901), in which the combination of 131I-MIBG with intensive chemotherapy and hematopoietic stem cell rescue was examined.
Patients are followed at 6 months, 1 year, and 2 years post ASCT, then as clinically indicated. Patients will be followed for like for any delayed toxicities realted to protocol therapy.
Objectives
The primary aim of this study is:
- To determine the response rate to 131I-MIBG, in combination with myeloablative chemotherapy, hematopoietic stem cell infusion and local radiation for patients with relapsed or refractory neuroblastoma.
The secondary aims of this study are:
- To further assess the hematopoietic and non-hematopoietic toxicity of 131I-MIBG, in combination with myeloablative chemotherapy, for patients with relapsed or refractory neuroblastoma.
- To determine, in patients with measurable soft tissue lesions, the tumor absorbed radiation dose (TSARD) following infusion of 131I-MIBG.
- To correlate the TSARD with tumor response in patients with measurable residual soft tissue disease.
Projected Accrual
A total of 40 patients will be accrued for this study within 2 years.
Entry Criteria
Disease Characteristics:
- Patients must have a diagnosis of neuroblastoma verified at diagnosis, or at the time of relapse, by histology and/or demonstration of clumps of tumor cells in bone marrow with elevated urinary catecholamine metabolites.
- Disease Status: Patients with high risk neuroblastoma must meet one of the following criteria:
- The presence of progressive disease (PD) prior to or following completion of induction therapy.
- The presence of mixed response (MR), or no response (NR) following completion of 4 courses of induction therapy.
- The presence of partial response (PR) following 4 courses of induction therapy, provided that the patient has never previously been enrolled on COG A3973 or other Phase III COG trials.
Measurable Disease: Patients must have evidence of MIBG avid disease, as determined by diagnostic MIBG scan obtained within 6 weeks of study entry. At least one "MIBG avid target lesion" that can be evaluated for response must be present at study entry. All patients must meet the following criteria for minimum number of autologous stem cells. The minimum number may be met by combining different types of stem cell products as listed below (IE: purged + unpurged PBSC): For purged peripheral blood stem cells (PBSC), a minimum of 1.0 x 106 viable CD34+ cells/kg (optimum, 5x106 viable CD34+ cells/kg) must be available. If less than 1.5 x 106 viable CD34+ cells/kg purged PBSC are available, then patient must also have a documented backup of unpurged PBSC with minimum of 2.0 x 106 CD34+ cells/kg For unpurged peripheral blood stem cells (PBSC), a minimum of 1.5 x 106 CD34+ cells/kg (optimum, 5x106 cells/kg) must be available. For purged bone marrow, a minimum of 1x108 mononuclear cells/kg (optimum >2x108 cells/kg or 8 x 104 CFU-GM/kg) must be available. All stem cell products must either have immunocytology results showing no detectable tumor cells, OR a bone marrow done within 4 weeks of stem cell collection must have no evidence of tumor by morphology.Patient Characteristics:
Age
- Patients must be ≥1 year of age at the time of study entry and <30 years of age at the time of initial diagnosis.
Performance status
- Patients must have a Lansky Play Scale ≥ 60%, or Karnofsky score ≥ 60%
Life expectancy
Hematopoietic
- Hemoblobin ≥ 10 g/dl (transfusion allowed)
- ANC ≥ 750/µL
- Platelets ≥ 50,000/µL (if no marrow involvement by morphologic exam / no transfusion allowed) Platelets > 20,000/µL (if metastatic tumor involvement of marrow by morphologic exam / transfusion allowed)
Hepatic
- Total bilirubin < 1.3 times normal
- SGPT (ALT) and SGOT (ALT) < 5 times normal
Renal
- Glomerular filtration rate (GFR) or 12-24hour creatinine clearance ≥ 60 mL/min/1.73m2 and
- Serum Creatinine ≤ 1.5 normal for range
Cardiovascular
- Normal ejection fraction ≥ 55% by echocardiogram or radionuclide MUGA evaluation
OR - Normal fractional shortening ≥ 27% documented by echocardiogram
Pulmonary
- No dyspnea at rest
- No oxygen requirement
- Normal lung function
Other
- Not pregnancy or breast feeding
Prior Concurrent Therapy:
Biologic therapy
- Patients who are Hepatitis B surface antigen positive or Hepatitis C positive are excluded.
- Patients with an active infection requiring intravenous antivirals, antibiotics or antifungals are excluded.
Chemotherapy
- See Disease Characteristics
- Patients who have received > 100 mg/m2 total dose prior melphalan therapy are excluded.
Endocrine therapy
Radiotherapy
- Prior TBI, prior total abdominal or whole liver XRT are excluded.
- Prior therapy with 131I-MIBG are excluded.
- A patient weight that would require exceeding a maximum total allowable dose of 131I-MIBG is excluded.
- Patients who are unable to cooperate with the radiation safety isolation procedures are excluded.
Surgery
Other
- Patients on prolonged antifungal therapy are still eligible if they are culture negative and biopsy negative in suspected residual radiographic lesions and they meet other organ function criteria.
- Patients with disease of any major organ system that would compromise their ability to withstand therapy are excluded.
- Patients who are on hemodialysis are excluded.
Who should I contact for more information?
Peggy Kaiser, RN, BSN
Cincinnati Children's Hospital Medical Center
Division of Hematology / Oncology
3333 Burnet Ave., Cincinnati, OH 45229-3039
Phone: 513-636-2799
cancer@cchmc.org
