NANT 2004-01: A Phase I Study Of Zoledronic Acid (Zometa) with Cyclophosphamide in Children with Recurrent or Refractory Neuroblastoma and Cortical Bone Involvement
| Type | Status | Age Range (yrs.) | Sponsor | Protocol ID |
|---|
| Treatment | Active | 0-30 | NANT | NANT 2004-01 |
Outline
Neuroblastoma, a tumor of the postganglionic sympathetic nervous system, is the most common extra cranial childhood solid tumor. It is well known for its dichotomous presentation. Approximately one half of children have localized tumors that can be cured with surgery alone. A small subset of children under one year of age who show disease involving the liver, skin, lymph nodes or bone marrow (Stage 4S neuroblastoma) have a good prognosis in spite of the extent of their disease. The remaining children have widespread metastatic disease or quite large, aggressive, localized tumors. These children have a poor long-term survival rate of approximately 30% despite intensive multimodality therapy. The metastatic pattern is predictable, with bone marrow and cortical bone being the most frequent distant sites.
Children with recurrent neuroblastoma are at high risk for bone metastases that can result in pain, fractures, and limitations to their quality of life. Bisphosphonates (BPs) may help reduce or prevent these metastatic lesions by decreasing or inhibiting osteoclast activity, thus changing the metastatic environment. Zometa has shown increased efficacy compared to other BPs in adults with bone metastases but has not yet been evaluated in children. This limited dose escalation trial will estimate the MTD of and adverse events associated with Zometa plus low dose oral cyclophosphamide in children with recurrent neuroblastoma.
The NANT (New Advances in Neuroblastoma Therapy) consortium is a cooperative group of 14 medical centers involved in neuroblastoma therapy.
Objectives
Primary Aims:
- To determine the maximum tolerated dose of Zometa given as a 15 minute intravenous infusion with a fixed dose of concomitant oral cyclophosphamide when administered in 28 day courses to children with recurrent or refractory neuroblastoma.
- To determine the toxicities of Zometa given on this schedule.
Secondary Aims:
- To preliminarily evaluate the antitumor activity of Zometa and concomitant oral cyclophosphamide in children with recurrent and/or refractory neuroblastoma within the confines of a Phase I study.
- To evaluate the pharmacokinetic behavior of Zometa in children with recurrent or refractory neuroblastoma.
- To obtain preliminary information about the biologic activity of Zometa in neuroblastoma through correlative studies assessing change in markers of bone resorption, cytokines and bone-related growth factors, and gamma-delta T-cells.
The FDA has approved Zometa for the treatment of adult patients with multiple myeloma and adult patients with documented bone metastases from solid tumors, in conjunction with standard cancer therapy.
Projected Accrual
A total of 12-24 patients will be accrued for this study within 2-3 years.
Entry Criteria
Disease Characteristics:
- Diagnosis: Patients must have a diagnosis of neuroblastoma either by histologic verification of neuroblastoma and/or demonstration of tumor cells in the bone marrow with increased urinary catecholamines.
- Disease Status: Patients must have high-risk neuroblastoma with at least ONE of the following:
- Recurrent/progressive disease.
- Refractory disease (i.e. less than a partial response to frontline therapy). No biopsy is required for eligibility for study.
- Persistent disease after at least a partial response to frontline therapy (i.e. patient has had at least a partial response to frontline therapy but still has residual disease by MIBG, CT/MRI, or bone marrow). Patients in this category are REQUIRED to have a biopsy of at least one residual site demonstrating viable neuroblastoma.
- Sites of Disease: Patients must have bone disease demonstrated by uptake on MIBG scan. If the patient's tumor is known to be non-avid for MIBG then the patient must have evidence of either new lesions or progression of prior lesions on bone scan or plain radiographs.
Patient Characteristics:
Age
- Patients must be ≤ 30 years of age inclusive when enrolled on study.
Performance status
- Patients must have a Karnofsky score or Lansky performance status ≥ 50%. Patients who are unable to walk because of paralysis or tumor pain, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
Life expectancy
- Patients must have a life expectancy of ≥ 2 months.
Hematopoietic
- ANC ≥ 750/µL
- Platelets ≥ 50,000/µL, transfusion independent (defined as no platelet transfusion for one week)
Note: Hematologic criteria must be met by all patients, regardless of neuroblastoma involvement in bone marrow.
Hepatic
- Total bilirubin ≤ 1.5 times normal for age, and
- SGPT (ALT) and SGOT (ALT) < 5 times normal
Renal
- Glomerular filtration rate (GFR) ≥ 70 mL/min/1.73m2 OR
- Age adjusted normal serum creatinine for ages (see below)
| Age | Maximum Serum Creatinine (mg/dL) |
|---|
| ≤ 5 years | 0.8 |
| > 5 and ≤ 10 years | 1.0 |
| > 10 and ≤ 15 years | 1.2 |
| > 15 years | 1.5 |
Other
- Ionized serum calcium ≥ 1.0 mmol/L (Patients are allowed to be on calcium supplements if serum calcium is stable.)
- Urinalysis with ≤ 1+ heme.
- Negative serum beta-HCG in females and use of effective contraception in females and males of childbearing potential.
- Patients with other ongoing serious medical issues must be approved by the study chair prior to enrollment.
Prior Concurrent Therapy:
Biologic therapy
- Patients must not have received biologics within 3 weeks of entry onto this study (4 weeks if prior nitrosourea).
- Patients must not be receiving any other radiotherapy at the time of study entry or while on study.
Chemotherapy
- Patients must not have received myelosuppressive chemotherapy within 3 weeks of entry onto this study (4 weeks if prior nitrosourea).
- Must not have received factors that support platelet or white cell number or function within 7 days or study entry.
- Patients must not be receiving any other anti-cancer agents at the time of study entry or while on study.
Endocrine therapy
Radiotherapy
- Patients must not have received radiation for a minimum of four weeks prior to study entry at the site of any lesion that was biopsied to document study eligibility. A minimum of six weeks is required following prior large field radiation therapy (i.e., TBI, craniospinal therapy, whole abdomen, total lung, or > 50 %marrow space).
- A minimum of six weeks is required following prior therapeutic doses of MIBG.
Surgery
Other
- Patients must not have had an autologous stem cell transplant within 3 months of entry onto this study. Patients status post-allogeneic stem cell transplant are excluded.
- Patients must not have received bisphosphonate therapy.
- Patients must not be receiving other investigational agents.
- Patients must not have an uncontrolled infection.
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
