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A Phase I Study of Zoledronic Acid (Zometa) With Cyclophosphamide in Children With Recurrent or Refractory Neuroblastoma and Cortical Bone Involvement (NANT 2004-01)

Phase 1
30 Years
Open (Enrolling)

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Trial Information

A Phase I Study of Zoledronic Acid (Zometa) With Cyclophosphamide in Children With Recurrent or Refractory Neuroblastoma and Cortical Bone Involvement (NANT 2004-01)

Zoledronic Acid (Zometa), a new generation, highly potent bisphosphonate used to treat
osteoporosis and hypercalcemia of malignancy, is widely used in adult malignancies with
potential for bone metastasis such as breast cancer, multiple myeloma and prostate cancer.
Bisphosphonates modulate the bone environment by toxicity to osteoclasts resulting in
decreased bone resorption. Zometa is the first bisphosphonate to affect both osteolytic and
osteoblastic metastatic lesions. In several large randomized studies in adults with
recurrent or advanced malignancies, patients randomized to Zometa had delay in progression
of bone metastases and less morbidity (skeletal related events) when compared to either
placebo or pamidronate. The toxicity profile of Zometa in adults has been tolerable and
includes hypocalcemia, temperature rise, and nausea. The most concerning toxicity is
decline in renal function that appears to be related to cumulative dose and the dose rate of
administration. In our pre-clinical studies bisphosphonates delayed progression of
osteolytic lesions in neuroblastoma tumors xenografted into immunocompromised mice while the
combination of Zometa with low dose cyclophosphamide appeared to prolong overall survival.
The primary aim of this study is to evaluate the maximum tolerated dose of Zometa combined
with low dose oral cyclophosphamide in children with recurrent or refractory neuroblastoma.
We will also evaluate the pharmacokinetics of Zometa in children with neuroblastoma and
examine the effect of Zometa on markers of bone resorption, cytokines and bone-related
growth factors.

Inclusion Criteria:

- Less than or equal to 30 years of age when enrolled on study.

- A diagnosis of neuroblastoma either by histologic verification of neuroblastoma
and/or demonstration of tumor cells in the bone marrow with increased urinary

- High-risk neuroblastoma with at least ONE of the following: 1. Recurrent/progressive
disease. 2. Refractory disease (i.e. less than a partial response to frontline
therapy). No biopsy is required for eligibility for study. 3. 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.

- 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.

- A Karnofsky or Lansky performance status of greater than or equal to 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 of greater than 2 months.

- Fully recovered from the acute toxic effects of all prior chemotherapy,
immunotherapy, or radiotherapy prior to entering this study. 1. Must not have
received within 3 weeks of entry onto this study (4 weeks if prior nitrosourea). 2.
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 (ie:
TBI, craniospinal therapy, whole abdomen, total lung, or over 50% marrow space). 3.
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. 4. A minimum of six weeks is required following prior therapeutic doses of
MIBG. 5. Must not have received factors that support platelet or white cell number or
function within 7 days of study entry. 6 Must not have received bisphosphonate

- Must not be receiving any other anti-cancer agents or radiotherapy at the time of
study entry or while on study.

- Organ Function Requirements Adequate Bone Marrow Function: a. ANC greater than or
equal to 750 b. Platelet count greater than or equal to 50,000, 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. Adequate Renal Function a. Glomerular Filtration Rate of greater than or
equal to 70 ml/min/1.73 m2, OR b. Age-adjusted normal serum creatinine for age
Adequate Liver Function a. Total bilirubin less than or equal to 1.5 x normal for
age, and b. SGPT (ALT) and SGOT (AST) less than 5 x normal for age.

- Ionized serum calcium greater than or equal to 1.0 mmol/L (Patients are allowed to be
on calcium supplements if serum calcium is stable)

- Urinalysis with less than or equal to 1+ heme.

- Reproductive Function: Negative serum beta-HCG in females and use of effective
contraception in females and males of child-bearing potential.

Exclusion Criteria:

- Status post-ALLOGENEIC stem cell transplant.

- Received prior bisphosphonate therapy.

- Receiving other investigational agents.

- Have an uncontrolled infection.

- Patients who, in the opinion of the investigator, may not be able to comply with the
safety monitoring requirements of the study.

- Pregnancy or breast feeding.

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:


Outcome Time Frame:

28 days, lifetime for delayed toxicities

Safety Issue:


Principal Investigator

Peter Zage, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Baylor College of Medicine


United States: Food and Drug Administration

Study ID:




Start Date:

April 2005

Completion Date:

August 2014

Related Keywords:

  • Neuroblastoma
  • BONE
  • Neuroblastoma



Children's Hospital of Philadelphia Philadelphia, Pennsylvania  19104
Children's Hospital Los Angeles Los Angeles, California  90027-0700
Texas Children's Cancer Center Houston, Texas  77030-2399
University of Wisconsin Medical Center Madison, Wisconsin  53792
USCF School of Medicine San Francisco, California  94143
Lucille Salter Packer Children's Hospital Stanford, California  94305
Indiana University-Riley Children's Hospital Indianapolis, Indiana  46202
Cincinnati Children's Hospital Cincinnati, Ohio  45229