Zoledronic Acid (ZOMETA) With Cyclophosphamide With Neuroblastoma and Cortical Bone Involvement

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00206388
Recruitment Status : Completed
First Posted : September 21, 2005
Last Update Posted : August 2, 2013
New Approaches to Neuroblastoma Therapy Consortium
Information provided by (Responsible Party):
Peter Zage, Baylor College of Medicine

Brief Summary:

The purposes of this study are:

  1. To find the highest dose of monthly intravenous Zometa that can be given with daily low doses of cyclophosphamide by mouth to children with recurrent or refractory neuroblastoma without causing severe side effects.
  2. To find out the side effects seen by giving Zometa and cyclophosphamide on this schedule at different dose levels.
  3. To measure blood and urine levels of Zometa during treatment
  4. 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.
  5. To measure the effects of Zometa on markers of bone breakdown found in urine, blood, and bone marrow
  6. To measure the effects of Zometa on the immune system.

Condition or disease Intervention/treatment Phase
NEUROBLASTOMA Drug: Zolendric acid Drug: Cyclophosphamide Phase 1

Detailed Description:
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.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 21 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Study of Zoledronic Acid (Zometa) With Cyclophosphamide in Children With Recurrent or Refractory Neuroblastoma and Cortical Bone Involvement (NANT 2004-01)
Study Start Date : April 2005
Actual Primary Completion Date : April 2008
Actual Study Completion Date : May 2013

Arm Intervention/treatment
Experimental: Zolendric acid with Cyclophosphamide
Zometa will be administered intravenously every 28 days beginning on day 0. Cyclophosphamide will be administered daily without interruption (unless toxicity supervenes) beginning day 0. Each course of therapy will be 28 days. On day 0 of each cycle, cyclophosphamide should be given first, followed by Zometa with a separation between the two drugs of at least one hour. All patients are required to take calcium and Vitamin D supplementation for the duration of study participation.
Drug: Zolendric acid
IV, 2mg/m2/dose on day 0
Other Name: Zometa
Drug: Cyclophosphamide
fixed dose of 25mg/m2/dose days 0-27
Other Name: CTX, Cytoxan

Primary Outcome Measures :
  1. Toxicity [ Time Frame: 28 days, lifetime for delayed toxicities ]
  2. Maximum tolerated dose (MTD) [ Time Frame: 28 days ]

Secondary Outcome Measures :
  1. Anti tumor activity [ Time Frame: 1-2 months post treatment ]
  2. Pharmacokinetics [ Time Frame: prior to infusion of first dose and 24h post ]
  3. Biologic activity [ Time Frame: during courses 1-4 ]

Information from the National Library of Medicine

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Ages Eligible for Study:   up to 30 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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 catecholamines.
  • 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 therapy.
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00206388

United States, California
Children's Hospital Los Angeles
Los Angeles, California, United States, 90027
USCF School of Medicine
San Francisco, California, United States, 94143
Lucille Salter Packer Children's Hospital
Stanford, California, United States, 94305
United States, Indiana
Indiana University-Riley Children's Hospital
Indianapolis, Indiana, United States, 46202
United States, Ohio
Cincinnati Children's Hospital
Cincinnati, Ohio, United States, 45229
United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
United States, Texas
Texas Children's Cancer Center
Houston, Texas, United States, 77030
United States, Wisconsin
University of Wisconsin Medical Center
Madison, Wisconsin, United States, 53792
Sponsors and Collaborators
Baylor College of Medicine
New Approaches to Neuroblastoma Therapy Consortium
Principal Investigator: Peter Zage, MD Baylor College of Medicine

Responsible Party: Peter Zage, Assistant Professor, Baylor College of Medicine Identifier: NCT00206388     History of Changes
Obsolete Identifiers: NCT00258414
Other Study ID Numbers: 16758
First Posted: September 21, 2005    Key Record Dates
Last Update Posted: August 2, 2013
Last Verified: August 2013

Keywords provided by Peter Zage, Baylor College of Medicine:

Additional relevant MeSH terms:
Neuroectodermal Tumors, Primitive, Peripheral
Neuroectodermal Tumors, Primitive
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Zoledronic acid
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Bone Density Conservation Agents