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

NEUROBLASTOMA Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00206388
• Other study ID #: 16758
• Secondary ID: ZOMETA
• Status: Completed
• Phase: Phase 1
• First received: September 14, 2005
• Last updated: August 1, 2013
• Start date: April 2005
• Est. completion date: May 2013

Study information

• Verified date: August 2013
• Source: Baylor College of Medicine
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationUnited States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

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.

Other known NCT identifiers

• NCT00258414

Recruitment information / eligibility

• Status: Completed
• Enrollment: 21
• Est. completion date: May 2013
• Est. primary completion date: April 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 30 Years

Eligibility

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.

Study Design

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

Related Conditions & MeSH terms

• NEUROBLASTOMA

Intervention

Drug:
• Zolendric acid
IV, 2mg/m2/dose on day 0
• Cyclophosphamide
fixed dose of 25mg/m2/dose days 0-27

Locations

Country	Name	City	State
United States	Cincinnati Children's Hospital	Cincinnati	Ohio
United States	Texas Children's Cancer Center	Houston	Texas
United States	Indiana University-Riley Children's Hospital	Indianapolis	Indiana
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	University of Wisconsin Medical Center	Madison	Wisconsin
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	USCF School of Medicine	San Francisco	California
United States	Lucille Salter Packer Children's Hospital	Stanford	California

Sponsors (2)

Lead Sponsor	Collaborator
Baylor College of Medicine	New Approaches to Neuroblastoma Therapy Consortium

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Toxicity		28 days, lifetime for delayed toxicities	Yes
Primary	Maximum tolerated dose (MTD)		28 days	Yes
Secondary	Anti tumor activity		1-2 months post treatment	Yes
Secondary	Pharmacokinetics		prior to infusion of first dose and 24h post	No
Secondary	Biologic activity		during courses 1-4	No