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ZD6474 Alone and in Combination With Retinoic Acid in Pediatric Neuroblastoma
This study is currently recruiting participants.
Verified by M.D. Anderson Cancer Center, October 2009
First Received: September 19, 2007   Last Updated: October 16, 2009   History of Changes
Sponsor: M.D. Anderson Cancer Center
Collaborator: AstraZeneca
Information provided by: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT00533169
  Purpose

Hypothesis:

ZD6474 will have significant antitumor activity in cases of relapsed and refractory neuroblastoma due to the combined inhibition of biologically relevant RET, VEGFR, and EGFR pathways, and it will have synergistic antitumor activity in combination with retinoid therapy.

Primary Objective:

To determine the pharmacokinetics, safety, dose-limiting toxicities, and maximum tolerated dose of ZD6474, alone and in combination with retinoic acid, in patients with relapsed or refractory neuroblastoma.

Secondary Objective:

To assess progression-free survival (PFS) and objective tumor response rates in children with relapsed and refractory neuroblastoma treated with ZD6474 +/- retinoic acid in the context of a Phase I trial.

Exploratory Objectives:

To explore blood-based biomarkers before and after treatment with ZD6474 alone and in combination with retinoic acid.

To investigate the presence, activation, and functional status of target receptors (RET, EGFR, VEGFR) and signalling pathways in archival tumor specimens when available.


Condition Intervention Phase
Neuroblastoma
Drug: ZD6474
Drug: Retinoic Acid
Phase I

Study Type: Interventional
Study Design: Treatment, Non-Randomized, Open Label, Active Control, Single Group Assignment, Safety/Efficacy Study
Official Title: A Phase I Study of ZD6474 (Zactima) Alone and in Combination With Retinoic Acid in Relapsed and Refractory Pediatric Neuroblastoma

Resource links provided by NLM:


Further study details as provided by M.D. Anderson Cancer Center:

Primary Outcome Measures:
  • Maximum tolerated dose (MTD) [ Time Frame: 28 day cycles, first 2 cycles used to determine dose-limiting toxicity ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 84
Study Start Date: September 2007
Estimated Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
1: Experimental
Part A = ZD6474 Alone; Part B, C = ZD6474 + Retinoic Acid
Drug: ZD6474
Part A = Starting dose 50 mg/m^2 by mouth daily for 28 days; Part B, C = Starting dose 50 mg/m^2 by mouth daily on days 2-28.
Drug: Retinoic Acid
Part B, C = 80 mg/m^2 by mouth twice daily for 2 consecutive weeks out of every four weeks (28 days).

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   2 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Provision of informed consent from subjects or their legal guardians
  2. Patients must have had histologic verification of neuroblastoma and/or demonstration of tumor cells in the bone marrow with increased urinary catecholamines (HVA and/or VMA) at the time of initial diagnosis, AND which has progressed on standard therapy, relapsed after standard therapy, or for which no standard curative therapy is known.
  3. Measurable or evaluable disease presence within 4 weeks of onset of study therapy: a. measurable tumor on MRI, CT scan or X-ray obtained prior to study entry. Patients who appear to have residual stable tumor upon completion of frontline therapy must undergo a biopsy to document presence of viable neuroblastoma. If only active target lesion was radiated of patients with stable disease, biopsy must be done at least 4 weeks after radiation was completed and must demonstrate viable neuroblastoma, OR
  4. (Continued # 3): Evaluable disease documented by bone marrow obtained prior to study entry with tumor cells seen on routine morphology (not by NSE staining only) of aspirate and/or biopsy OR
  5. (Continued # 3) Evaluable disease documented by MIBG scan or bone scan obtained within 4 weeks prior to study entry with positive uptake at a minimum of one site. Patients who appear to have residual stable MIBG positive lesions upon completion of frontline therapy must undergo a biopsy to document the presence of viable neuroblastoma. If the patient has only one MIBG positive lesion and that lesion was radiated, a biopsy must be done at least 4 weeks after radiation was completed and must demonstrate viable neuroblastoma.
  6. Performance status - Lansky play or karnofsky score of >40
  7. Age >/=2 years at time of enrollment

Exclusion Criteria:

  1. Lab results: a) ANC <1000/mm^3, hemoglobin <7.0 g/dL, platelets <20,000/mm^3 (hemoglobin and platelets may be supported by transfusions); b) Serum bilirubin >1.5x institutional upper limit of normal (IULN); c) Serum creatinine >1.5 x per IULN or creatinine clearance <or equal to 70 ml/min/1.73m^2; d) Potassium, <4.0 mmol/L despite supplement; Serum calcium or ionized calcium >IULN; Magnesium out of normal range per institutional guidelines despite supplement; e) ALT > 2.5 X IULN or alkaline phosphatase (ALP) >2.5 X IULN or > 5X IULN if judged by the investigator to be related to liver metastases
  2. Evidence of severe or uncontrolled systemic disease or any concurrent condition which in the Investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol.
  3. History of symptomatic or medically managed arrhythmia (multifocal premature ventricular contractions (PVCs), bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation) (>/= NCI CTCAE grade 3) or asymptomatic sustained ventricular tachycardia. Atrial fibrillation controlled on medication is not excluded.
  4. Previous history of QTc prolongation as a result from other medication that required discontinuation of that medication.
  5. Congenital long QT syndrome, or 1st degree relative with unexplained sudden death under 40 years of age.
  6. Presence of left bundle branch block
  7. QTc with Bazett's correction that is unmeasurable, or >/=480 msec on screening ECG. If a patient has QTc >/=480 msec on screening ECG, the screen ECG may be repeated twice (at least 24 hours apart). The average QTc from the three screening ECGs must be <480 msec in order for the patient to be eligible for the study.
  8. Use of any concomitant medication that may cause QTc prolongation, induce Torsades de Pointes or induce CYP3A4 function
  9. Clinically significant cardiac event such as myocardial infarction, TIA, or CVA within 3 months before entry; or presence of cardiac disease that, in the opinion of the Investigator, increases the risk of ventricular arrhythmia.
  10. Hypertension > 95th percentile for age (either systolic or diastolic) or > 140/90 for patients >18 years of age and uncontrolled by oral medication at onset of study therapy.
  11. Currently active diarrhea that may affect the ability of the patient to absorb the ZACTIMA.
  12. Women who are currently pregnant or breastfeeding.
  13. Receipt of any investigational agents within 14 days prior to commencing study treatment, or prior receipt of ZACTIMA at any time
  14. Last dose of prior chemotherapy discontinued less than 2 weeks before the start of study therapy.
  15. Last radiation therapy within the last 4 weeks before the start of study therapy, except palliative radiotherapy to non-index lesions
  16. Any unresolved non-hematologic toxicity greater than CTC grade 1 from previous anti-cancer therapy, except for platinum-induced hearing loss.
  17. Any evidence of active graft versus host disease after stem cell transplant.
  18. Major surgery within 4 weeks, or incompletely healed surgical incision before starting study therapy.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00533169

Contacts
Contact: Peter E. Zage, MD, PhD 713-792-6624

Locations
United States, Texas
U.T.M.D. Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Principal Investigator: Peter E. Zage, MD, PhD            
Sponsors and Collaborators
M.D. Anderson Cancer Center
AstraZeneca
Investigators
Principal Investigator: Peter E. Zage, MD, PhD U.T.M.D. Anderson Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: U.T.M.D. Anderson Cancer Center ( Peter E. Zage, MD, PhD/Assistant Professor )
Study ID Numbers: 2006-0807
Study First Received: September 19, 2007
Last Updated: October 16, 2009
ClinicalTrials.gov Identifier: NCT00533169     History of Changes
Health Authority: United States: Food and Drug Administration

Keywords provided by M.D. Anderson Cancer Center:
Neuroblastoma
ZD6474
Zactima
Isotretinoin
13-Cis Retinoic Acid
Accutane
Pediatric Neuroblastoma

Additional relevant MeSH terms:
Neuroectodermal Tumors, Primitive
Neoplasms by Histologic Type
Antineoplastic Agents
Neoplasms, Nerve Tissue
Pharmacologic Actions
Neuroblastoma
Keratolytic Agents
Neuroectodermal Tumors
Neoplasms
Therapeutic Uses
Neoplasms, Germ Cell and Embryonal
Isotretinoin
Tretinoin
Neoplasms, Neuroepithelial
Dermatologic Agents
Neuroectodermal Tumors, Primitive, Peripheral
Neoplasms, Glandular and Epithelial

ClinicalTrials.gov processed this record on November 09, 2009