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A Phase I Study of ZD6474 (Zactima) Alone and in Combination With Retinoic Acid in Relapsed and Refractory Pediatric Neuroblastoma


Phase 1
2 Years
N/A
Not Enrolling
Both
Neuroblastoma

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Trial Information

A Phase I Study of ZD6474 (Zactima) Alone and in Combination With Retinoic Acid in Relapsed and Refractory Pediatric Neuroblastoma


The Study Drugs:

ZD6474 is a drug that slows down the function of proteins in tumor cells called protein
tyrosine kinases. Tyrosine kinases normally cause tumor cells to grow. It is thought to
have anti-cancer effects when given with or without other chemotherapy drugs.

Isotretinoin has been shown to help stop the growth of neuroblastoma cells. It helps cells
look more normal and grow more slowly.

Study Drug Dose Level and Drug Administration:

There will be 3 parts in the study. If you have medulloblastoma, you will be assigned to
Part A. If you have neuroblastoma, you will be assigned to Part A, Part B, or Part C.

In Part A, participants will receive the study drug ZD6474 alone. In the Part B portion,
participants will receive ZD6474 along with isotretinoin. In Part C, an additional number of
participants will be enrolled and will receive ZD6474 along with isotretinoin at the highest
dose level that was found in Part B.

Part A Treatment:

Participants in Part A will take ZD6474 daily by mouth in the form of pills or liquid for 28
days. This 28-day period is called a study "cycle." In Part A, the study drug will be
given at different doses. Three (3) participants will be enrolled in each dose level. New
groups will continue to be enrolled at higher doses until intolerable side effects are seen.
If you are assigned to Part A, the dose assigned to you will depend on the number of
participants that have been enrolled before you and the side effects they may have
experienced.

Part B Treatment:

Once the highest tolerable dose of ZD6474 is found, participants will then begin enrolling
in Part B.

Participants in Part B will take ZD6474 daily by mouth in the form of pills or liquid on
Days 2-28 of each 28-day cycle. Participants will also take isotretinoin by mouth 2 times a
day every day for 2 weeks in a row, at some point during each 28-day cycle.

Part C Treatment:

In Part C, participants will follow the same schedule as in Part B.

Drug Diary (all participants):

You will be given a "diary" to record when you take the study drugs. You will need to bring
the diary with you to each study visit. At each visit, you will also be asked about any
side effects that you may be experiencing.

Study Visits (all participants):

During the first 2 months of the study, you will have a study visit weekly. After the first
2 months, you will have study visits at least 1 time a month.

At these visits, the following tests and procedures will be performed:

- Your complete medical history will be recorded.

- You will have a physical exam.

- Blood (about 2 teaspoons) and urine will be collected for routine tests. Before each
cycle, some of the blood collection will be used for blood clotting tests. Once a
month, this routine blood/urine test will include a pregnancy test for women who are
able to have children.

- You will be asked about any drugs you may be taking and if you have been able to
maintain a healthy diet.

Before every other cycle, the following tests and procedures will be performed:

- You may have a CT scan, MRI scan, and/or bone scan to check the status of the disease.

- You may have bone marrow aspirations and a bone marrow biopsy to check the status of
the disease.

- If you have neuroblastoma, you may have an MIBG scan to check the status of the
disease.

- If you have neuroblastoma, urine will be collected to test your HVA and VMA levels.

Once a week during Weeks 1, 2, 4, 9, 13, and then up to 7 days before every other cycle, you
will have ECGs to make sure that your heart remains healthy.

Before each cycle, urine will be collected for routine tests and you will have an ECHO to
make sure that your heart remains healthy.

Pharmacokinetic Testing:

Extra blood samples will be drawn during the study for pharmacokinetic (PK) test. PK tests
are used to measure the amount of study drug in the blood. The amount of blood draw will be
about 1/2 teaspoon each time.

Blood will be drawn for PK testing at the following time points:

- On Day 1 of Cycle 1, before and 6 hours after taking ZD6474

- On Days 2, 8, 15 and 22 of Cycle 1 before you take ZD6474

- On Days 1, 8 and 15 of Cycle 2 before you take ZD6474

- On Day 1 of Cycles 4, 6, and 8 before taking ZD6474

If you are 1 of the first 3 participants enrolled in the study, blood will be drawn at 2, 4,
6, and 8 or 12 and 24 hours after the very first dose during Cycle 1.

Length of Study:

You may remain on study for as long as you are benefitting. You will be taken off study
early if the disease gets worse or intolerable side effects occur.

End-Of-Study Visit:

Once you are off study, you will have an end-of-study visit. At this visit, the following
tests and procedures will be performed. If any tests or procedure has been performed in the
last month, it will not be repeated.

- Your complete medical history will be recorded.

- You will be asked about any drugs you may be taking.

- You will have a physical exam.

- Blood (about 2 teaspoons) and urine will be collected for routine tests.

- You will have an ECHO.

- You will have an ECG.

- You may have a CT scan, MRI scan, and/or a bone scan to check the status of the
disease.

- You may have bone marrow aspirations and a bone marrow biopsy to check the status of
the disease.

- If you have neuroblastoma, you will have an MIBG scan to check the status of the
disease.

- If you have neuroblastoma, urine will be collected to test your HVA and VMA levels.

Follow-up Visits:

You will have follow-up visits every month once you are off study. These visits will
continue indefinitely. At these visits, you will have the following tests and procedures
performed.

- Your complete medical history will be recorded.

- You will have a physical exam.

- Blood (about 2 teaspoons) and urine will be collected for routine tests.

This is an investigational study. ZD6474 is FDA approved for the treatment of follicular,
medullary, anaplastic, and locally advanced and metastatic papillary thyroid cancer.
Isotretinoin is FDA approved for acne. The use of these drugs for this disease and the use
of the drugs together is investigational. Up to 66 patients will take part in this study.
All will be enrolled at M. D. Anderson.


Inclusion Criteria:



1. Provision of informed consent from subjects or their legal guardians

2. Patients must have had histologic verification of neuroblastoma,
ganglioneuroblastoma, or ganglioneuroma, and/or demonstration of tumor cells in the
bone marrow with increased urinary catecholamines (Vanillylmandelic Acid (VMA) and/or
Homovanillic Acid (HVA)), OR histologic verification of medulloblastoma, 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 magnetic resonance imaging (MRI), computed tomography (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 or medulloblastoma. 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 tumor, OR

4. (Con't # 3): Evaluable disease documented by bone marrow obtained prior to study
entry with tumor cells seen on routine morphology (not by Neuron Specific Enolase
(NSE) staining only) of aspirate and/or biopsy OR

5. (Con't # 3) (for neuroblastoma patients only) Evaluable disease documented by MIBG
(metaiodobenzylguanidine) 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) Absolute neutrophil count (ANC) <750/mm^3, hemoglobin <7.0 g/dL,
platelets <20,000/mm^3 (hemoglobin and platelets may be supported by transfusions);
b) Serum bilirubin >1.5 * institutional upper limit of normal (IULN); c) Serum
creatinine >1.5 * per IULN or creatinine clearance 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 * IULN or alkaline phosphatase (ALP) >2.5 * IULN or > 5 * 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) (>/= National Cancer Institute (NCI) Common
Terminology Criteria for Adverse Events (CTCAE) grade 3) or asymptomatic sustained
ventricular tachycardia. Atrial fibrillation controlled on medication is not
excluded.

4. Previous history of Corrected QT (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
Electrocardiography (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.

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Maximum tolerated dose (MTD)

Outcome Description:

MTD is highest dose level in which 6 participants have been treated with at most 2 experiencing dose limiting toxicity (DLT).

Outcome Time Frame:

28 day cycles, first 2 cycles used to determine dose-limiting toxicity

Safety Issue:

Yes

Principal Investigator

Peter E. Zage, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

M.D. Anderson Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

2006-0807

NCT ID:

NCT00533169

Start Date:

September 2007

Completion Date:

February 2011

Related Keywords:

  • Neuroblastoma
  • Neuroblastoma
  • ZD6474
  • Zactima
  • Isotretinoin
  • 13-Cis Retinoic Acid
  • Accutane
  • Pediatric Neuroblastoma
  • Neuroblastoma

Name

Location

U.T.M.D. Anderson Cancer CenterHouston, Texas  77030