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A Phase I/II Study of PF-02341066, an Oral Small Molecule Inhibitor of Anaplastic Lymphoma Kinase (ALK) and c-Met, in Children With Relapsed/Refractory Solid Tumors, Primary CNS Tumors, and Anaplastic Large Cell Lymphoma

Phase 1/Phase 2
1 Year
21 Years
Open (Enrolling)
Brain and Central Nervous System Tumors, Lymphoma, Neuroblastoma, Unspecified Childhood Solid Tumor, Protocol Specific

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Trial Information

A Phase I/II Study of PF-02341066, an Oral Small Molecule Inhibitor of Anaplastic Lymphoma Kinase (ALK) and c-Met, in Children With Relapsed/Refractory Solid Tumors, Primary CNS Tumors, and Anaplastic Large Cell Lymphoma



- To estimate the maximum-tolerated dose and recommended phase II dose of crizotinib
administered orally twice daily to children with relapsed or refractory solid tumors or
anaplastic large cell lymphoma (ALCL).

- To define and describe the toxicities of this drug when administered on this schedule.

- To characterize the pharmacokinetics of this drug in these patients.


- To preliminarily define the antitumor activity of this drug within the confines of a
phase I study.

- To obtain initial phase II data on the antitumor activity of this drug in children with
relapsed or refractory neuroblastoma or ALCL.

- To preliminarily examine the relationship between response to treatment and anaplastic
lymphoma kinase gene status (e.g., the presence of a mutation, duplication,
amplification, and/or translocation) in children with relapsed or refractory
neuroblastoma or ALCL.

- To preliminarily examine the relationship between minimal residual disease status and
clinical response to treatment in children with ALCL.

OUTLINE: This is a multicenter, phase I dose-escalation study followed by a phase II study.

Patients receive oral crizotinib twice daily on days 1-28. Treatment repeats every 28 days
in the absence of disease progression or unacceptable toxicity.

Plasma and whole blood samples are collected for pharmacokinetic and pharmacogenomic
analysis. Tumor tissue (from patients with neuroblastoma) and bone marrow and/or peripheral
blood (from patients with anaplastic large cell lymphoma) samples are collected for further
correlative laboratory studies.

After completion of study treatment, patients are followed up periodically.

Inclusion Criteria


- Histologically confirmed* malignancy at original diagnosis or relapse, including the

- Solid tumors (phase I)

- CNS tumors (phase I)

- Neurologic deficits must have been relatively stable for ≥ 1 week before
study enrollment

- Anaplastic large cell lymphoma (ALCL) (phase I or II)

- No primary cutaneous ALCL

- Confirmed anaplastic lymphoma kinase (ALK) fusion proteins, ALK mutations, or
ALK amplification (defined as > 4-fold increase in the ALK signal number as
compared to reference signal number on chromosome 2q arm) (phase I)

- Neuroblastoma (phase I or II) NOTE: *Histologic confirmation is not required for
patients with diffuse intrinsic brain stem tumors, optic pathway tumors, or
pineal region tumors with elevations of serum or CSF tumor markers (e.g.,
alpha-fetoprotein or beta-HCG).

- Relapsed or refractory disease

- Measurable and/or evaluable disease

- Patients with neuroblastoma must have measurable tumor on MRI, CT scan, or x-ray
obtained within the past 2 weeks and/or evaluable tumor by MIBG scan and/or bone
marrow involvement with tumor cells seen on routine morphology

- Patients with ALCL enrolled in the phase II portion of the trial must have
measurable disease

- No known curative therapy or therapy proven to prolong survival with an acceptable
quality of life exists


- Karnofsky performance status (PS) 50-100% (for patients > 16 years of age) or Lansky
PS 50-100% (for patients ≤ 16 years of age)

- Patients who are up in a wheelchair and are unable to walk due to paralysis will
be considered ambulatory for the purpose of assessing PS

- ANC ≥ 1,000/mm^3 (≥ 750/mm^3 in patients with metastatic bone marrow disease)

- Platelet count ≥ 75,000/mm^3 (transfusion independent, defined as no platelet
transfusions within the past 7 days) in patients without bone marrow involvement OR ≥
25,000/mm^3 (platelet transfusions allowed) in patients with metastatic bone marrow

- Hemoglobin ≥ 8.0 g/dL (RBC transfusions allowed)

- Creatinine clearance or radioisotope GFR ≥ 70 mL/min OR serum creatinine based on
age/gender as follows:

- ≤ 0.6 mg/dL (for patients 1 year of age)

- ≤ 0.8 mg/dL (for patients 2 to 5 years of age)

- ≤ 1.0 mg/dL (for patients 6 to 9 years of age)

- ≤ 1.2 mg/dL (for patients 10 to 12 years of age)

- ≤ 1.4 mg/dL (for female patients ≥ 13 years of age)

- ≤ 1.5 mg/dL (for male patients 13 to 15 years of age)

- ≤ 1.7 mg/dL (for male patients ≥ 16 years of age)

- Bilirubin (sum of conjugated and unconjugated) ≤ 1.5 times upper limit of normal for

- SGPT ≤ 110 U/L

- Serum albumin ≥ 2 g/dL

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- Body surface area ≥ 0.4 mm² (for patients enrolled at dose levels 0 and 1 only)

- Able to swallow capsules or a liquid suspension/solution

- Able to comply with the safety monitoring requirements of the study, in the opinion
of the investigator

- No uncontrolled infection

- No evidence of active graft vs host disease

- Not refractory to red cell or platelet transfusion (in patients with metastatic bone
marrow disease)


- Recovered from prior chemotherapy, immunotherapy, or radiotherapy

- No prior crizotinib

- At least 6 months since prior total-body radiotherapy (TBI), craniospinal
radiotherapy, or radiotherapy to ≥ 50% of the pelvis

- At least 3 months since prior bone marrow or stem cell transplant (without TBI) (≥ 6
weeks for patients with neuroblastoma or patients with confirmed ALK fusion proteins,
ALK mutations, or ALK amplification)

- No evidence of active graft-vs-host disease

- At least 6 weeks since prior therapeutic doses of MIBG

- At least 6 weeks since other prior substantial bone marrow radiotherapy

- At least 2 weeks since prior local palliative radiotherapy (small port)

- More than 3 weeks since prior myelosuppressive chemotherapy (6 weeks for
nitrosoureas) for patients with solid tumors

- At least 14 days since prior cytotoxic therapy for patients with ALCL who relapse
while receiving cytotoxic therapy

- Patients with lymphoma who relapse during standard maintenance therapy are
eligible at time of relapse

- Cytoreduction with hydroxyurea may be initiated and continued for up to 24 hours
before the start of study treatment

- At least 7 days since prior growth factor therapy

- At least 7 days since prior biological agents

- At least 7 days or 3 half-lives (whichever is longer) since prior monoclonal antibody

- More than 12 days since prior and no concurrent potent CYP3A4 inducers including, but
not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin,
tipranavir, ritonavir, or St. John wort

- More than 7 days since prior and no concurrent potent CYP3A4 inhibitors including,
but not limited to ketoconazole, itraconazole, miconazole, clarithromycin,
erythromycin, ritonavir, indinavir, nelfinavir, saquinavir, amprenavir, delavirdine,
nefazodone, diltiazem, verapamil, or grapefruit juice

- No concurrent medications known to be metabolized by CYP3A4 with narrow therapeutic
indices, including pimozide, aripiprazole, triazolam, ergotamine, and halofantrine

- No other concurrent anticancer therapy (including chemotherapy, radiotherapy,
immunotherapy, or biologic therapy), except for hydroxyurea for patients with ALCL or
decadron for patients with CNS tumors

- No other concurrent investigational drugs

- Concurrent corticosteroids for CNS tumors allowed provided the dose has been stable
or decreasing for the past 7 days

Type of Study:


Study Design:

Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum-tolerated dose and recommended phase II dose of crizotinib in children with relapsed or refractory solid tumors or anaplastic large cell lymphoma (ALCL)

Safety Issue:


Principal Investigator

Yael P. Mosse, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Children's Hospital of Philadelphia



Study ID:




Start Date:

September 2009

Completion Date:

Related Keywords:

  • Brain and Central Nervous System Tumors
  • Lymphoma
  • Neuroblastoma
  • Unspecified Childhood Solid Tumor, Protocol Specific
  • unspecified childhood solid tumor, protocol specific
  • recurrent neuroblastoma
  • recurrent childhood anaplastic large cell lymphoma
  • recurrent childhood brain stem glioma
  • recurrent childhood cerebellar astrocytoma
  • recurrent childhood cerebral astrocytoma
  • recurrent childhood anaplastic astrocytoma
  • recurrent childhood anaplastic oligoastrocytoma
  • recurrent childhood anaplastic oligodendroglioma
  • recurrent childhood fibrillary astrocytoma
  • recurrent childhood gemistocytic astrocytoma
  • recurrent childhood giant cell glioblastoma
  • recurrent childhood glioblastoma
  • recurrent childhood gliomatosis cerebri
  • recurrent childhood gliosarcoma
  • recurrent childhood oligoastrocytoma
  • recurrent childhood oligodendroglioma
  • recurrent childhood pilocytic astrocytoma
  • recurrent childhood pilomyxoid astrocytoma
  • recurrent childhood pleomorphic xanthoastrocytoma
  • recurrent childhood protoplasmic astrocytoma
  • recurrent childhood subependymal giant cell astrocytoma
  • recurrent childhood visual pathway and hypothalamic glioma
  • recurrent childhood visual pathway glioma
  • recurrent childhood medulloblastoma
  • recurrent childhood ependymoma
  • recurrent childhood pineoblastoma
  • recurrent childhood supratentorial primitive neuroectodermal tumor
  • childhood choroid plexus tumor
  • childhood craniopharyngioma
  • childhood ependymoblastoma
  • childhood medulloepithelioma
  • childhood grade I meningioma
  • childhood grade II meningioma
  • childhood grade III meningioma
  • childhood central nervous system germ cell tumor
  • recurrent childhood spinal cord neoplasm
  • childhood infratentorial ependymoma
  • childhood supratentorial ependymoma
  • childhood high-grade cerebellar astrocytoma
  • childhood high-grade cerebral astrocytoma
  • childhood low-grade cerebellar astrocytoma
  • childhood low-grade cerebral astrocytoma
  • childhood atypical teratoid/rhabdoid tumor
  • Lymphoma
  • Lymphoma, Large B-Cell, Diffuse
  • Lymphoma, Non-Hodgkin
  • Nervous System Neoplasms
  • Neuroblastoma
  • Central Nervous System Neoplasms
  • Lymphoma, Large-Cell, Anaplastic
  • Neoplasms



Children's Hospital of Philadelphia Philadelphia, Pennsylvania  19104
Vanderbilt-Ingram Cancer Center Nashville, Tennessee  37232-6838
Children's Hospital of Orange County Orange, California  92668
Children's National Medical Center Washington, District of Columbia  20010-2970
Children's Hospital and Regional Medical Center - Seattle Seattle, Washington  98105
Children's Memorial Hospital - Chicago Chicago, Illinois  60614
St. Jude Children's Research Hospital Memphis, Tennessee  38105-2794
Midwest Children's Cancer Center at Children's Hospital of Wisconsin Milwaukee, Wisconsin  53226
Cincinnati Children's Hospital Medical Center Cincinnati, Ohio  45229-3039
Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas Dallas, Texas  75390
Baylor University Medical Center - Houston Houston, Texas  77030-2399
UCSF Helen Diller Family Comprehensive Cancer Center San Francisco, California  94115
AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus Atlanta, Georgia  30322
Dana-Farber/Harvard Cancer Center at Dana-Farber Cancer Institute Boston, Massachusetts  02115
C.S. Mott Children's Hospital at University of Michigan Medical Center Ann Arbor, Michigan  48109-0286
Masonic Cancer Center at University of Minnesota Minneapolis, Minnesota  55455
Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis St. Louis, Missouri  63110
Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center New York, New York  10032
Nationwide Children's Hospital Columbus, Ohio  43205-2696
Knight Cancer Institute at Oregon Health and Science University Portland, Oregon  97239-3098
Children's Hospital of Pittsburgh of UPMC Pittsburgh, Pennsylvania  15213
Riley's Children Cancer Center at Riley Hospital for Children Indianapolis, Indiana  46202-5225
UAB Comprehensive Cancer Center Birmingham, Alabama  35294
Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office Bethesda, Maryland  20892-1182
Children's Hospital Colorado Center for Cancer and Blood Disorders Aurora, Colorado  80045