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Crizotinib in Treating Younger Patients With Relapsed or Refractory Solid Tumors or Anaplastic Large Cell Lymphoma

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ClinicalTrials.gov Identifier: NCT00939770
Recruitment Status : Completed
First Posted : July 15, 2009
Last Update Posted : February 22, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group

Brief Summary:
This phase I/II trial the studies side effects and best dose of crizotinib and to see how well it works in treating young patients with solid tumors or anaplastic large cell lymphoma that has returned after a period of improvement or does not respond to treatment. Crizotinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. (Phase I completed 2/15/13)

Condition or disease Intervention/treatment Phase
ALK Fusion Protein Expression ALK Gene Amplification ALK Gene Mutation ALK Positive c-MET Gene Amplification MET Gene Mutation Recurrent Childhood Anaplastic Large Cell Lymphoma Recurrent Malignant Solid Neoplasm Recurrent Neuroblastoma Refractory Anaplastic Large Cell Lymphoma Refractory Malignant Solid Neoplasm Refractory Neuroblastoma Drug: Crizotinib Other: Laboratory Biomarker Analysis Other: Pharmacological Study Other: Questionnaire Administration Phase 1 Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) and recommend a Phase 2 dose of PF-02341066 (crizotinib) administered orally twice daily to children with relapsed/refractory solid tumors and anaplastic large cell lymphoma (ALCL). (completed 2/15/13) II. To define and describe the toxicities of PF-02341066 administered on this schedule.

III. To characterize the pharmacokinetics of PF-02341066 in children with refractory cancer.

SECONDARY OBJECTIVES:

I. To preliminarily define the anti-tumor activity of PF-02341066 within the confines of a Phase 1 study. (completed 2/15/13) II. To obtain initial Phase 2 data on the anti-tumor activity of PF-02341066 in children with relapsed/refractory neuroblastoma and ALCL.

III. To preliminarily examine the relationship between anaplastic lymphoma kinase (ALK) status (e.g, the presence of a mutation, duplication, amplification, and/or translocation) in patients with neuroblastoma (NB) or ALCL and response to PF-02341066.

IV. To preliminarily examine the relationship between minimal residual disease (MRD) status and clinical response to PF-02341066 in patients with ALCL.

V. To use a questionnaire to gather preliminary information on the palatability of the oral solution formulation of PF-02341066.

VI. To evaluate for potential alterations in bone growth in pediatric patients.

OUTLINE: This is a phase I dose-escalation study (completed 2/15/13) followed by a phase II study.

Patients receive crizotinib orally (PO) twice daily (BID) on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

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


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 122 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2 Study of PF-02341066, an Oral Small Molecule Inhibitor of Anaplastic Lymphoma Kinase (ALK) and C-Met, in Children With Relapsed/Refractory Solid Tumors and Anaplastic Large Cell Lymphoma
Actual Study Start Date : September 21, 2009
Actual Primary Completion Date : December 31, 2018
Actual Study Completion Date : December 31, 2018


Arm Intervention/treatment
Experimental: Treatment (crizotinib)
Patients receive crizotinib PO BID on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: Crizotinib
Given PO
Other Names:
  • MET Tyrosine Kinase Inhibitor PF-02341066
  • PF-02341066
  • PF-2341066
  • Xalkori

Other: Laboratory Biomarker Analysis
Correlative studies

Other: Pharmacological Study
Correlative studies

Other: Questionnaire Administration
Ancillary studies




Primary Outcome Measures :
  1. Maximum-tolerated dose and recommended phase II dose of crizotinib [ Time Frame: 28 days ]
    The descriptions and grading scales found in the revised National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event (AE) reporting. The MTD/RP2D is defined as the maximum dose at which fewer than one-third of patients experience dose limiting toxicity.

  2. Incidence of toxicities of crizotinib [ Time Frame: Up to 30 days post-treatment ]
    The descriptions and grading scales found in the revised NCI CTCAE version 4.0 will be utilized for AE reporting.

  3. PK AUC [ Time Frame: Day 1 of course 1 ]
    Pharmacokinetics of crizotinib: Area under the plasma concentration (AUC).


Secondary Outcome Measures :
  1. Antitumor activity of crizotinib in children with relapsed or refractory solid tumors or anaplastic large cell lymphoma (ALCL) [ Time Frame: Up to 8 years ]
    This study will use a minor modification of the (RECIST) Response Evaluation Criteria in Solid Tumors from the NCI for assessment of radiographic response.

  2. Antitumor activity of crizotinib in children with relapsed or refractory neuroblastoma or anaplastic large cell lymphoma (ALCL) [ Time Frame: Up to 8 years ]
    This study will use a minor modification of the RECIST from the NCI for assessment of radiographic response.

  3. Minimal residual disease (MRD) status [ Time Frame: Up to 8 years ]
    MRD status will be reported descriptively. The relationship between MRD status and clinical response to treatment will be examined in children with ALCL.



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Ages Eligible for Study:   13 Months to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients receiving the formulated capsules must have a body surface area (BSA) >= 0.63 m^2 at the time of study enrollment
  • Patients must have had histologic verification of malignancy at original diagnosis or relapse
  • * Phase 1 (Part A1) - COMPLETE: Patients with relapsed or refractory solid tumors or anaplastic large cell lymphoma (excluding patients with primary or metastatic central nervous system [CNS] tumors or patients with primary cutaneous ALCL)
  • * Phase 1 (Part A2) - COMPLETE: Patients with confirmed ALK fusion proteins, ALK mutations, ALK amplification (defined as greater than 4-fold increase in the ALK signal number as compared to reference signal number on chromosome 2q arm) or MET proto-oncogene, receptor tyrosine kinase (MET) mutation or amplification; testing to confirm the presence of ALK fusion proteins, ALK mutations, ALK amplification or evidence of MET mutation or amplification for eligibility purposes must be performed as a Clinical Laboratory Improvement Act (CLIA)-certified assay; ALK immunohistochemistry can be used as a surrogate for fluorescent in situ hybridization (FISH) for patients with inflammatory myofibroblastic tumors (IMT) or ALCL
  • ** Note: Evidence for MET mutation or amplification is defined as:

    • Positive for c-Met amplification by FISH; or
    • Positive for known c-Met kinase domain activating mutations including V1110L, H1112L, H1112Y, H1124D, M1149T, T1191I, V1206L, L1213V, V1238I, M1268T, P1009S, T1010I, R988C, V941L, but excluding Y1248C, Y1248H, Y1248D, and Y1253D; or
    • Chromosomal translocations that lead to altered transcriptional regulation of c-Met and/or hepatocyte growth factor (HGF) including metastatic alveolar soft part sarcoma, clear cell sarcoma, rhabdomyosarcoma, or translocation associated renal cell carcinoma)
  • * Phase 1 (Part A3) - COMPLETE: Patients with relapsed or refractory neuroblastoma, with or without bone marrow involvement, who are not eligible for Part A1 or A2 or cannot enroll on Part A1 because of stratum suspension or lack of available slots (these patients will be enrolled at one dose level below the dose level at which patients on Part A1 are actively enrolling)
  • * Phase 2 (Part B): Patients with ALK+ relapsed or refractory neuroblastoma
  • * Phase 2 (Part C): Patients with ALK+ relapsed or refractory ALCL (excluding patients with primary cutaneous ALCL)
  • * Phase 2 (Part A2): Patients with diagnoses other than neuroblastoma or ALCL with confirmed ALK fusion proteins, ALK mutations, ALK amplification (defined as greater than 4-fold increase in the ALK signal number as compared to reference signal number on chromosome 2q arm) or MET mutation or amplification; testing to confirm the presence of ALK fusion proteins, ALK mutations, ALK amplification or evidence of MET mutation or amplification for eligibility purposes must be performed as a CLIA-certified assay; ALK immunohistochemistry can be used as a surrogate for FISH for patients with IMT
  • Disease status:

    • Phase 1 (Part A): Patients must have either measurable and/or evaluable disease
    • Phase 2 (Part B): Patients with neuroblastoma must have proven ALK+ disease with either measurable and/or evaluable disease as indicated below:

      • Measurable tumor on magnetic resonance imaging (MRI), computed tomography (CT) scan or X-ray obtained within 2 weeks prior to study enrollment
      • Evaluable tumor by meta-iodobenzyl guanidine I 123 (MIBG) scan and/or bone marrow involvement with tumor cells seen on routine morphology
    • Phase 2 (Part C): Patients must have proven ALK+ disease with either measurable or evaluable disease
  • Performance level: Karnofsky >= 50 for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age); Note: patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
  • Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy:

    • Myelosuppressive chemotherapy:

      • Solid tumors: Patients with solid tumors must not have received chemotherapy within 3 weeks of enrollment onto this study (6 weeks if prior nitrosourea)
      • Lymphoma: Patients with lymphoma who relapse during standard maintenance therapy are eligible at time of relapse; for patients with ALCL who relapse while they are receiving cytotoxic therapy, at least 14 days must have elapsed since the completion of cytotoxic therapy; Note: cytoreduction with hydroxyurea can be initiated and continued for up to 24 hours prior to the start of PF-02341066
  • At least 7 days since the completion of therapy with a growth factor
  • At least 7 days since the completion of therapy with a biologic agent; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur; the duration of this interval must be discussed with the study chair
  • At least 7 days or 3 half-lives, whichever is longer, must have elapsed since prior treatment with a monoclonal antibody
  • >= 2 weeks (wks) for local palliative radiation therapy (XRT) (small port); >= 6 weeks must have elapsed since treatment with therapeutic doses of MIBG; >= 6 months must have elapsed if prior total body irradiation (TBI), craniospinal XRT or >= 50% radiation of pelvis; >= 6 wks must have elapsed if other substantial bone marrow (BM) radiation
  • Bone marrow/stem cell transplant or infusion without TBI:

    • Part A1 or Part C: No evidence of active graft vs host disease and >= 3 months must have elapsed since stem cell transplant or infusion
    • Part A2, Part A3, or Part B: No evidence of active graft vs host disease and >= 6 weeks must have elapsed since stem cell transplant or infusion
  • At least 42 days after the completion of any type of immunotherapy, e.g. tumor vaccines
  • Patients must not have received prior therapy with PF-02341066
  • Patients on Part A1 or Part C of the study:

    • For patients with solid tumors or ALCL without bone marrow involvement:

      • Peripheral absolute neutrophil count (ANC) >= 1,000/mm^3
      • Platelet count >= 75,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions within a 7 day period prior to enrollment)
      • Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions)
    • Patients with known bone marrow metastatic disease:

      • Peripheral absolute neutrophil count (ANC) >= 750/mm^3
      • Platelet count >= 25,000/mm^3 (may receive platelet transfusions)
      • Hemoglobin >= 8.0 g/dL (may receive RBC transfusions)
      • Not known to be refractory to RBC or platelet transfusions Transfusions are permitted to meet both the platelet and hemoglobin criteria; Note: patients with known bone marrow metastatic disease are not evaluable for hematological toxicity for the purposes of dose escalation
  • Patients eligible for Part A2, Part A3, or Part B of the study must meet the hematologic criteria below for enrollment:

    • Peripheral absolute neutrophil count (ANC) >= 750/mm^3
    • Platelet count >= 25,000/mm^3 (may receive platelet transfusions)
    • Hemoglobin >= 8.0 g/dL (may receive RBC transfusions)
    • Not known to be refractory to red cell or platelet transfusions Transfusions are permitted to meet both the platelet and hemoglobin criteria
  • Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 ml/min/1.73 m^2 or a serum creatinine based on age/gender as follows:

    • 1 to < 2 years: 0.6 mg/dL
    • 2 to < 6 years: 0.8 mg/dL
    • 6 to < 10 years: 1 mg/dL
    • 10 to < 13 years: 1.2 mg/dL
    • 13 to < 16 years: 1.5 mg/dL (male), 1.4 mg/dL (female)
    • >= 16 years: 1.7 mg/dL (male), 1.4 mg/dL (female)
  • Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age
  • Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 110 U/L; for the purpose of this study, the ULN for SGPT is 45 U/L
  • Serum albumin >= 2 g/dL
  • Corrected QT interval (QTc) =< 480 msec
  • All patients and/or their parents or legal guardians must sign a written informed consent; assent, when appropriate, will be obtained according to institutional guidelines
  • Patients taking the capsule formulation must be able to swallow capsules; feeding tube administration is allowed for patients receiving the oral solution (OS)

Exclusion Criteria:

  • Pregnant or breast-feeding women will not be entered on this study; pregnancy tests must be obtained in girls who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method
  • Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for the prior 7 days are not eligible
  • Patients who are currently receiving another investigational drug are not eligible
  • Patients who are currently receiving other anti-cancer agents, with the exception of hydroxyurea for patients with ALCL, are not eligible
  • As PF-02341066 is an inhibitor of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4), patients chronically receiving medications known to be metabolized by CYP3A4 and with narrow therapeutic indices including pimozide, aripiprazole, triazolam, ergotamine and halofantrine are not eligible; the topical use of these medications (if applicable) is allowed
  • Patients chronically receiving drugs that are known potent CYP3A4 inhibitors within 7 days prior to study enrollment, including but not limited to, ketoconazole, itraconazole, miconazole, clarithromycin, erythromycin, ritonavir, indinavir, nelfinavir, saquinavir, amprenavir, delavirdine, nefazodone, diltiazem, verapamil, and grapefruit juice are not eligible; the topical use of these medications (if applicable), e.g. 2% ketoconazole cream, is allowed
  • Patients chronically receiving drugs that are known potent CYP3A4 inducers within 12 days prior to study enrollment, including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, tipranavir, ritonavir, and St. John?s wort are not eligible; the topical use of these medications (if applicable) is allowed
  • Patients with known interstitial fibrosis or interstitial lung disease are not eligible
  • Patients with a known history of myocardial infarction or cerebrovascular accident are not eligible
  • Patients with central nervous system (CNS) tumors or known CNS metastases are not eligible; patients with a history of CNS metastases that have been surgically resected are eligible only if the baseline evaluation shows no evidence of current CNS metastases; patients with any evidence of CNS metastases on baseline evaluation are not eligible, regardless of whether the lesions have been previously treated and/or appear stable
  • Patients who have an uncontrolled infection are not eligible
  • Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible

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 ClinicalTrials.gov identifier (NCT number): NCT00939770


  Show 28 Study Locations
Sponsors and Collaborators
Children's Oncology Group
National Cancer Institute (NCI)
Investigators
Principal Investigator: Yael P Mosse COG Phase I Consortium

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Children's Oncology Group
ClinicalTrials.gov Identifier: NCT00939770     History of Changes
Obsolete Identifiers: NCT01182896
Other Study ID Numbers: ADVL0912
NCI-2011-01937 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
COG-ADVL0912
P10666
CDR0000647587
ADVL0912 ( Other Identifier: COG Phase I Consortium )
ADVL0912 ( Other Identifier: CTEP )
UM1CA097452 ( U.S. NIH Grant/Contract )
First Posted: July 15, 2009    Key Record Dates
Last Update Posted: February 22, 2019
Last Verified: January 2019

Additional relevant MeSH terms:
Lymphoma
Neoplasms
Lymphoma, Non-Hodgkin
Neuroblastoma
Lymphoma, Large-Cell, Anaplastic
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Neuroectodermal Tumors, Primitive, Peripheral
Neuroectodermal Tumors, Primitive
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Lymphoma, T-Cell
Crizotinib
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action