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

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Basic Trial Information

PhaseTypeAgeTrial IDs
Phase II, Phase IBiomarker/Laboratory analysis, Treatment1 to 21ADVL0912
NCI-2011-01937, CDR0000647587, COG-ADVL0912, NCT01182896, P10666, NCT00939770

Trial Description

Summary

This phase I/II trial is studying the 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)

Further Study Information

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.

Eligibility Criteria

Inclusion Criteria:

Patients taking the capsule formulation must be able to swallow capsules; feeding tube administration is allowed for patients receiving the oral solution (OS)

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

Corrected QT interval (QTc) =< 480 msec

Serum albumin >= 2 g/dL

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)

Patients eligible for Part A2, Part A3, or Part B of the study must meet the hematologic criteria below for enrollment:

Peripheral 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

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:

  • 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

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

>= 2 weeks 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 weeks must have elapsed if other substantial bone marrow (BM) radiation

At least 7 days or 3 half-lives, whichever is longer, must have elapsed since prior treatment with a monoclonal antibody

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 since the completion of therapy with a growth factor

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

Performance level: Karnofsky >= 50 for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age); Note: Patients who are up in a wheelchair and are unable to walk due to paralysis will be considered ambulatory for the purpose of assessing the performance score

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

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

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)

  • 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 HGF including metastatic alveolar soft part sarcoma, clear cell sarcoma, rhabdomyosarcoma, or translocation associated renal cell carcinoma)

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 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

Patients must have had histologic verification of malignancy at original diagnosis or relapse

Patients receiving the formulated capsules must have a body surface area (BSA) >= 0.63 m^2 at the time of study enrollment

Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age

Patients must not have received prior therapy with PF-02341066

At least 42 days after the completion of any type of immunotherapy, e.g. tumor vaccines

Phase 2 (Part C): Patients with ALK+ relapsed or refractory ALCL (excluding patients with primary cutaneous ALCL)

Phase 2 (Part B): Patients with ALK+ relapsed or refractory neuroblastoma

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)

Phase 1 (Part A1) - COMPLETE: Patients with relapsed or refractory solid tumors or anaplastic large cell lymphoma (ALCL) (excluding patients with primary or metastatic central nervous system [CNS] tumors or patients with primary cutaneous ALCL)

Exclusion Criteria:

Patients who have an uncontrolled infection 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 with a known history of myocardial infarction or cerebrovascular accident are not eligible

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 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

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 who are currently receiving other anti-cancer agents, with the exception of hydroxyurea for patients with ALCL, are not eligible

Patients who are currently receiving another investigational drug are not eligible

Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for the prior 7 days are not eligible

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 who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible

Patients with known interstitial fibrosis or interstitial lung disease are not eligible

Trial Contact Information

Trial Lead Organizations / Sponsors / Collaborators

COG Phase I Consortium

  • National Cancer Institute
Yael P. Mosse, Principal Investigator

Trial Sites

U.S.A.

Alabama
Birmingham

Children's Hospital of Alabama

Alyssa Terry Reddy
Ph: 205-934-0309

Alyssa Terry Reddy
Principal Investigator

California
Orange

Childrens Hospital of Orange County

Ivan I. Kirov
Ph: 714-997-3000

Ivan I. Kirov
Principal Investigator

San Francisco

UCSF Medical Center-Mission Bay

Steven G. DuBois
Ph: 877-827-3222

Steven G. DuBois
Principal Investigator

Colorado
Aurora

Children's Hospital Colorado

Lia Gore
Ph: 720-777-6672

Lia Gore
Principal Investigator

District of Columbia
Washington

Children's National Medical Center

Jeffrey Stuart Dome
Ph: 202-884-2549

Jeffrey Stuart Dome
Principal Investigator

Georgia
Atlanta

Children's Healthcare of Atlanta - Egleston

Cynthia J. Wetmore
Ph: 888-785-1112

Cynthia J. Wetmore
Principal Investigator

Illinois
Chicago

Lurie Children's Hospital-Chicago

Stewart Goldman
Ph: 773-880-4562

Stewart Goldman
Principal Investigator

Indiana
Indianapolis

Riley Hospital for Children

James Merrill Croop
Ph: 317-274-2552

James Merrill Croop
Principal Investigator

Massachusetts
Boston

Dana-Farber Cancer Institute

Suzanne Shusterman
Ph: 877-442-3324

Suzanne Shusterman
Principal Investigator

Minnesota
Minneapolis

University of Minnesota Medical Center-Fairview

Emily G. Greengard
Ph: 612-624-2620

Emily G. Greengard
Principal Investigator

Missouri
Saint Louis

Washington University School of Medicine

Robert J. Hayashi
Ph: 800-600-3606
Email: info@siteman.wustl.edu

Robert J. Hayashi
Principal Investigator

New York
New York

Columbia University Medical Center

Julia Glade-Bender
Ph: 212-305-8615

Julia Glade-Bender
Principal Investigator

Ohio
Columbus

Nationwide Children's Hospital

Mark Anthony Ranalli
Ph: 614-722-2708

Mark Anthony Ranalli
Principal Investigator

Oregon
Portland

Oregon Health and Science University

Suman Malempati
Ph: 503-494-1080
Email: trials@ohsu.edu

Suman Malempati
Principal Investigator

Pennsylvania
Philadelphia

Children's Hospital of Philadelphia

Elizabeth Fox
Ph: 215-590-2810

Elizabeth Fox
Principal Investigator

Pittsburgh

Children's Hospital of Pittsburgh of UPMC

Jean M. Tersak
Ph: 412-692-5573

Jean M. Tersak
Principal Investigator

Tennessee
Memphis

St. Jude Children's Research Hospital

Wayne Lee Furman
Ph: 866-278-5833
Email: info@stjude.org

Wayne Lee Furman
Principal Investigator

Nashville

Vanderbilt University/Ingram Cancer Center

Scott C. Borinstein
Ph: 800-811-8480

Scott C. Borinstein
Principal Investigator

Texas
Houston

Baylor College of Medicine

Karen Ruth Rabin
Ph: 713-798-1354
Email: burton@bcm.edu

Karen Ruth Rabin
Principal Investigator

Washington
Seattle

Seattle Children's Hospital

Julie Ruggieri Park
Ph: 866-987-2000

Julie Ruggieri Park
Principal Investigator

Wisconsin
Milwaukee

Midwest Children's Cancer Center

Michael Edward Kelly
Ph: 414-805-4380

Michael Edward Kelly
Principal Investigator

Canada

Ontario
Toronto

Hospital for Sick Children

Sylvain Baruchel
Ph: 416-813-7654ext2027
Email: jason.mcguire@sickkids.ca

Sylvain Baruchel
Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00939770

Note: Information about participating sites on pharmaceutical industry trials may be incomplete. Please visit the ClinicalTrials.gov record via the link above for more information about participating sites.