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

Phase 1

Completed

Conditions: Recurrent Childhood Anaplastic Large Cell Lymphoma
Recurrent Neuroblastoma
Recurrent Malignant Solid Neoplasm
Refractory Anaplastic Large Cell Lymphoma
Refractory Neuroblastoma
Refractory Malignant Solid Neoplasm

Interventions: Drug: Crizotinib
Other: Laboratory Biomarker Analysis
Other: Pharmacological Study
Other: Questionnaire Administration

Registration Number: NCT00939770

Lead Sponsor: Children's Oncology Group

Brief Summary: This phase 1/2 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 1 completed 2/15/13)

Detailed Description: PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) and recommend a Phase 2 dose of 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 Crizotinib administered on this schedule.

III. To characterize the pharmacokinetics of Crizotinib in children with refractory cancer.

SECONDARY OBJECTIVES:

I. To preliminarily define the anti-tumor activity of Crizotinib 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 Crizotinib 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 Crizotinib.

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

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

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

OUTLINE: This is a phase 1 dose-escalation study (completed 2/15/13) followed by a phase 2 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 122

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 Crizotinib
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 Crizotinib
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 Crizotinib 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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Treatment (crizotinib)	Laboratory Biomarker Analysis	Patients receive crizotinib PO BID on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
Treatment (crizotinib)	Pharmacological Study	Patients receive crizotinib PO BID on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
Treatment (crizotinib)	Questionnaire Administration	Patients receive crizotinib PO BID on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
Treatment (crizotinib)	Crizotinib	Patients receive crizotinib PO BID on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Maximum-tolerated Dose and Recommended Phase 2 Dose of Crizotinib	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.
Number of Participants With Toxicities of Crizotinib	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.
Steady State C Max of Crizotinib	Cycle 1 (day 15- 28) pre-dose, 1, 2,4, 6-8 hours post dose	Mean with standard deviation of peak of serum concentration curve at steady state by dose level.
Steady State C Average of Crizotinib	Cycle 1 (day 15-28) pre-dose, 1, 2, 4, 6-8 hours post-dose	Mean with standard deviation of average serum concentration curve at steady state by dose level.
Steady State AUC of Crizotinib	Cycle 1 (day 15-28) pre-dose, 1, 2, 4, 6-8 hours post-dose	Mean with standard deviation of area under the serum concentration curve at steady state by dose level.
Steady State Clearance of Crizotinib	Cycle 1 (day 15-28) pre-dose, 1, 2, 4, 6-8 hour post-dose	Mean with standard deviation of the elimination of crizotinib at steady state by dose level.

Secondary Outcome Measures

Name	Time	Method
Number of Participants (Relapsed or Refractory Neuroblastoma or Anaplastic Large Cell Lymphoma (ALCL)) With Response to Crizotinib	Up to 8 years	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR
Number of Participants With Minimum Residual Disease (MRD)	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.
Number of Participants (Relapsed or Refractory Solid Tumors or Anaplastic Large Cell Lymphoma (ALCL))With Response to Crizotinib	Up to 8 years	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR

Trial Locations

Locations (28): Nationwide Children's Hospital
🇺🇸
Columbus, Ohio, United States
Children's Hospital of Philadelphia
🇺🇸
Philadelphia, Pennsylvania, United States
Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
🇺🇸
Houston, Texas, United States
Cincinnati Children's Hospital Medical Center
🇺🇸
Cincinnati, Ohio, United States
Children's National Medical Center
🇺🇸
Washington, District of Columbia, United States
Dana-Farber Cancer Institute
🇺🇸
Boston, Massachusetts, United States
St. Jude Children's Research Hospital
🇺🇸
Memphis, Tennessee, United States
C S Mott Children's Hospital
🇺🇸
Ann Arbor, Michigan, United States
Children's Hospital of Orange County
🇺🇸
Orange, California, United States
Children's Healthcare of Atlanta - Egleston
🇺🇸
Atlanta, Georgia, United States
Lurie Children's Hospital-Chicago
🇺🇸
Chicago, Illinois, United States
Riley Hospital for Children
🇺🇸
Indianapolis, Indiana, United States
Washington University School of Medicine
🇺🇸
Saint Louis, Missouri, United States
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
🇺🇸
New York, New York, United States
Children's Hospital of Pittsburgh of UPMC
🇺🇸
Pittsburgh, Pennsylvania, United States
UT Southwestern/Simmons Cancer Center-Dallas
🇺🇸
Dallas, Texas, United States
Seattle Children's Hospital
🇺🇸
Seattle, Washington, United States
Hospital for Sick Children
🇨🇦
Toronto, Ontario, Canada
University of Alabama at Birmingham Cancer Center
🇺🇸
Birmingham, Alabama, United States
UCSF Medical Center-Mission Bay
🇺🇸
San Francisco, California, United States
Children's Hospital of Alabama
🇺🇸
Birmingham, Alabama, United States
Oregon Health and Science University
🇺🇸
Portland, Oregon, United States
Vanderbilt University/Ingram Cancer Center
🇺🇸
Nashville, Tennessee, United States
UCSF Medical Center-Parnassus
🇺🇸
San Francisco, California, United States
Children's Hospital Colorado
🇺🇸
Aurora, Colorado, United States
National Institutes of Health Clinical Center
🇺🇸
Bethesda, Maryland, United States
University of Minnesota/Masonic Cancer Center
🇺🇸
Minneapolis, Minnesota, United States
Children's Hospital of Wisconsin
🇺🇸
Milwaukee, Wisconsin, United States