Crizotinib and Combination Chemotherapy 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 IBiomarker/Laboratory analysis, Treatment13 months to 21 yearsADVL1212
NCI-2012-01968, CDR0000734059, COG-ADVL1212, NCT01606878

Trial Description

Summary

This phase I trial studies the side effects and the best dose of crizotinib when given together with combination chemotherapy in treating younger patients with solid tumors or anaplastic large cell lymphoma that has returned or does not respond to treatment. Crizotinib may stop the growth of tumor or cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cyclophosphamide, topotecan hydrochloride, dexrazoxane hydrochloride, doxorubicin hydrochloride, and vincristine sulfate, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving crizotinib together with combination chemotherapy may be a better treatment for patients with solid tumors or anaplastic large cell lymphoma.

Further Study Information

PRIMARY OBJECTIVES:

I. To estimate the recommended phase 2 dose (RP2D) or maximum tolerated dose (MTD) of crizotinib administered orally twice daily in combination with topotecan (topotecan hydrochloride) and cyclophosphamide in children with refractory/relapsed solid tumors or anaplastic large cell lymphoma (ALCL).

II. To define and describe the toxicities of crizotinib in combination with topotecan and cyclophosphamide administered on this schedule.

III. To estimate the recommended phase 2 dose (RP2D) or maximum tolerated dose (MTD) of crizotinib administered orally twice daily in combination with vincristine (vincristine sulfate) and doxorubicin (doxorubicin hydrochloride)/dexrazoxane (dexrazoxane hydrochloride) in children with refractory/relapsed solid tumors or ALCL.

IV. To define and describe the toxicities of crizotinib in combination with vincristine and doxorubicin/dexrazoxane administered on this schedule.

V. To characterize the pharmacokinetics of crizotinib in children with relapsed/refractory cancer when combined with either topotecan and cyclophosphamide or vincristine and doxorubicin/dexrazoxane.

SECONDARY OBJECTIVES:

I. To preliminarily define the antitumor activity of crizotinib in combination with either topotecan and cyclophosphamide or vincristine and doxorubicin/dexrazoxane within the confines of a Phase 1 study.

II. To preliminarily examine the relationship between anaplastic lymphoma kinase (ALK) status in patients with neuroblastoma or ALCL and response to crizotinib in combination with either topotecan and cyclophosphamide or vincristine and doxorubicin/dexrazoxane.

III. To preliminarily examine the relationship between minimal residual disease (MRD) status and clinical response to crizotinib in combination with either topotecan and cyclophosphamide or vincristine and doxorubicin/dexrazoxane in patients with ALCL.

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

V. To examine ALK and MET proto-oncogene (c-Met) expression, copy number and mutations status in archival tumor tissue from solid tumor and ALCL patients.

VI. To use a questionnaire to gather information on the acceptability of the crizotinib capsule formulation.

OUTLINE: This is a dose-escalation study of crizotinib. Patients are assigned to Part A or Part B based on the treating physician's choice and availability of a reservation. After closure of Part A and Part B, patients are assigned to Part C.

PART A (CLOSED TO ACCRUAL 10/3/14): Patients receive crizotinib (oral solution) orally (PO) twice daily (BID) on days 1-21, cyclophosphamide intravenously (IV) once daily (QD) on days 1-5, and topotecan hydrochloride IV QD on days 1-5. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.

PART B (CLOSED TO ACCRUAL 10/3/14): Patients receive crizotinib (oral solution) PO BID as in Part A. Patients also receive vincristine sulfate IV on day 1, dexrazoxane hydrochloride IV on day 1, and doxorubicin hydrochloride IV over 15 minutes on day 1. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.

PART C: Patients receive crizotinib (capsule formulation) PO BID, cyclophosphamide IV QD, and topotecan hydrochloride IV QD as in Part A. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.

Eligibility Criteria

Inclusion Criteria:

Tumor tissue must be sent; if tumor tissue is unavailable, the study chair must be notified prior to enrollment

Part C: Patients must have a body surface area (BSA) >= 1.07 m^2 at the time of study enrollment

All patients and/or their parents or legally authorized representatives must sign a written informed consent; assent, when appropriate, will be obtained according to institutional guidelines

For patients on Part B: shortening fraction of >= 27% by echocardiogram or ejection fraction of >= 50% by gated radionuclide study

Corrected QT interval (QTc) =< 480 msec

Serum albumin >= 2 g/dL

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

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:

Age 1 to < 2 years: 0.6 mg/dL

Age 2 to < 6 years: 0.8 mg/dL

Age 6 to < 10 years: 1 mg/dL

Age 10 to < 13 years: 1.2 mg/dL

Age 13 to < 16 years: 1.5 mg/dL (males) and 1.4 mg/dL (females)

Age >= 16 years: 1.7 mg/dL (males) and 1.4 mg/dL (females)

Patients with known bone marrow metastatic disease will be eligible for study provided they meet the blood counts (may receive transfusions provided they are not known to be refractory to red cell or platelet transfusions); these patients will not be evaluable for hematologic toxicity; if dose-limiting hematologic toxicity is observed, all subsequent patients enrolled must be evaluable for hematologic toxicity

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

Peripheral absolute neutrophil count (ANC) >= 1000/mm^3

Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)

Karnofsky >= 60% 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

Patient’s current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life

Patients must have either measurable or evaluable disease

Patients must have had histologic verification of malignancy at original diagnosis or relapse; all patients with relapsed or refractory solid tumors or anaplastic large cell lymphoma (ALCL) are eligible except for patients with primary or metastatic central nervous system (CNS) tumors or patients with primary cutaneous ALCL

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

Patients must have fully recovered from the acute toxic effects of all prior anti-cancer chemotherapy

Myelosuppressive chemotherapy:

  • Solid tumors: at least 21 days after the last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea)
  • ALCL:

*** Patients with ALCL who relapse while receiving standard maintenance chemotherapy will not be required to have a waiting period before enrollment onto this study

*** Patients who relapse while they are not receiving standard maintenance therapy, must have fully recovered from all acute toxic effects of prior therapy; at least 14 days must have elapsed after the completion of cytotoxic therapy

Hematopoietic growth factors: at least 14 days after the last dose of a long-acting growth factor (e.g. Neulasta) or 7 days for short-acting growth factor; 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

Biologic (anti-neoplastic agent): at least 7 days after the last dose of 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

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

Monoclonal antibodies: at least 3 half-lives of the antibody after the last dose of a monoclonal antibody

Radiation therapy (XRT):

  • Solid tumors: at least 14 days after local palliative XRT (small port); >= 6 weeks must have elapsed since treatment with therapeutic doses of metaiodobenzylguanidine (MIBG); at least 150 days must have elapsed if prior total body irradiation (TBI), craniospinal XRT or if >= 50% radiation of pelvis; at least 42 days must have elapsed if other substantial bone marrow (BM) radiation
  • ALCL: at least 14 days after local palliative XRT (small port); at least 84 days must have elapsed if prior TBI, craniospinal XRT or if >= 50% radiation of pelvis; at least 42 days must have elapsed if other substantial BM radiation

Stem cell infusion without TBI: no evidence of active graft vs. host disease and at least 84 days must have elapsed after transplant and >= 42 days for autologous stem cell infusion after iodine (I)131-MIBG therapy

Patients must not have received prior therapy with crizotinib

Prior anthracycline dose: patients with a total lifetime cumulative anthracycline dose of > 650 mg/m^2 at the time of enrollment are not eligible for Part B of the study

Exclusion Criteria:

Part C: Patients must be able to swallow intact capsules

Parts A and B: Patients who are able to swallow liquid or use a nasogastric or gastrostomy (G) tube are 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

Patients who have a primary or metastatic CNS tumor at the time of study enrollment are not eligible; a prior history of metastatic CNS tumor is allowed as long as there is no evidence of CNS disease at study enrollment

Patients who have received a prior solid organ transplantation are not eligible

Patients who have an uncontrolled infection 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

Patients chronically receiving medications known to be metabolized by cytochrome P 450, family 3, subfamily A, polypeptide 4 (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 receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant are not eligible for this trial

Patients who are currently receiving other anti-cancer agents 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 at least 7 days prior to enrollment 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 during treatment and for 3 months after stopping treatment

Trial Contact Information

Trial Lead Organizations / Sponsors / Collaborators

COG Phase I Consortium

  • National Cancer Institute
Emily Greengard, 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

Children's 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

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

Glen Lew
Ph: 404-785-1112

Glen Lew
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

Michigan
Ann Arbor

C S Mott Children's Hospital

Rajen Mody
Ph: 800-865-1125

Rajen Mody
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
Cincinnati

Cincinnati Children's Hospital Medical Center

John Peter Perentesis
Ph: 513-636-2799

John Peter Perentesis
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

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 NCT01606878

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.