|Phase I||Biomarker/Laboratory analysis, Treatment||Active||13 months to 21 years||NCI, Other||ADVL1212|
NCI-2012-01968, U01CA097452, COG-ADVL1212, NCT01606878
This phase I trial studies the side effects and the best dose of crizotinib giving together with combination chemotherapy in treating younger patients with relapsed or refractory solid tumors or anaplastic large cell lymphoma. 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 or by stopping them from dividing
Further Study Information
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 and doxorubicin/dexrazoxane 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 refractory cancer when combined with either topotecan and cyclophosphamide or vincristine and doxorubicin/dexrazoxane.
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.
OUTLINE: This is a dose-escalation study of crizotinib. Patients are assigned to part A or part B study based on the treating physician's choice and availability of a reservation.
Part A: Patients receive crizotinib orally (PO) twice daily (BID) on days 1-21, cyclophosphamide IV once daily (QD) on days 1-5, topotecan hydrochloride IV QD on days 1-5, and filgrastim or pegfilgrastim beginning on day 6 and continuing until blood count recovers. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
Part B: Patients receive crizotinib PO BID as in part A. Patients also receive vincristine sulfate IV on day 1, dexrazoxane hydrochloride IV on day 1, doxorubicin hydrochloride IV over 15 minutes on day 1, and filgrastim or pegfilgrastim beginning on day 2 and continuing until blood count recovers. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 30 days.
- 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
- Patients must have either measurable or evaluable disease
- 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 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
- Karnofsky ≥ 60% for patients > 16 years of age and Lansky ≥ 50% for patients ≤ 16 years of age (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)
- For patients with solid tumors or ALCL without known bone marrow involvement:
- Peripheral absolute neutrophil count (ANC) ≥ 1,000/mm³
- Platelet count ≥ 100,000/mm³ (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
- Patients with known bone marrow metastatic disease will be eligible for study provided they meet the blood count criteria (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
- Creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 70 mL/min OR a serum creatinine based on age/gender as follows:
- 0.6 mg/dL (1 to < 2 years of age)
- 0.8 mg/dL (2 to < 6 years of age)
- 1.0 mg/dL (6 to < 10 years of age)
- 1.2 mg/dL (10 to < 13 years of age)
- 1.5 mg/dL (male) or 1.4 mg/dL (female) (13 to < 16 years of age)
- 1.7 mg/dL (male) or 1.4 mg/dL (female) ≥ 16 years of age)
- Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN) for age
- Serum glutamic 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
- QTc ≤ 480 msec
- Shortening fraction of ≥ 27% by echocardiogram or ejection fraction of ≥ 50% by gated radionuclide study
- 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
- Patients must be able to swallow liquid; nasogastric or gastric (G) tube administration is allowed
- 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
- See Disease Characteristics
- Patients must have fully recovered from the acute toxic effects of all prior anti-cancer chemotherapy
- Solid tumors: At least 21 days since the last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea)
- 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
- 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
- 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
- At least 42 days since the completion of any type of immunotherapy, e.g., tumor vaccines
- At least 3 half-lives of the antibody after the last dose of a monoclonal antibody
- Solid tumors: At least 14 days since prior local palliative radiotherapy (XRT) (small port); ≥ 6 weeks must have elapsed since treatment with therapeutic doses of I^131 iobenguane (MIBG); at least 150 days must have elapsed if prior total-body irradiation (TBI), craniospinal XRT, or ≥ 50% radiation to 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 ≥ 50% radiation to pelvis; at least 42 days must have elapsed if other substantial BM radiation
- No evidence of active graft-vs-host disease and at least 84 days must have elapsed after stem cell transplant without TBI and ≥ 42 days for autologous stem cell infusion after I^131-MIBG therapy
- Patients must not have received prior therapy with crizotinib
- Patients with a total lifetime cumulative anthracycline dose of > 650 mg/m² at the time of enrollment are not eligible for Part B of the study
- 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
- Patients who are currently receiving another investigational drug are not eligible
- Patients who are currently receiving other anticancer agents including chemotherapy, radiotherapy, immunotherapy, or biologic therapy are not eligible
- 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
- As crizotinib is an inhibitor of cytochrome P450 3A4 (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
- 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
- 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 wort are not eligible
- Patients who have received a prior solid organ transplantation are not eligible
Trial Lead Organizations/Sponsors
Children's Oncology GroupNational Cancer Institute
|Emily Lipsitz||Principal Investigator|
|Children's Hospital of Alabama at University of Alabama at Birmingham|
|Joseph G Pressey||Ph: 205-934-0309|
|Children's Oncology Group|
|Children's Hospital of Orange County|
|Violet Shen||Ph: 714-997-3000|
|UCSF Helen Diller Family Comprehensive Cancer Center|
|Steven G DuBois||Ph: 877-827-3222|
|District of Columbia|
|Children's National Medical Center|
|Jeffrey S Dome||Ph: 202-884-2549|
|AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus|
|Glen Lew||Ph: 404-785-1112|
|Ann and Robert H. Lurie Children's Hospital of Chicago|
|Stewart Goldman||Ph: 773-880-4562|
|Riley's Children Cancer Center at Riley Hospital for Children|
|James M Croop||Ph: 317-274-2552|
|C.S. Mott Children's Hospital at University of Michigan Medical Center|
|Rajen Mody||Ph: 800-865-1125|
|Masonic Cancer Center at University of Minnesota|
|Emily G Greengard||Ph: 612-624-2620|
|Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis|
|Robert J Hayashi||Ph: 800-600-3606|
|Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center|
|Julia G Bender||Ph: 212-305-8615|
|Cincinnati Children's Hospital Medical Center|
|John P Perentesis||Ph: 513-636-2799|
|Knight Cancer Institute at Oregon Health and Science University|
|Linda C. Stork||Ph: 503-494-1080|
|Children's Hospital of Philadelphia|
|Elizabeth Fox||Ph: 215-590-2810|
|Children's Hospital of Pittsburgh of UPMC|
|Arthur K Ritchey||Ph: 412-692-5573|
|St. Jude Children's Research Hospital|
|Wayne L Furman||Ph: 901-595-4644|
|Dan L. Duncan Cancer Center at Baylor College of Medicine|
|Lisa R Bomgaars||Ph: 713-798-1354|
|Children's Hospital and Regional Medical Center - Seattle|
|Julie R Park||Ph: 866-987-2000|
|Midwest Children's Cancer Center at Children's Hospital of Wisconsin|
|Michael E Kelly||Ph: 414-805-4380|
|Hospital for Sick Children|
|Sylvain Baruchel||Ph: 416-813-7654ext2027|
Link to the current ClinicalTrials.gov record.
NLM Identifer NCT01606878
ClinicalTrials.gov processed this data on October 17, 2013
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