A Phase 1 Study of Crizotinib in Combination With Conventional Chemotherapy for Relapsed or Refractory Solid Tumors or Anaplastic Large Cell Lymphoma
Overview
- Phase
- Phase 1
- Intervention
- Crizotinib
- Conditions
- Childhood Solid Neoplasm
- Sponsor
- Children's Oncology Group
- Enrollment
- 46
- Locations
- 23
- Primary Endpoint
- Maximum Tolerated Dose (MTD) of Crizotinib
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief 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.
Detailed Description
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. PART D: Patients receive crizotinib (microsphere 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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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
- •Patients 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
- •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
- •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)
- •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
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 during treatment and for 3 months after stopping treatment
- •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 anti-cancer agents 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
- •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 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 receiving PPIs and H2 blockers are not eligible for Part D
- •Patients who have an uncontrolled infection are not eligible
Arms & Interventions
Part A (crizotinib, cyclophosphamide, topotecan hydrochloride)
Patients receive crizotinib (oral solution) PO BID on days 1-21, cyclophosphamide IV 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. (closed to accrual 10/3/14)
Intervention: Crizotinib
Part A (crizotinib, cyclophosphamide, topotecan hydrochloride)
Patients receive crizotinib (oral solution) PO BID on days 1-21, cyclophosphamide IV 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. (closed to accrual 10/3/14)
Intervention: Cyclophosphamide
Part A (crizotinib, cyclophosphamide, topotecan hydrochloride)
Patients receive crizotinib (oral solution) PO BID on days 1-21, cyclophosphamide IV 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. (closed to accrual 10/3/14)
Intervention: Laboratory Biomarker Analysis
Part A (crizotinib, cyclophosphamide, topotecan hydrochloride)
Patients receive crizotinib (oral solution) PO BID on days 1-21, cyclophosphamide IV 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. (closed to accrual 10/3/14)
Intervention: Pharmacological Study
Part A (crizotinib, cyclophosphamide, topotecan hydrochloride)
Patients receive crizotinib (oral solution) PO BID on days 1-21, cyclophosphamide IV 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. (closed to accrual 10/3/14)
Intervention: Questionnaire Administration
Part A (crizotinib, cyclophosphamide, topotecan hydrochloride)
Patients receive crizotinib (oral solution) PO BID on days 1-21, cyclophosphamide IV 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. (closed to accrual 10/3/14)
Intervention: Topotecan Hydrochloride
Part B (crizotinib, vincristine, dexrazoxane, doxorubicin)
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. (closed to accrual 10/3/14)
Intervention: Crizotinib
Part B (crizotinib, vincristine, dexrazoxane, doxorubicin)
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. (closed to accrual 10/3/14)
Intervention: Dexrazoxane Hydrochloride
Part B (crizotinib, vincristine, dexrazoxane, doxorubicin)
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. (closed to accrual 10/3/14)
Intervention: Doxorubicin Hydrochloride
Part B (crizotinib, vincristine, dexrazoxane, doxorubicin)
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. (closed to accrual 10/3/14)
Intervention: Laboratory Biomarker Analysis
Part B (crizotinib, vincristine, dexrazoxane, doxorubicin)
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. (closed to accrual 10/3/14)
Intervention: Pharmacological Study
Part B (crizotinib, vincristine, dexrazoxane, doxorubicin)
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. (closed to accrual 10/3/14)
Intervention: Questionnaire Administration
Part B (crizotinib, vincristine, dexrazoxane, doxorubicin)
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. (closed to accrual 10/3/14)
Intervention: Vincristine Sulfate
Part C (crizotinib, cyclophosphamide, topotecan hydrochloride)
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.
Intervention: Crizotinib
Part C (crizotinib, cyclophosphamide, topotecan hydrochloride)
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.
Intervention: Cyclophosphamide
Part C (crizotinib, cyclophosphamide, topotecan hydrochloride)
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.
Intervention: Laboratory Biomarker Analysis
Part C (crizotinib, cyclophosphamide, topotecan hydrochloride)
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.
Intervention: Pharmacological Study
Part C (crizotinib, cyclophosphamide, topotecan hydrochloride)
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.
Intervention: Questionnaire Administration
Part C (crizotinib, cyclophosphamide, topotecan hydrochloride)
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.
Intervention: Topotecan Hydrochloride
Part D (crizotinib, cyclophosphamide, topotecan hydrochloride)
Patients receive crizotinib (microsphere 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.
Intervention: Crizotinib
Part D (crizotinib, cyclophosphamide, topotecan hydrochloride)
Patients receive crizotinib (microsphere 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.
Intervention: Cyclophosphamide
Part D (crizotinib, cyclophosphamide, topotecan hydrochloride)
Patients receive crizotinib (microsphere 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.
Intervention: Laboratory Biomarker Analysis
Part D (crizotinib, cyclophosphamide, topotecan hydrochloride)
Patients receive crizotinib (microsphere 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.
Intervention: Pharmacological Study
Part D (crizotinib, cyclophosphamide, topotecan hydrochloride)
Patients receive crizotinib (microsphere 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.
Intervention: Questionnaire Administration
Part D (crizotinib, cyclophosphamide, topotecan hydrochloride)
Patients receive crizotinib (microsphere 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.
Intervention: Topotecan Hydrochloride
Outcomes
Primary Outcomes
Maximum Tolerated Dose (MTD) of Crizotinib
Time Frame: Up to 21 days
The MTD of crizotinib administered with combination chemotherapy based on the incidence of dose-limiting toxicity (DLT) at which fewer than one-third of patients experience DLT, as assessed by NCI CTCAE version 4.0.
Area Under the Concentration
Time Frame: Up to 21 days
Median (min, max) of the area under the concentration time curve for crizotinib assessed in course 1 at 1, 2, 4, 6-8 hours, and 15-21 days post-administration stratified by dose level and study part.
Number of Patients With Dose Limiting Toxicity (DLT)
Time Frame: Up to 21 days
Number of patients of all DLT reported as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. stratified by dose level and study part.
Secondary Outcomes
- Response Rate(Up to 2 years)
- ALK Status and Response to Crizotinib(up to 2 years)
- Acceptability of Crizotinib Microsphere Formulation Palatability(Up to 1 week)
- MRD Status and Response to Crizotinib(Up to 2 years)
- ALK Expression for Crizotinib(Up to 7 days)
- Acceptability of Crizotinib Capsule Formulation Palatability(Up to 1 week)