Childhood Solid Neoplasm, Recurrent Childhood Anaplastic Large Cell Lymphoma, Recurrent Neuroblastoma
Conditions
Keywords
Crizotinib, Chemotherapy, Solid Tumors, Anaplastic Large Cell Lymphoma
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.
Interventions
DRUGVincristine Sulfate
Given IV
DRUGCrizotinib
Given PO
DRUGCyclophosphamide
Given IV
DRUGDexrazoxane Hydrochloride
Given IV
DRUGDoxorubicin Hydrochloride
Given IV
OTHERLaboratory Biomarker Analysis
Correlative studies
OTHERPharmacological Study
Correlative studies
OTHERQuestionnaire Administration
Ancillary studies
DRUGTopotecan Hydrochloride
Given IV
Sponsors
National Cancer Institute (NCI)
Children's Oncology Group
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
13 Months to 21 Years
Healthy volunteers
No
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) * 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 * 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) * 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 * 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) * 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 * For patients on Part B: shortening fraction of \>= 27% by echocardiogram or ejection fraction of \>= 50% by gated radionuclide study * 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 * Part C: Patients must have a body surface area (BSA) \>= 1.07 m\^2 at the time of study enrollment * Part D: Patients must have a body surface area (BSA) \>= 0.43 m\^2 at the time of study enrollment * Tumor tissue must be sent; if tumor tissue is unavailable, the study chair must be notified prior to enrollment
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 * Patients who have received a prior solid organ transplantation 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 in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible * Parts A and B: Patients who are able to swallow liquid or use a nasogastric or gastrostomy (G) tube are eligible * Part C: Patients must be able to swallow intact capsules * Part D: Patients must be able to swallow liquid
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) of Crizotinib | 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. |
| Number of Patients With Dose Limiting Toxicity (DLT) | 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. |
| Area Under the Concentration | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| ALK Expression for Crizotinib | Up to 7 days | Median (p25, p75) ALK expression stratified by dose level and study part |
| Response Rate | Up to 2 years | Number of patients of response-evaluable participants with response (CR/PR) assessed according to Response Evaluation Criteria in Solid Tumors version 1.1 including CR: disappearance of all target and non-target lesions; PR: at least 30% decrease in the sum of the diameters of target lesions |
| Acceptability of Crizotinib Microsphere Formulation Palatability | Up to 1 week | Number of patients who at least accept palatability of microsphere formation in the first week |
| Acceptability of Crizotinib Capsule Formulation Palatability | Up to 1 week | Number of patients who at least accept palatability of capsule formulation in the first week |
| ALK Status and Response to Crizotinib | up to 2 years | Number of patients who respond (CR/PR) to crizotinib in combination with either topotecan and cyclophosphamide or vincristine and doxorubicin/dexraroxane stratified by ALK positive or negative status |
| MRD Status and Response to Crizotinib | Up to 2 years | Frequency (%) of patients who respond (CR/PR) to crizotinib in combination with either topotecan and cyclophosphamide or vincristine and doxorubicin/dexraroxane stratified by MRD status |
Countries
Canada, United States
Participant flow
Recruitment details
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 and Part D.
Participants by arm
| Arm | Count |
|---|---|
| Part A Dose Level 1 Patients receive 165 mg/m\^2 crizotinib (oral solution) PO BID on days 1-21, 250 mg/m\^2 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) | 6 |
| Part A Dose Level 2 Patients receive 215 mg/m\^2 crizotinib (oral solution) PO BID on days 1-21, 250 mg/m\^2 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) | 4 |
| Part B Dose Level 1 Patients receive 165 mg/m\^2 crizotinib (oral solution) PO BID as in Part A. Patients also receive 1.5 mg/m\^2 vincristine sulfate IV on day 1, 450 mg/m\^2 dexrazoxane hydrochloride IV on day 1, and 45 mg/m\^2 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) | 5 |
| Part B Dose Level 2 Patients receive 215 mg/m\^2 crizotinib (oral solution) PO BID as in Part A. Patients also receive 1.5 mg/m\^2 vincristine sulfate IV on day 1, 450 mg/m\^2 dexrazoxane hydrochloride IV on day 1, and 45 mg/m\^2 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) | 3 |
| Part B Dose Level 3 Patients receive 280 mg/m\^2 crizotinib (oral solution) PO BID as in Part A. Patients also receive 1.5 mg/m\^2 vincristine sulfate IV on day 1, 450 mg/m\^2 dexrazoxane hydrochloride IV on day 1, and 45 mg/m\^2 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) | 3 |
| Part C Dose Level 1 Patients receive 165 mg/m\^2 crizotinib (capsule formulation) PO BID, 250 mg/m\^2 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. | 4 |
| Part C Dose Level 2 Patients receive 215 mg/m\^2 crizotinib (capsule formulation) PO BID, 250 mg/m\^2 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. | 6 |
| Part C Dose Level 3 Patients receive 280 mg/m\^2 crizotinib (capsule formulation) PO BID, 250 mg/m\^2 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. | 3 |
| Part D Dose Level 1 Patients receive 165 mg/m\^2 crizotinib (microsphere formulation) PO BID, 250 mg/m\^2 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. | 6 |
| Part D Dose Level 2 Patients receive 215 mg/m\^2 crizotinib (microsphere formulation) PO BID, 250 mg/m\^2 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. | 3 |
| Part PK Dose Level 2 Patients receive 215 mg/m\^2 crizotinib (microsphere formulation) PO BID, 250 mg/m\^2 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. | 3 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 3 | 0 |
| Overall Study | Lack of Efficacy | 1 | 1 | 1 | 2 | 1 | 2 | 1 | 2 | 2 | 0 | 1 |
| Overall Study | Physician Decision | 1 | 0 | 2 | 1 | 1 | 1 | 2 | 0 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 2 | 2 | 0 | 1 | 1 | 2 | 1 | 2 | 0 | 2 |
Baseline characteristics
| Characteristic | Part A Dose Level 2 | Part B Dose Level 1 | Part B Dose Level 2 | Part B Dose Level 3 | Part C Dose Level 1 | Part C Dose Level 2 | Part C Dose Level 3 | Part D Dose Level 1 | Part D Dose Level 2 | Part A Dose Level 1 | Part PK Dose Level 2 | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 4 Participants | 2 Participants | 2 Participants | 3 Participants | 2 Participants | 5 Participants | 3 Participants | 6 Participants | 3 Participants | 4 Participants | 1 Participants | 35 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 3 Participants | 1 Participants | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants | 11 Participants |
| Age, Continuous | 12.5 years | 19 years | 6 years | 11 years | 17.5 years | 15 years | 17 years | 13.5 years | 17 years | 16 years | 20 years | 15 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 4 Participants | 2 Participants | 2 Participants | 4 Participants | 4 Participants | 3 Participants | 5 Participants | 3 Participants | 6 Participants | 2 Participants | 39 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 3 Participants | 4 Participants | 3 Participants | 2 Participants | 3 Participants | 5 Participants | 2 Participants | 4 Participants | 3 Participants | 3 Participants | 3 Participants | 35 Participants |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 1 Participants | 2 Participants | 2 Participants | 3 Participants | 1 Participants | 3 Participants | 1 Participants | 2 Participants | 2 Participants | 22 Participants |
| Sex: Female, Male Male | 1 Participants | 3 Participants | 2 Participants | 1 Participants | 2 Participants | 3 Participants | 2 Participants | 3 Participants | 2 Participants | 4 Participants | 1 Participants | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 4 | 1 / 5 | 0 / 3 | 0 / 3 | 1 / 4 | 0 / 6 | 0 / 3 | 0 / 6 | 0 / 3 | 0 / 3 |
| other Total, other adverse events | 6 / 6 | 4 / 4 | 5 / 5 | 3 / 3 | 3 / 3 | 4 / 4 | 6 / 6 | 3 / 3 | 6 / 6 | 3 / 3 | 3 / 3 |
| serious Total, serious adverse events | 3 / 6 | 3 / 4 | 1 / 5 | 1 / 3 | 2 / 3 | 3 / 4 | 3 / 6 | 1 / 3 | 3 / 6 | 3 / 3 | 2 / 3 |
Outcome results
Primary
Area Under the Concentration
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.
Time frame: Up to 21 days
Population: All Toxicity evaluable patients. There were no data for Part A Dose Level 2, Part B Dose Level 3, and Part D Dose Level 1.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part C (Crizotinib, Cyclophosphamide, Topotecan Hydrochloride) | Area Under the Concentration | 3792.5 hr*ug/mL |
| Part A Dose Level 2 | Area Under the Concentration | 1549.3 hr*ug/mL |
| Part B Dose Level 1 | Area Under the Concentration | 4070.5 hr*ug/mL |
| Part B Dose Level 2 | Area Under the Concentration | 1612 hr*ug/mL |
| Part B Dose Level 3 | Area Under the Concentration | 3796.6 hr*ug/mL |
| Part C Dose Level 1 | Area Under the Concentration | 7462.8 hr*ug/mL |
| Part C Dose Level 2 | Area Under the Concentration | 3248 hr*ug/mL |
| Part C Dose Level 3 | Area Under the Concentration | 8881.3 hr*ug/mL |
Primary
Maximum Tolerated Dose (MTD) of Crizotinib
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.
Time frame: Up to 21 days
Population: Parts A, B and D MTD/RP2D were not assessed. As of Amendment #3, due to the possibility that many of the non-hematologic DLTs observed to date on the study are related to the palatability of the OS rather than due to true toxicity of the investigational agent, Parts A and B were closed and Part C was then opened to determine the MTD/ RP2D. As of Amendment #4, a new microsphere formulation was added for Part D, but there was no MTD/RP2D.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part C (Crizotinib, Cyclophosphamide, Topotecan Hydrochloride) | Maximum Tolerated Dose (MTD) of Crizotinib | 215 mg/m^2 |
Primary
Number of Patients With Dose Limiting Toxicity (DLT)
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.
Time frame: Up to 21 days
Population: All Toxicity evaluable patients
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part C (Crizotinib, Cyclophosphamide, Topotecan Hydrochloride) | Number of Patients With Dose Limiting Toxicity (DLT) | 2 Participants |
| Part A Dose Level 2 | Number of Patients With Dose Limiting Toxicity (DLT) | 2 Participants |
| Part B Dose Level 1 | Number of Patients With Dose Limiting Toxicity (DLT) | 0 Participants |
| Part B Dose Level 2 | Number of Patients With Dose Limiting Toxicity (DLT) | 0 Participants |
| Part B Dose Level 3 | Number of Patients With Dose Limiting Toxicity (DLT) | 2 Participants |
| Part C Dose Level 1 | Number of Patients With Dose Limiting Toxicity (DLT) | 0 Participants |
| Part C Dose Level 2 | Number of Patients With Dose Limiting Toxicity (DLT) | 1 Participants |
| Part C Dose Level 3 | Number of Patients With Dose Limiting Toxicity (DLT) | 2 Participants |
| Part D Dose Level 1 | Number of Patients With Dose Limiting Toxicity (DLT) | 3 Participants |
| Part D Dose Level 2 | Number of Patients With Dose Limiting Toxicity (DLT) | 3 Participants |
| Part PK Dose Level 2 | Number of Patients With Dose Limiting Toxicity (DLT) | 1 Participants |
Secondary
Acceptability of Crizotinib Capsule Formulation Palatability
Number of patients who at least accept palatability of capsule formulation in the first week
Time frame: Up to 1 week
Population: All Toxicity evaluable patients
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part C (Crizotinib, Cyclophosphamide, Topotecan Hydrochloride) | Acceptability of Crizotinib Capsule Formulation Palatability | 0 Participants |
| Part A Dose Level 2 | Acceptability of Crizotinib Capsule Formulation Palatability | 0 Participants |
| Part B Dose Level 1 | Acceptability of Crizotinib Capsule Formulation Palatability | 0 Participants |
| Part B Dose Level 2 | Acceptability of Crizotinib Capsule Formulation Palatability | 0 Participants |
| Part B Dose Level 3 | Acceptability of Crizotinib Capsule Formulation Palatability | 0 Participants |
| Part C Dose Level 1 | Acceptability of Crizotinib Capsule Formulation Palatability | 3 Participants |
| Part C Dose Level 2 | Acceptability of Crizotinib Capsule Formulation Palatability | 5 Participants |
| Part C Dose Level 3 | Acceptability of Crizotinib Capsule Formulation Palatability | 3 Participants |
| Part D Dose Level 1 | Acceptability of Crizotinib Capsule Formulation Palatability | 0 Participants |
| Part D Dose Level 2 | Acceptability of Crizotinib Capsule Formulation Palatability | 0 Participants |
| Part PK Dose Level 2 | Acceptability of Crizotinib Capsule Formulation Palatability | 3 Participants |
Secondary
Acceptability of Crizotinib Microsphere Formulation Palatability
Number of patients who at least accept palatability of microsphere formation in the first week
Time frame: Up to 1 week
Population: All Toxicity evaluable patients
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part C (Crizotinib, Cyclophosphamide, Topotecan Hydrochloride) | Acceptability of Crizotinib Microsphere Formulation Palatability | 0 Participants |
| Part A Dose Level 2 | Acceptability of Crizotinib Microsphere Formulation Palatability | 0 Participants |
| Part B Dose Level 1 | Acceptability of Crizotinib Microsphere Formulation Palatability | 0 Participants |
| Part B Dose Level 2 | Acceptability of Crizotinib Microsphere Formulation Palatability | 0 Participants |
| Part B Dose Level 3 | Acceptability of Crizotinib Microsphere Formulation Palatability | 0 Participants |
| Part C Dose Level 1 | Acceptability of Crizotinib Microsphere Formulation Palatability | 0 Participants |
| Part C Dose Level 2 | Acceptability of Crizotinib Microsphere Formulation Palatability | 0 Participants |
| Part C Dose Level 3 | Acceptability of Crizotinib Microsphere Formulation Palatability | 0 Participants |
| Part D Dose Level 1 | Acceptability of Crizotinib Microsphere Formulation Palatability | 4 Participants |
| Part D Dose Level 2 | Acceptability of Crizotinib Microsphere Formulation Palatability | 2 Participants |
| Part PK Dose Level 2 | Acceptability of Crizotinib Microsphere Formulation Palatability | 0 Participants |
Secondary
ALK Expression for Crizotinib
Median (p25, p75) ALK expression stratified by dose level and study part
Time frame: Up to 7 days
Population: ALK expression data were not and never will be collected.
Secondary
ALK Status and Response to Crizotinib
Number of patients who respond (CR/PR) to crizotinib in combination with either topotecan and cyclophosphamide or vincristine and doxorubicin/dexraroxane stratified by ALK positive or negative status
Time frame: up to 2 years
Population: Neuroblastoma patients
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part C (Crizotinib, Cyclophosphamide, Topotecan Hydrochloride) | ALK Status and Response to Crizotinib | ALK Negative | 1 Participants |
| Part C (Crizotinib, Cyclophosphamide, Topotecan Hydrochloride) | ALK Status and Response to Crizotinib | ALK Positive | 0 Participants |
| Part A Dose Level 2 | ALK Status and Response to Crizotinib | ALK Negative | 1 Participants |
| Part A Dose Level 2 | ALK Status and Response to Crizotinib | ALK Positive | 0 Participants |
| Part B Dose Level 1 | ALK Status and Response to Crizotinib | ALK Negative | 1 Participants |
| Part B Dose Level 1 | ALK Status and Response to Crizotinib | ALK Positive | 0 Participants |
| Part B Dose Level 2 | ALK Status and Response to Crizotinib | ALK Negative | 0 Participants |
| Part B Dose Level 2 | ALK Status and Response to Crizotinib | ALK Positive | 0 Participants |
| Part B Dose Level 3 | ALK Status and Response to Crizotinib | ALK Positive | 0 Participants |
| Part B Dose Level 3 | ALK Status and Response to Crizotinib | ALK Negative | 0 Participants |
| Part C Dose Level 1 | ALK Status and Response to Crizotinib | ALK Negative | 0 Participants |
| Part C Dose Level 1 | ALK Status and Response to Crizotinib | ALK Positive | 0 Participants |
| Part C Dose Level 2 | ALK Status and Response to Crizotinib | ALK Positive | 0 Participants |
| Part C Dose Level 2 | ALK Status and Response to Crizotinib | ALK Negative | 0 Participants |
| Part C Dose Level 3 | ALK Status and Response to Crizotinib | ALK Negative | 0 Participants |
| Part C Dose Level 3 | ALK Status and Response to Crizotinib | ALK Positive | 0 Participants |
| Part D Dose Level 1 | ALK Status and Response to Crizotinib | ALK Negative | 0 Participants |
| Part D Dose Level 1 | ALK Status and Response to Crizotinib | ALK Positive | 0 Participants |
| Part D Dose Level 2 | ALK Status and Response to Crizotinib | ALK Positive | 0 Participants |
| Part D Dose Level 2 | ALK Status and Response to Crizotinib | ALK Negative | 0 Participants |
| Part PK Dose Level 2 | ALK Status and Response to Crizotinib | ALK Positive | 0 Participants |
| Part PK Dose Level 2 | ALK Status and Response to Crizotinib | ALK Negative | 0 Participants |
Secondary
MRD Status and Response to Crizotinib
Frequency (%) of patients who respond (CR/PR) to crizotinib in combination with either topotecan and cyclophosphamide or vincristine and doxorubicin/dexraroxane stratified by MRD status
Time frame: Up to 2 years
Population: Outcome Measure was specific to ALCL patients. There were zero ALCL patients, therefore, there are no data to report.
Secondary
Response Rate
Number of patients of response-evaluable participants with response (CR/PR) assessed according to Response Evaluation Criteria in Solid Tumors version 1.1 including CR: disappearance of all target and non-target lesions; PR: at least 30% decrease in the sum of the diameters of target lesions
Time frame: Up to 2 years
Population: Evaluable patients for response
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part C (Crizotinib, Cyclophosphamide, Topotecan Hydrochloride) | Response Rate | 2 Participants |
| Part A Dose Level 2 | Response Rate | 0 Participants |
| Part B Dose Level 1 | Response Rate | 1 Participants |
| Part B Dose Level 2 | Response Rate | 1 Participants |
| Part B Dose Level 3 | Response Rate | 0 Participants |
| Part C Dose Level 1 | Response Rate | 1 Participants |
| Part C Dose Level 2 | Response Rate | 1 Participants |
| Part C Dose Level 3 | Response Rate | 1 Participants |
| Part D Dose Level 1 | Response Rate | 0 Participants |
| Part D Dose Level 2 | Response Rate | 0 Participants |
| Part PK Dose Level 2 | Response Rate | 0 Participants |