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

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.

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

- 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

- 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

- 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 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