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Phase 1 Study of Crizotinib (IND#105573) in Combination With Conventional Chemotherapy for Relapsed or Refractory Solid Tumors or Anaplastic Large Cell Lymphoma


Phase 1
1 Year
21 Years
Not Enrolling
Both
Recurrent Childhood Anaplastic Large Cell Lymphoma, Recurrent Neuroblastoma, Unspecified Childhood Solid Tumor, Protocol Specific

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Trial Information

Phase 1 Study of Crizotinib (IND#105573) in Combination With Conventional Chemotherapy for 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 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.

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.

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.


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

- 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)

- 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

- 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

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Adverse events as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

Outcome Time Frame:

21 days

Safety Issue:

Yes

Principal Investigator

Emily Lipsitz

Investigator Role:

Principal Investigator

Investigator Affiliation:

Children's Oncology Group

Authority:

United States: Food and Drug Administration

Study ID:

ADVL1212

NCT ID:

NCT01606878

Start Date:

March 2013

Completion Date:

March 2015

Related Keywords:

  • Recurrent Childhood Anaplastic Large Cell Lymphoma
  • Recurrent Neuroblastoma
  • Unspecified Childhood Solid Tumor, Protocol Specific
  • Lymphoma
  • Lymphoma, Large B-Cell, Diffuse
  • Lymphoma, Non-Hodgkin
  • Neuroblastoma
  • Lymphoma, Large-Cell, Anaplastic
  • Neoplasms

Name

Location

Children's Oncology GroupArcadia, California  91006-3776