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A Phase 1 Study of the c-Met Inhibitor, Tivantinib (ARQ 197, IND# 112603) in Children With Relapsed or Refractory Solid Tumors


Phase 1
13 Months
21 Years
Open (Enrolling)
Both
Unspecified Childhood Solid Tumor, Protocol Specific

Thank you

Trial Information

A Phase 1 Study of the c-Met Inhibitor, Tivantinib (ARQ 197, IND# 112603) in Children With Relapsed or Refractory Solid Tumors


PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) and/or recommended phase 2 dose of
tivantinib administered orally twice daily to children with refractory solid tumors.

II. To define and describe the toxicities of tivantinib administered on this schedule.

III. To characterize the pharmacokinetics of tivantinib (capsule as well as powder
formulation) in children with refractory cancer.

SECONDARY OBJECTIVES:

I. To preliminarily define the antitumor activity of tivantinib within the confines of a
phase 1 study.

II. To preliminarily investigate whether cytochrome P450 (CYP450) polymorphisms impact
pharmacokinetics or toxicity of tivantinib.

III. To preliminarily investigate whether tumor c-Met and/or hepatocyte growth factor (HGF)
expression or downstream c-Met signaling correlate with clinical response to tivantinib.

OUTLINE: This is a dose-escalation study.

Patients receive tivantinib orally (PO) twice daily (BID) on days 1-28. Treatment repeats
every 28 days for up to 12 courses in the absence of disease progression or unacceptable
toxicity.

After completion of study treatment, patients are followed up for 30 days.


Inclusion Criteria:



- PART A: Patients on dose levels -1 or 1 must have a body surface area (BSA) >= 0.65
m^2 at the time of study enrollment; patients on dose levels 2 or 3 must have a BSA
>= 0.45 m^2 at the time of study enrollment

- PART B: There is no minimum body surface area requirement for patients in part B

- Patients with relapsed or refractory solid tumors including central nervous system
(CNS) tumors are eligible; patients must have had histologic verification of
malignancy at original diagnosis or relapse except in patients with intrinsic brain
stem tumors, optic pathway gliomas, or patients with pineal tumors and elevations of
cerebrospinal fluid (CSF) or serum tumor markers including alpha-fetoprotein or
beta-human chorionic gonadotropin (HCG)

- 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 >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16
years of age; note: neurologic deficits in patients with CNS tumors must have been
stable or improving for at least 7 days prior to study enrollment; 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: At least 21 days after the last dose of
myelosuppressive chemotherapy (42 days if prior nitrosourea)

- 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): At least 14 days after local palliative XRT (small
port); 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

- Stem cell infusion without TBI: No evidence of active graft vs. host disease and
at least 84 days must have elapsed after transplant or stem cell infusion

- Patients may not have received prior therapy with tivantinib

- 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 involvement will be eligible for study provided they
meet the blood counts above (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; at least 5 of every cohort of 6 patients with a
solid tumor must be evaluable for hematologic toxicity for the dose escalation part
of the study; 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) >=
70ml/min/1.73 m^2 or a serum creatinine based on age/gender as follows:

- 1 to < 2 years: 0.6 mg/dL

- 2 to < 6 years: 0.8 mg/dL

- 6 to < 10 years: 1.0 mg/dL

- 10 to < 13 years: 1.2 mg/dL

- 13 to < 16 years: 1.5 mg/dL (males); 1.4 mg/dL (females)

- >= 16 years: 1.7 mg/dL (males); 1.4 mg/dL (females)

- 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

- 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

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

- 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 must not be receiving any of the following for at least 24 hours prior to
enrollment: omeprazole, esoprazole, lansoprazole, pantoprazole, rifampin, omeprazole,
fluvoxamine, or moclobemide

- Patients must not be receiving any of the following for at least 24 hours prior to
enrollment: atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole,
nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin (TAO),
voriconazole, rifampicin, rifabutin, rifapentine, phenytoin, carbamazepine,
phenobarbital, or St. John's Wort

- Nasogastric or G tube administration is not allowed; patients in part A must be able
to swallow capsules

- Patients who have an uncontrolled infection are not eligible

- Patients who have received a prior solid organ transplantation 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

- Patients with >= grade 2 bradycardia or with a known history >= grade 2 cardiac
arrhythmia are not eligible

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

MTD defined as the maximum dose at which fewer than one-third of patients experience dose-limiting toxicity (DLT) using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

Outcome Time Frame:

28 days

Safety Issue:

Yes

Principal Investigator

James Geller

Investigator Role:

Principal Investigator

Investigator Affiliation:

COG Phase I Consortium

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2012-02163

NCT ID:

NCT01725191

Start Date:

October 2012

Completion Date:

Related Keywords:

  • Unspecified Childhood Solid Tumor, Protocol Specific
  • Neoplasms

Name

Location

Baylor College of MedicineHouston, Texas  77030
Children's Hospital of PhiladelphiaPhiladelphia, Pennsylvania  19104
Washington University School of MedicineSaint Louis, Missouri  63110
Midwest Children's Cancer CenterMilwaukee, Wisconsin  53226
Children's National Medical CenterWashington, District of Columbia  20010-2970
St. Jude Children's Research HospitalMemphis, Tennessee  38105-2794
Cincinnati Children's Hospital Medical CenterCincinnati, Ohio  45229-3039
Children's Hospital of Pittsburgh of UPMCPittsburgh, Pennsylvania  15213
Children's Hospital of AlabamaBirmingham, Alabama  35233
Oregon Health and Science UniversityPortland, Oregon  97201
Seattle Children's HospitalSeattle, Washington  98105
Childrens Memorial HospitalChicago, Illinois  60614
Columbia University Medical CenterNew York, New York  10032
University of Minnesota Medical Center-FairviewMinneapolis, Minnesota  55455
C S Mott Children's HospitalAnn Arbor, Michigan  48109
Riley Hospital for ChildrenIndianapolis, Indiana  46202
Childrens Hospital of Orange CountyOrange, California  92868-3874
Children's Healthcare of Atlanta - EglestonAtlanta, Georgia  30322
University of California San Francisco Medical Center-ParnassusSan Francisco, California  94143