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A Phase I Study of ARQ 197 in Combination With IV Topotecan in Advanced Solid Tumors With an Expansion Cohort in Small Cell Lung Cancer

Phase 1
18 Years
Open (Enrolling)
Recurrent Small Cell Lung Cancer, Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

A Phase I Study of ARQ 197 in Combination With IV Topotecan in Advanced Solid Tumors With an Expansion Cohort in Small Cell Lung Cancer


I. To establish the recommended phase 2 dose (RP2D) for the combination of ARQ 197
(tivantinib) and intravenous (IV) topotecan (topotecan hydrochloride).

II. To describe the toxicities of ARQ 197 and IV topotecan at each dose studied.

III. To characterize the pharmacokinetic behavior of ARQ 197 given concurrent use of IV

IV. To obtain preliminary information regarding the effect of ARQ 197 and IV topotecan on
met proto-oncogene (hepatocyte growth factor receptor) (c-Met) and focal adhesion kinase
(FAK) phosphorylation in circulating tumor cells and in tumor biopsies.

V. To document all clinical responses to ARQ 197 with IV topotecan.

OUTLINE: This is a dose-escalation study of tivantinib and topotecan hydrochloride.

Patients receive tivantinib orally (PO) twice daily (BID) on days 1-21 and topotecan
hydrochloride IV over 30 minutes on days 1-5. Courses repeat every 21 days in the absence of
disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 4 weeks.

Inclusion Criteria:

- Patients must have histologically confirmed malignancy that is metastatic or
unresectable and for which standard curative or palliative measures do not exist or
are no longer effective; for the expansion group, patients must have histologically
or cytologically confirmed small cell lung cancer previously treated with one or more
chemotherapy or chemoradiotherapy regimens, at least one of which must have been

- Karnofsky >= 60%

- Life expectancy of greater than 12 weeks

- Hemoglobin >= 9.0 g/dL

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Total bilirubin =< 1.5 X institutional upper limit of normal

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT])
=< 2.5 X institutional upper limit of normal (=< 5 X institutional upper limit of
normal if the rise can be attributed to liver metastases)

- Serum creatinine =< 1.5 X institutional upper limit of normal OR creatinine clearance
>= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and
for the duration of study participation; should a woman become pregnant or suspect
she is pregnant while she or her partner is participating in this study, she should
inform her treating physician immediately; men treated or enrolled on this protocol
must also agree to use adequate contraception prior to the study, for the duration of
study participation, and 4 months after completion of ARQ 197 administration

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier

- Patients who are receiving any other investigational agents

- Patients with untreated brain metastases should be excluded from this clinical trial;
however patients with stable brain disease (off corticosteroids) at least 2 weeks
after completion of appropriate therapy for their brain metastases are eligible;
patients who require enzyme-inducing anti-convulsants (EIAC) should be switched to
non-EIAC and be on a stable dose of the new agent for at least 2 weeks prior to
treatment on this protocol

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to ARQ 197 or topotecan

- The metabolism and consequently overall pharmacokinetics of ARQ 197 could be altered
by inhibitors and/or inducers or other substrates of cytochrome P450 2C19 (CYP2C19)
and cytochrome P450 3A4 (CYP3A4); while inhibitors/inducers of these cytochrome P450
isoenzymes are not specifically excluded, investigators should be aware that ARQ 197
exposure may be altered by the concomitant administration of these drugs; caution
should be applied when CYP2C19 inhibitors such as omeprazole, fluvoxamine,
fluconazole, ticlopidine, rabeprazole, fluoxetine, and moclobemide, or strong CYP3A4
inhibitors such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole,
nefazodone, nelfinavir, ritonavir, saquinavir, ciprofloxacin, telithromycin,
troleandomycin (TAO), or voriconazole, are used as concomitant therapy; because the
lists of these agents are changing, it is important to consult an updated list; as
part of the enrollment/informed consent procedures, the patient will be counseled on
the risk of interactions with other agents, and what to do if new medications need to
be prescribed or if the patient is considering a new over-the-counter medicine or
herbal product

- History of congestive heart failure defined as class II to IV per New York Heart
Association (NYHA) classification; active coronary artery disease (CAD); clinically
significant bradycardia or other uncontrolled, cardiac arrhythmia defined as >= grade
3 according to National Cancer Institute (NCI) Common Terminology Criteria for
Adverse Events (CTCAE), version 4.0, or uncontrolled hypertension; myocardial
infarction occurring within 6 months prior to study entry (myocardial infarction
occurring > 6 months prior to study entry is permitted)

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with ARQ 197

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible

- Patients previously treated with topotecan are ineligible

- Patients previously treated with ARQ 197 are ineligible

- Patients unable to swallow ARQ 197 pills are ineligible

Type of Study:


Study Design:

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

Outcome Measure:

Toxicities, graded according to the NCI CTCAE version 4.0

Outcome Description:

The toxicities observed at each dose level will be summarized in terms of type (organ affected or laboratory determination such as absolute neutrophil count), severity (by CTCAE), attribution, time of onset (i.e. course number), duration, and reversibility or outcome. Tables will be created to summarize these toxicities and side effects by dose and by course.

Outcome Time Frame:

Up to 30 days after completion of study treatment

Safety Issue:


Principal Investigator

Stephen Liu

Investigator Role:

Principal Investigator

Investigator Affiliation:

City of Hope Medical Center


United States: Food and Drug Administration

Study ID:




Start Date:

July 2012

Completion Date:

Related Keywords:

  • Recurrent Small Cell Lung Cancer
  • Unspecified Adult Solid Tumor, Protocol Specific
  • Lung Neoplasms
  • Small Cell Lung Carcinoma
  • Neoplasms



University of Pittsburgh Cancer Institute Pittsburgh, Pennsylvania  15213
City of Hope Medical Center Duarte, California  91010
USC Norris Comprehensive Cancer Center Los Angeles, California  90089
UC Davis Comprehensive Cancer Center Sacramento, California  95817
Penn State Milton S Hershey Medical Center Hershey, Pennsylvania  17033