Tivantinib and Topotecan Hydrochloride in Treating Patients With Advanced or Metastatic Solid Tumors

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

This phase I trial studies the side effects and best dose of tivantinib and topotecan hydrochloride in treating patients with advanced or metastatic solid tumors. Tivantinib and topotecan hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Study Overview

• Status: Completed
• Conditions: Adult Solid Neoplasm
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Biological: Pegfilgrastim; Drug: Topotecan Hydrochloride; Drug: Tivantinib

Detailed Description

PRIMARY OBJECTIVES:

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 topotecan.

IV. 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, topotecan hydrochloride IV over 30 minutes on days 1-5, and pegfilgrastim subcutaneously (SC) on day 6. 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.

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope Comprehensive Cancer Center
    • Los Angeles, California, United States, 90033
      • USC / Norris Comprehensive Cancer Center
    • Sacramento, California, United States, 95817
      • University of California Davis Comprehensive Cancer Center
    • South Pasadena, California, United States, 91030
      • City of Hope South Pasadena
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Wayne State University/Karmanos Cancer Institute
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033-0850
      • Penn State Milton S Hershey Medical Center
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh Cancer Institute (UPCI)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 platinum-based

  • As of amendment dated 01/24/2014 the study will not be pursuing an expansion cohort in small cell lung cancer
• 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 glutamate 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (tivantinib, topotecan hydrochloride, pegfilgrastim); Patients receive tivantinib PO BID on days 1-21, topotecan hydrochloride IV over 30 minutes on days 1-5, and pegfilgrastim SC on day 6. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies; Biological: Pegfilgrastim; Given SC; Other Names: Filgrastim SD-01; filgrastim-SD/01; HSP-130; Neulasta; Neulastim; Pegfilgrastim Biosimilar HSP-130; SD-01; SD-01 sustained duration G-CSF; Drug: Topotecan Hydrochloride; Given IV; Other Names: Hycamtin; Hycamptamine; SKF S-104864-A; Topotecan HCl; topotecan hydrochloride (oral); Drug: Tivantinib; Given PO; Other Names: ARQ 197; ARQ-197; c-Met Inhibitor ARQ 197

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse events graded according to the NCI CTCAE version 4.0	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.	Up to 4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tumor response as evaluated by Response Evaluation Criteria in Solid Tumors version 1.1	All responses will be reported; because of the potential heterogeneity of the patients, no attempt will be made to summarize these for the patients included in the dose escalation phase.	Up to 4 weeks
Progression-free survival (PFS)	PFS will be reported; because of the potential heterogeneity of the patients, no attempt will be made to summarize these for the patients included in the dose escalation phase.	The time from start of treatment until first evidence of disease progression or death due to any cause, assessed up to 4 weeks
Overall survival (OS)	OS will be reported; because of the potential heterogeneity of the patients, no attempt will be made to summarize these for the patients included in the dose escalation phase.	The time from start of treatment until death due to any cause, assessed up to 4 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics behavior of tivantinib given concurrently with topotecan hydrochloride	Summarized by dose level with simple summary statistics: means (possibly after transformation) or medians, ranges, and standard deviations (if numbers and distribution permit). Scatterplots will be used to explore possible associations between the dose and day 1 AUC, dose and levels on day 1 and day 5, and between these pharmacokinetic determinations and toxicity experienced (as reflected in the maximum grade of toxicity experienced). All data summaries based on pharmacokinetic studies will be descriptive and exploratory.	At baseline, at 2, 3, 4, and 8 hours of day 1 and at 12 hours after evening dose of day 4 (on day 5)
CYP2C19 genotype	The association between CYP2C19 genotype and ARQ 197 levels, and toxicity will also be displayed and summarized. All data summaries based on pharmacodynamic studies will be descriptive and exploratory.	Baseline

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Barbara Gitlitz, City of Hope Comprehensive Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): July 24, 2012
• Primary Completion (Actual): March 29, 2018
• Study Completion (Actual): March 29, 2018

Study Registration Dates

• First Submitted: July 30, 2012
• First Submitted That Met QC Criteria: July 30, 2012
• First Posted (Estimate): August 1, 2012

Study Record Updates

• Last Update Posted (Actual): April 3, 2018
• Last Update Submitted That Met QC Criteria: April 2, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunologic Factors; Topoisomerase Inhibitors; Adjuvants, Immunologic; Topoisomerase I Inhibitors; Lenograstim; Topotecan
• Other Study ID Numbers: NCI-2012-01220 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); P30CA033572 (U.S. NIH Grant/Contract); U01CA062505 (U.S. NIH Grant/Contract); UM1CA186717 (U.S. NIH Grant/Contract); 9152 (Other Identifier: CTEP); CDR0000738072; PHI-68 (Other Identifier: City of Hope Comprehensive Cancer Center)