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

This study is currently recruiting participants.
Verified April 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01654965
First received: July 30, 2012
Last updated: April 9, 2014
Last verified: April 2014
  Purpose

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.


Condition Intervention Phase
Unspecified Adult Solid Tumor, Protocol Specific
Drug: tivantinib
Drug: topotecan hydrochloride
Biological: pegfilgrastim
Other: laboratory biomarker analysis
Other: pharmacological study
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Incidence of adverse events graded according to the NCI CTCAE version 4.0 [ Time Frame: Up to 4 weeks ] [ Designated as safety issue: Yes ]
    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.


Secondary Outcome Measures:
  • Tumor response as evaluated by Response Evaluation Criteria in Solid Tumors version 1.1 [ Time Frame: Up to 4 weeks ] [ Designated as safety issue: No ]
    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.

  • Progression-free survival (PFS) [ Time Frame: The time from start of treatment until first evidence of disease progression or death due to any cause, assessed up to 4 weeks ] [ Designated as safety issue: No ]
    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.

  • Overall survival (OS) [ Time Frame: The time from start of treatment until death due to any cause, assessed up to 4 weeks ] [ Designated as safety issue: No ]
    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.


Other Outcome Measures:
  • Pharmacokinetics behavior of tivantinib given concurrently with topotecan hydrochloride [ Time Frame: 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) ] [ Designated as safety issue: No ]
    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.

  • CYP2C19 genotype [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    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.


Estimated Enrollment: 34
Study Start Date: July 2012
Estimated Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Drug: tivantinib
Given PO
Other Name: ARQ 197
Drug: topotecan hydrochloride
Given IV
Other Names:
  • hycamptamine
  • Hycamtin
  • SKF S-104864-A
  • TOPO
Biological: pegfilgrastim
Given SC
Other Names:
  • Filgrastim SD-01
  • GCSF-SD01
  • Neulasta
  • SD-01 sustained duration G-CSF
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01654965

Locations
United States, California
City of Hope Recruiting
Duarte, California, United States, 91010
Contact: Barbara J. Gitlitz    323-865-3900    gitlitz@usc.edu   
Principal Investigator: Barbara J. Gitlitz         
University of Southern California/Norris Cancer Center Recruiting
Los Angeles, California, United States, 90033
Contact: James S. Hu    323-865-3900    jameshu@usc.edu   
Principal Investigator: James S. Hu         
University of California at Davis Cancer Center Recruiting
Sacramento, California, United States, 95817
Contact: David R. Gandara    916-734-3771    david.gandara@ucdmc.ucdavis.edu   
Principal Investigator: David R. Gandara         
City of Hope South Pasadena Recruiting
South Pasadena, California, United States, 91030
Contact: Stephen C. Koehler    626-396-2900    Skoehler@cohmg.com   
Principal Investigator: Stephen C. Koehler         
United States, Michigan
Barbara Ann Karmanos Cancer Institute Recruiting
Detroit, Michigan, United States, 48201
Contact: Shirish M. Gadgeel    313-576-8753    gadgeels@karmanos.org   
Principal Investigator: Shirish M. Gadgeel         
United States, Pennsylvania
Penn State Milton S Hershey Medical Center Recruiting
Hershey, Pennsylvania, United States, 17033-0850
Contact: Chandra P. Belani    717-531-1078    cbelani@psu.edu   
Principal Investigator: Chandra P. Belani         
University of Pittsburgh Cancer Institute Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: Ahmad A. Tarhini    412-648-6507    tarhiniaa@upmc.edu   
Principal Investigator: Ahmad A. Tarhini         
Sponsors and Collaborators
Investigators
Principal Investigator: Barbara Gitlitz Beckman Research Institute
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01654965     History of Changes
Other Study ID Numbers: NCI-2012-01220, NCI-2012-01220, CDR0000738072, PHI-68, 9152, P30CA033572, U01CA062505
Study First Received: July 30, 2012
Last Updated: April 9, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Neoplasms
Topotecan
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on April 17, 2014