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A Phase 1, Open-Label, Single-Sequence Crossover Study Assessing the Effect of Tivantinib (ARQ 197) on the Pharmacokinetics of Omeprazole/S-Warfarin/Caffeine/Midazolam and Digoxin in Cancer Subjects

Phase 1
18 Years
Open (Enrolling)
Solid Tumors

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Trial Information

A Phase 1, Open-Label, Single-Sequence Crossover Study Assessing the Effect of Tivantinib (ARQ 197) on the Pharmacokinetics of Omeprazole/S-Warfarin/Caffeine/Midazolam and Digoxin in Cancer Subjects

Nonclinical studies have indicated that tivantinib (parent molecule) has the potential to
inhibit CYP3A4 ([I]/Ki=0.15, midazolam as substrate), CYP2C19 ([I]/Ki=0.98), CYP2C9
([I]/Ki=0.44), and CYP1A ([I]/Ki=0.37), and the efflux transporter P glycoprotein (P-gp)
(I2/IC50=82) at the clinical concentrations being studied in the Phase 3 development
program. In addition, tivantinib has major circulating plasma metabolite(s) which also have
been shown in nonclinical studies to exhibit similar CYP inhibition potential. The results
of this study will evaluate the potential of tivantinib to influence the pharmacokinetics of
CYP3A4/CYP2C19/CYP2C9/CYP1A and/or P-gp substrates, and help to provide the guidance to
clinicians on co-administration of tivantinib with drugs metabolized by
CYP3A4/CYP2C19/CYP2C9/ CYP1A and/or transported by P-gp.

Inclusion Criteria:

1. Have a histologically or cytologically confirmed advanced solid tumor at screening;

2. Male or female ≥ 18 years of age;

3. Subjects (male and female) of childbearing potential must agree to use double barrier
contraceptive measures or avoid intercourse during the study and for 90 days after
the last dose of study drug. In addition, all female subjects of childbearing
potential must have a negative pregnancy test result before initiating study

4. An Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2;

5. Adequate bone marrow, liver, clotting, and renal function, defined as:

Platelet count ≥ 100 x 10^9/L, Hemoglobin (Hb) ≥ 9.0 g/dL, ANC ≥ 1.5 × 109/L, Total
bilirubin ≤ 1.5 x the upper limit of normal (ULN), Alanine aminotransferase (ALT) and
aspartate aminotransferase (AST) ≤ 3 x ULN (≤ 5 x ULN for subjects with liver
metastases), International normalized ratio ≤ 1.5, Serum creatinine ≤ 1.5 x ULN;

6. Able to provide written informed consent, comply with protocol visits and procedures,
be able to take oral medication, and not have any active infection or chronic
co-morbidity that would interfere with therapy; and

7. Subjects must be fully informed about their illness and the investigational nature of
the study protocol (including foreseeable risks and possible side effects) and must
sign and date an IRB approved ICF (including HIPAA authorization, if applicable)
before performance of any study specific procedures or tests.

Exclusion Criteria:

1. History of cardiac disease:

- Active coronary artery disease, defined as myocardial infarction (MI), unstable
angina, coronary artery bypass graft, or stenting within 6 months prior to study
entry (an MI that occurred > 6 months prior to study entry is permitted);

- Evidence of uncontrolled symptomatic bradycardia or other cardiac arrhythmia
defined as ≥ Grade 2 according to National Cancer Institute (NCI) Common
Terminology Criteria for Adverse Events (CTCAE), version 4, or uncontrolled

2. Active, clinically serious infection(s) defined as ≥ Grade 2 according to NCI CTCAE,
version 4;

3. Family or personal history of coagulopathy;

4. History of hypersensitivity or adverse reactions to omeprazole, digoxin, warfarin,
caffeine, midazolam, or vitamin K;

5. Known metastatic brain or meningeal tumors, unless the subject is > 3 months from
definitive therapy and clinically stable (supportive therapy with steroids or
anticonvulsant medications is allowed) with respect to the tumor at the time of first
dose of study drug;

6. Pregnant or breastfeeding;

7. Any major surgical procedure within 3 weeks prior to first dose of study drug;

8. Significant gastrointestinal disorder(s), in the opinion of the Investigator (eg,
Crohn's disease, ulcerative colitis, extensive gastric resection);

9. Received anti-cancer therapy, including antibody, retinoid, or hormonal treatment
(except megestrol acetate as supportive care), and radiation, within 3 weeks before
dosing. Prior and concurrent use of hormone replacement therapy, the use of
gonadotropin-releasing hormone modulators for prostate cancer, and the use of
somatostatin analogs for neuroendocrine tumors are permitted;

10. Received any other investigational drug within 3 weeks prior to dosing;

11. Received tivantinib as prior therapy;

12. Substance abuse or medical, psychological, or social conditions that may, in the
opinion of the Investigator, interfere with the subject's participation in the
clinical study or evaluation of the clinical study results;

13. Any condition that is unstable or that could jeopardize the safety of the subject and
the subject's protocol compliance, including known human immunodeficiency virus,
hepatitis B virus, or hepatitis C virus infection;

14. Inability to swallow oral medications that could interfere with the absorption of

15. Administration or possibility of initiating or continuing any treatment with any
known Cytochrome P450 (CYP)3A4, CYP2C19, CYP1A2, CYP2C9, and P-glycoprotein
enzyme-altering drugs (inducer or inhibitor) or non-drug agents or systemic gastric
pH modifiers (ie, ranitidine, proton pump inhibitors etc) within the 14 days prior to
dosing and/or during the primary objective phase after initiation of the study
treatment; or

16. Clinical diagnosis of hepatic impairment from chronic liver cirrhosis with
confirmation by either previous liver biopsy or imaging, regardless of liver function
test results at screening.

Type of Study:


Study Design:

Endpoint Classification: Pharmacokinetics Study, Intervention Model: Crossover Assignment, Masking: Open Label

Outcome Measure:

Area under the plasma concentration versus time curve (AUC) for S-Warfarin, Caffeine, Midazolam and Digoxin

Outcome Description:

Parameters of S-warfarin/caffeine/midazolam and digoxin (area under the concentration-time curve from time 0 to the last quantifiable concentration [AUC last] and area under the curve from time of dosing extrapolated to infinity [AUC 0-inf]) when warfarin/caffeine/midazolam and digoxin are administered alone or in combination with tivantinib

Outcome Time Frame:

Pharmacokinetic sampling will be done on days 1, 4, 6, 10, 11, 14, 16 (designated as days -5, -2, 1, 5, 6, 9, 11 in the study protocol)

Safety Issue:


Principal Investigator

Hamim Zahir, BPharm, PhD

Investigator Role:

Study Director

Investigator Affiliation:

Daiichi-Sankyo Pharma Development


United States: Food and Drug Administration

Study ID:




Start Date:

December 2011

Completion Date:

May 2013

Related Keywords:

  • Solid Tumors
  • Oncology
  • pharmacokinetics
  • PK interaction in advanced solid tumors with our drug and other drugs



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