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A Phase I/II Trial of the c-Met Inhibitor, Tivantinib, in Combination With FOLFOX for the Treatment of Patients With Advanced Solid Tumors (Phase I) and Previously Untreated Metastatic Adenocarcinoma of the Distal Esophagus, Gastroesophageal (GE) Junction, or Stomach (Phase II)

Phase 1/Phase 2
18 Years
Open (Enrolling)
Malignant Solid Tumour, Gastrooesophageal Cancer

Thank you

Trial Information

A Phase I/II Trial of the c-Met Inhibitor, Tivantinib, in Combination With FOLFOX for the Treatment of Patients With Advanced Solid Tumors (Phase I) and Previously Untreated Metastatic Adenocarcinoma of the Distal Esophagus, Gastroesophageal (GE) Junction, or Stomach (Phase II)

This is a Phase I, open-label, non-randomized, dose-escalation study with a Phase II portion
planned upon reaching the Maximum Tolerated Dose or recommended Phase II dose (RP2D). Phase
I: The first cycle of the Phase I portion of the trial will be considered the Dose Limiting
Toxicity evaluation period. Patients with advanced solid tumors will be treated with
Tivantinib on Days 1 to 14 and with FOLFOX on Day 1. Following evaluation of the Dose
Limiting Toxicities, doses will be escalated/reduced according to the protocol with 3 to 6
patients treated per dose level until the Maximum Tolerated Dose is determined.

Inclusion Criteria:

- Life expectancy ≥12 weeks.

- Karnofsky performance status ≥70%

- Patients must have measurable disease per RECIST Version 1.1.

- Adequate hematologic function defined as:

- Absolute neutrophil count (ANC) ≥1500/μL

- Hemoglobin (Hgb) ≥9 g/dL (5.6 mmol/L)

- Platelets ≥100,000/uL

- Adequate liver function defined as:

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST <2.5 x the
institutional upper limit of normal (ULN) or ≤5.0 x the institutional ULN in patients
with liver metastases.

- Total bilirubin within normal limits (WNL) (or ≤1.5 x the institutional ULN in
patients with liver metastases; or total bilirubin ≤3.0 x ULN with direct bilirubin
within normal limits in patients with well documented Gilbert Syndrome).

- Serum creatinine <1.5 X ULN or calculated 24-hour creatinine clearance >40 mL/min.

- Patients who are on coumadin should have an INR value within the therapeutic range
(i.e., 2 to 3 x ULN). Patients who are on stable, chronic doses of coumadin are


•Patients must have histologically confirmed solid tumor malignancy that is metastatic or
unresectable and for which standard therapy would include FOLFOX or for which standard
curative or palliative measures do not exist or are no longer effective.


- Histologic documentation of adenocarcinoma of the esophagus, GE junction, or stomach.

- Metastatic GE cancer as documented by radiologic study or surgical evidence of
metastatic disease.

- No prior chemotherapy for metastatic disease. Previous combined modality therapy for
locally advanced disease is allowed if completed ≥6 months prior to recurrence
(acceptable chemotherapy drugs include 5-FU, capecitabine, cisplatin, carboplatin,
paclitaxel, oxaliplatin, and docetaxel).

- Prior radiation therapy is allowed. At least 4 weeks must have elapsed from
completion of the radiation therapy and all signs of toxicity must have resolved.

- Prior adjuvant chemotherapy is allowed if completed ≥6 months prior to the
documentation of metastatic disease.

Exclusion Criteria:

- Patients with known central nervous system (CNS) metastases may be enrolled, provided
the metastases have undergone treatment, the patient is asymptomatic, and the patient
does not require antiepileptic drugs or steroids as treatment for the CNS metastases.

- Patients with poorly controlled or clinically significant atherosclerotic vascular
disease including New York Heart Association Grade 3 or greater congestive heart
failure; unstable angina ; myocardial infarction, cardiovascular accident, transient
ischemic accidents, angioplasty, cardiac or vascular stenting in the past 6 months;
or ventricular arrhythmia requiring medication. Patients with previously diagnosed
symptomatic bradycardia will be ineligible.

- Medical history of prolonged QT syndrome (>450 ms).

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, or psychiatric illness/social situations that would limit safety or
compliance with study requirements.

- History of hypersensitivity to active or inactive excipients of any component of
treatment (5-FU, leucovorin, oxaliplatin, or Tivantinib), or known dipyrimidine
dehydrogenase deficiency.

- Patients with evidence of bleeding diathesis or significant coagulopathy (in the
absence of therapeutic anticoagulation).

- Significant vascular disease (e.g., aortic aneurysm requiring surgical repair, or
recent peripheral arterial thrombosis) ≤6 months prior to Day 1 of treatment.

- Any known positive test for human immunodeficiency virus, hepatitis C virus or acute
or chronic hepatitis B infection.

- Mental condition that would prevent patient comprehension of the nature of, and risk
associated with, the study.

- Use of any non-approved or investigational agent ≤28 days or 5 half-lives prior to
administration of the first dose of study drug, whichever is shorter.

- Patients may not receive any other investigational or anti-cancer treatments while
participating in this study.

- Impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter drug absorption (e.g. active inflammatory bowel disease,
uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome).

- Inability to swallow whole capsules.


•Patients who have had radiation therapy, hormonal therapy, biologic therapy,
investigational agents, or chemotherapy for cancer within 28 days or 5 half-lives of the
chemotherapy or biologic/targeted agents, whichever is shorter, prior to Day 1 of the


•Past or current history of neoplasm other than the entry diagnosis with the exception of
treated non-melanoma skin cancer or carcinoma in situ of the cervix, or other cancers
cured by local therapy alone and a disease free survival ≥5 years.

Type of Study:


Study Design:

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

Outcome Measure:

Maximum Tolerated Dose

Outcome Description:

Phase I portion of trial: to determine the Maximum Tolerated Dose/ recommended Phase II dose of Tivantinib plus FOLFOX in patients with advanced solid tumors.

Outcome Time Frame:

18 Months

Safety Issue:


Principal Investigator

Johanna C Bendell, M.D.

Investigator Role:

Study Chair

Investigator Affiliation:

Sarah Cannon Research Institute


United States: Food and Drug Administration

Study ID:




Start Date:

July 2012

Completion Date:

January 2015

Related Keywords:

  • Malignant Solid Tumour
  • Gastrooesophageal Cancer
  • Advanced solid tumors
  • First-Line Metastatic GE cancer
  • c-Met Inhibitor
  • Tivantinib
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Neoplasms



Tennessee Oncology, PLLCClarksville, Tennessee  37043