Phase I/II Trial of Tivantinib With FOLFOX for the Treatment of Advanced Solid Tumors and Previously Untreated Metastatic Adenocarcinoma of the Distal Esophagus, Gastroesophageal Junction or Stomach

Gastroesophageal Cancer Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01611857
• Other study ID #: SCRI GI 157
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: June 1, 2012
• Last updated: January 15, 2016
• Start date: July 2012
• Est. completion date: August 2015

Study information

• Verified date: January 2016
• Source: SCRI Development Innovations, LLC
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

We propose a Phase I trial of Tivantinib plus FOLFOX for the treatment of patients with advanced solid tumors followed by a Phase II portion for patients with first-line metastatic GE cancer. We hypothesize that the response rate (RR) will be improved from 45% to at least 65% under this regimen.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 47
• Est. completion date: August 2015
• Est. primary completion date: July 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 eligible.

PHASE I ONLY

•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.

PHASE II ONLY

• 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.

PHASE I ONLY

•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 study.

PHASE II ONLY

•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.

Study Design

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

Related Conditions & MeSH terms

• Adenocarcinoma
• Gastroesophageal Cancer
• Malignant Solid Tumour
• Neoplasms

Intervention

Drug:
• Tivantinib
Patients with advanced solid tumors will be treated with Tivantinib on Days 1 to 14
• FOLFOX
This treatment regimen will be repeated on Day 1 of each 14-day (2 week) cycle.

Locations

Country	Name	City	State
United States	Tennessee Oncology - Chattanooga	Chattanooga	Tennessee
United States	South Carolina Oncology Associates	Columbia	South Carolina
United States	Florida Cancer Specialists-South	Fort Myers	Florida
United States	Center for Cancer and Blood Disorders	Fort Worth	Texas
United States	Tennessee Oncology, PLLC	Nashville	Tennessee
United States	Yale University School of Medicine	New Haven	Connecticut
United States	Oklahoma University	Oklahoma City	Oklahoma
United States	Florida Cancer Specialists-Sarasota	Sarasota	Florida
United States	Florida Cancer Specialists-North	St. Petersburg	Florida

Sponsors (2)

Lead Sponsor	Collaborator
SCRI Development Innovations, LLC	Daiichi Sankyo Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The number of patients with adverse events as a measure of safety and tolerability	Study Phase I: the maximum tolerated dose (MTD) will be defined as the highest dose level at which no more than 1 of 6 patients experiences a dose-limiting toxicity, assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.	18 Months	Yes
Primary	Response Rate	Study Phase II: response rate is defined as the proportion of complete and partial responders among all treated patients. Best overall response is the best response recorded from start of treatment until disease progression.	18 Months	No
Secondary	Progression Free Survival	Study Phase II: Defined as the time from first treatment until objective tumor progression or death from any cause, assessed by RECIST v1.1.	every 8 weeks until treatment discontinuation, projected 18 months and then every 3 months thereafter up to 5 years from start of treatment.	No
Secondary	Overall Survival	Defined as the time from first treatment until death from any cause, assessed by RECIST v1.1.	every 8 weeks until treatment discontinuation, an expected average of 18 months, then every 12 weeks thereafter up to 5 years from start of treatment.	No
Secondary	Time to Progression	Defined as the time from first treatment until objective tumor progression, assessed using RECIST v1.1.	every 8 weeks until progressive disease, expected 18 months.	No