Dose Escalation Study of ARQ 197 in Combination With Gemcitabine in Adult Patients With Advanced Solid Tumors

July 20, 2012 updated by: ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)

A Phase 1 Dose Escalation Study of ARQ 197 Administered in Combination With Gemcitabine in Adult Patients With Advanced Solid Tumors

This is an open-label, dose-escalation/de-escalation study of ARQ 197 administered orally in combination with gemcitabine. The study is designed to determine the safety, tolerability and maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of ARQ 197 when administered in combination with gemcitabine to patients with advanced solid tumors.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Enrollment of an initial cohort of 3 or 6 patients will follow the traditional "3 + 3" dose escalation scheme. These patients will be treated with ARQ 197 and gemcitabine. ARQ 197 will be administered by mouth BID continuously. Gemcitabine will be administered by intravenous infusion over 30 minutes once weekly for 3 consecutive weeks followed by a week of rest. The dosing schedules of ARQ 197 and gemcitabine will be as described below.

ARQ 197 will be administered per the following cohorts, starting from week 1 of treatment.

Cohort------ARQ 197 (mg BID)

0-----------120, continuously

1-----------240, continuously

A-----------120 (repeated treatments of 2 weeks followed by a 1 week pause)

B-----------240 (repeated treatments of 2 weeks followed by a 1 week pause)

C-----------360 (repeated treatments of 2 weeks followed by a 1 week pause)

D-----------360 (repeated treatments of 3 weeks followed by a 1 week pause)

E-----------360, continuously

In case of DLT, intermediate dosing cohorts will be explored, administering ARQ 197 for 5 days instead of 7 during the weeks of ARQ 197 administration.

For cohorts 0 and 1, gemcitabine is administered at the dose of 1000mg/sqm from week 1 of treatment, 4 weeks in a row for the first month, then for 3 consecutive weeks followed by a week of pause. For all other cohorts, gemcitabine will be administered starting from week 2 of treatment at the dose of 1000mg/sqm, for 3 consecutive weeks followed by a week of pause.

Additional treatment cohorts may be enrolled to explore intermediate, higher or lower doses of ARQ 197, as indicated by the tolerability, safety profile, and pharmacokinetic (PK) profile.

Once a safe and recommended dose level is determined, an Expanded Cohort of up to 60 patients with non-resectable cholangiocarcinoma (10 patients), breast carcinoma (10 patients), ovarian carcinoma (10 patients), endometrial carcinoma and carcinoma of the cervix (10 patients in total, at least five with endometrial carcinoma). Each group of 10 patients may enroll up to three patients who received at least 5-week gemcitabine treatment. The cohort will also include up to 20 patients with pancreatic carcinoma (up to five out of 20 patients may have received at least 5-week gemcitabine treatment).

Study Type

Interventional

Enrollment (Actual)

74

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Georgia
      • Atlanta, Georgia, United States, 30341
    • Oklahoma
      • Oklahoma City, Oklahoma, United States, 73104
    • Tennessee
      • Nashville, Tennessee, United States, 37203
    • Texas
      • Houston, Texas, United States, 77024

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

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:

  • Written informed consent granted prior to initiation of any study-specific screening procedures, given with the understanding that the patient has the right to withdraw from the study at any time, without prejudice
  • 18 year of age or older
  • Histologically or cytologically confirmed locally advanced, inoperable or metastatic primary solid tumors
  • Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤1
  • Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x upper limit of normal (ULN) or ≤ 5 x ULN with metastatic liver disease
  • Hemoglobin ≥ 10 g/dl (or ≥ 9 g/dl for expanded cohort)
  • Total bilirubin ≤ 1.5 x ULN
  • Serum creatinine ≤ 1.5 x ULN
  • Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L
  • Platelets ≥ 100 x 10^9/L
  • Women of childbearing potential must have a negative pregnancy test performed within seven days prior to the start of study drug
  • Male and female subjects of child-bearing potential must agree to use double-barrier contraceptive measures, oral contraception, or avoidance of intercourse during the study and for 90 days after last investigational drug dose received

Exclusion Criteria:

  • Other cancer within the last three years, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri or basal or squamous cell carcinoma of the skin
  • Previous anti-cancer chemotherapy, radiotherapy, major surgery, immunotherapy or investigational agents within 4 weeks prior to the first day of study defined treatment
  • History of cardiac disease: congestive heart failure defined as Class II to IV per New York Heart Association (NYHA) classification; active coronary artery disease (CAD); previously diagnosed bradycardia or other cardiac arrhythmia defined as ≥ Grade 2 according to National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) (version 3.0), or uncontrolled hypertension; myocardial infarction occurred within 6 months prior to study entry (myocardial infarction occurred > 6 months prior to study entry is permitted)
  • Active clinically serious infections defined as ≥ Grade 2 according to NCI CTCAE, version 3.0
  • Substance abuse, medical, psychological or social conditions that may, in the opinion of the Investigator, interfere with the patient's participation in the study or evaluation of the study results
  • Any condition that is unstable or which could jeopardize the safety of the patient and his/her protocol compliance
  • Known human immunodeficiency virus (HIV) infection
  • Pregnancy or breast-feeding
  • Inability to swallow oral medications
  • Significant gastrointestinal disorder, in the opinion of the Investigator, could interfere with the absorption of ARQ 197 and/or gemcitabine (e.g. significant, uncontrolled inflammatory bowel disease or extensive small bowel resection)
  • Central nervous system metastases

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: ARQ 197 in combination with gemcitabine
Drug: Treatment with ARQ 197 in combination with gemcitabine
Enrollment of an initial cohort of 3 or 6 patients will follow the traditional "3 + 3" dose escalation scheme. These patients will be treated with ARQ 197 and gemcitabine. ARQ 197 will be administered by mouth BID continuously. Gemcitabine will be administered by intravenous infusion over 30 minutes once weekly for 3 consecutive weeks followed by a week of rest.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
To determine the safety, tolerability and maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of ARQ 197 when administered in combination with gemcitabine.
Time Frame: Patients will remain on study until unacceptable toxicity, disease progression (clinical or radiological) or another discontinuation criterion is met.
Patients will remain on study until unacceptable toxicity, disease progression (clinical or radiological) or another discontinuation criterion is met.

Secondary Outcome Measures

Outcome Measure
Time Frame
To determine the pharmacokinetic profiles of ARQ 197, gemcitabine and dFdU inactive metabolite of gemcitabine when administered in combination.
To assess the preliminary anti-tumor activity of ARQ 197 when administered in combination with gemcitabine.
Time Frame: Patients will remain on study until unacceptable toxicity, disease progression (clinical or radiological) or another discontinuation criterion is met.
Patients will remain on study until unacceptable toxicity, disease progression (clinical or radiological) or another discontinuation criterion is met.
To evaluate dynamic changes of hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and soluble c-Met in patients' peripheral blood that are associated with treatment of ARQ 197 plus gemcitabine.
Time Frame: Patients will remain on study until unacceptable toxicity, disease progression (clinical or radiological) or another discontinuation criterion is met.
Patients will remain on study until unacceptable toxicity, disease progression (clinical or radiological) or another discontinuation criterion is met.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

March 1, 2009

Primary Completion (Actual)

February 1, 2011

Study Completion (Actual)

April 1, 2011

Study Registration Dates

First Submitted

April 1, 2009

First Submitted That Met QC Criteria

April 1, 2009

First Posted (Estimate)

April 2, 2009

Study Record Updates

Last Update Posted (Estimate)

July 23, 2012

Last Update Submitted That Met QC Criteria

July 20, 2012

Last Verified

July 1, 2012

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ARQ 197-117

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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