An Exploratory Biomarker Study of ARQ 501 in Patients With Advanced Solid Tumors

This study is designed to evaluate the response of several biomarkers in patients treated with ARQ 501. The results of the study may help the sponsor understand the effect of the study drug on these biomarkers and their respective role in cancer growth control.

Study Overview

• Status: Completed
• Conditions: Advanced Solid Tumors
• Intervention / Treatment: Drug: ARQ 501

Detailed Description

ARQ 501 is an investigational anticancer agent that consists of a fully synthetic small molecule version of β-lapachone (3,4-dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione) in a stable formulation for intravenous (IV) administration. ARQ 501 selectively induces apoptosis in cancer cells by the direct activation of the cellular checkpoints without damaging deoxyribonucleic acid (DNA) or microtubules. This therapeutic approach is known as Activated Checkpoint Therapy (ACT)sm. ACTsm is a novel strategy for treating and preventing cancers. Cell cycle checkpoints constitute an internal surveillance system that detects cellular, especially genetic, damage and either allows the cells to repair the damage, or induces apoptosis when damage is not repairable. Cancer cells are selectively eliminated upon checkpoint activation due to presence of irreparable DNA damage. It is believed that the rapid and selective induction of apoptosis in cancer cells by ARQ 501 is caused by a correspondingly rapid and sustained increase of the pro-apoptotic protein E2F1.

Preclinical studies have shown that exposure to ARQ 501 results in the activation or inactivation of a panel of 5 biomarkers. Time course changes in human tumor xenograft biomakers in athymic mice after exposure to ARQ 501 can be classified into 3 biomarker groups: those that changed shortly after exposure and returned to normal within 24 hours; those that changed shortly after exposure and remained for 24 hours or longer; and those that changed after 24 hours or later.

The primary objective is to evaluate the response of biomarkers in patients treated with ARQ 501. The exploratory study will help to illuminate the pharmacodynamics of these biomarkers, their roles in the cancer growth control, and their potential predictive or prognostic values for the disease and treatment of ARQ 501 in humans.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana Farber Cancer Institute

Participation Criteria

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:

1. Able to provide signed and dated informed consent prior to study-specific screening procedures.
2. Patients must have histologically or cytologically confirmed advanced solid tumor(s).
3. Measurable disease as defined by RECIST (see Section 9.0).
4. Patients must have Karnofsky performance status (KPS) ≥ 70%.
5. Male or female patients of child-producing potential must agree to contraception or avoidance of pregnancy measures during the study and for 30 days after the infusion of ARQ 501.
6. Females of childbearing potential must have a negative serum pregnancy test within seven days prior to the administration of study drug.
7. ≥ 18 years old.
8. Hemoglobin ≥ 10 g/dL
9. Absolute neutrophil count (ANC) ≥ 1.5 x 10 9/L (≥1,500/mm3).
10. Platelets ≥ 100 x 10 9/L (≥ 100,000/mm3).
11. Total bilirubin ≤ 1.5 x upper limit of normal (ULN) or ≤ 3.0 x ULN with metastatic liver disease.
12. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN or ≤ 5.0 x ULN with metastatic liver disease.
13. Creatinine ≤ 1.5 × ULN

Exclusion Criteria:

1. Active, uncontrolled systemic infection considered opportunistic, life threatening or clinically significant at the time of treatment
2. Received anticancer chemotherapy, immunotherapy, radiotherapy, surgery or investigational agents within four weeks of first infusion
3. Symptomatic or untreated central nervous system (CNS) involvement
4. Previous exposure to ARQ 501

Study Plan

How is the study designed?

Design Details

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
To evaluate the pharmacodynamics of a panel of biomarkers following administration of ARQ 501	Up to 30 hours after a single dose of ARQ 501

Secondary Outcome Measures

Outcome Measure
To further characterize the safety and tolerability of ARQ 501
To assess anti-tumor activity of ARQ 501

Collaborators and Investigators

• Sponsor: ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)
• Investigators: Principal Investigator: Geoffrey Shapiro, MD, PhD, Dana-Farber Cancer Institute

Study record dates

Study Major Dates

• Study Start: August 1, 2007
• Primary Completion (Actual): August 1, 2008
• Study Completion (Actual): August 1, 2008

Study Registration Dates

• First Submitted: August 30, 2007
• First Submitted That Met QC Criteria: August 30, 2007
• First Posted (Estimate): September 3, 2007

Study Record Updates

• Last Update Posted (Estimate): October 19, 2011
• Last Update Submitted That Met QC Criteria: October 17, 2011
• Last Verified: October 1, 2011

More Information

Terms related to this study

• Keywords: solid tumors; biopsy
• Additional Relevant MeSH Terms: Neoplasms; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Beta-lapachone
• Other Study ID Numbers: ARQ 501-109