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

NCT00827177 | Completed Phase 1

• 1 other identifier: ARQ 197-116
• Study Type: interventional
• Target: 87
• Locations: 2 countries
• Sites: 4

Brief Summary

This is an open-label, dose-escalation study of ARQ 197 administered orally in combination with sorafenib.

Conditions

Advanced Solid Tumors

Keywords

dose escalation; safety; tolerability; tumor; PK; hepatocellular carcinoma; renal cell carcinoma; melanoma; non-small cell lung cancer; breast cancer

Outcome Measures

Primary Outcomes (1)

• To identify maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of ARQ 197 when administered in combination with sorafenib.

  6 to 9 months. Patients will remain on study until progression of disease, unacceptable toxicity, or other discontinuation criterion is met.

Secondary Outcomes (3)

• To determine the pharmacokinetic profiles of ARQ 197 and sorafenib.

  Patients will remain on study until progression of disease, unacceptable toxicity, or other discontinuation criterion is met.

• To assess the preliminary anti-tumor activity of ARQ 197 when administered in combination with sorafenib.

  Patients will remain on study until progression of disease, unacceptable toxicity, or other 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 sorafenib.

  Patients will remain on study until progression of disease, unacceptable toxicity, or other discontinuation criterion is met.

Study Arms (1)

ARQ 197 in combination with sorafenib

EXPERIMENTAL

Drug: Treatment with ARQ 197 in combination with sorafenib

Interventions

Treatment with ARQ 197 in combination with sorafenib DRUG

Patients will be treated with ARQ 197 and sorafenib at Dose Level 1 (ARQ 197 360 mg twice daily (bid) and sorafenib 200 mg bid). Patients with HCC will start treatment with ARQ 197 at 240 mg bid and sorafenib 200 mg bid. Enrollment of subsequent patient cohort will depend on the safety and tolerability of the combination treatment in the initial cohort. If \< 33% patients treated at Dose Level 1 experience dose-limiting toxicity(ies) (DLT) by the end of first treatment cycle (4 weeks), then next cohort of 6 patients will be enrolled and treated at Dose Level 2 (ARQ 197 360 mg bid and sorafenib 400 mg bid). If ≥ 33% patients treated at Dose Level 1 experience DLT(s) by the end of first treatment cycle, the next cohort of 6 patients will be enrolled and treated at Dose Level 0 (ARQ 197 240 mg bid and sorafenib 200 mg bid).

ARQ 197 in combination with sorafenib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent granted prior to initiation of any study-specific screening procedures
• year of age or older
• Histologically or cytologically confirmed locally advanced, inoperable or metastatic solid tumors. In the two expansion cohorts, only patients with histologically or cytologically confirmed HCC, RCC, breast cancer, NSCLC and melanoma are eligible. An exception for this criterion is that patients with HCC may be enrolled without histological confirmation of disease so long as they meet the following criteria for diagnosis of HCC (and all other protocol eligibility criteria):
• Lesion \> 2cm in diameter
• α-fetoprotein (AFP) \> 200 ng/mL
• Radiological appearance of mass is suggestive of HCC
• Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤1
• Adequate bone marrow, liver, and renal functions, defined as:
• Platelet count ≥ 100 × 10\^9/L (≥ 60 × 10\^9/L for HCC patients enrolled in the expanded cohort)
• Hemoglobin ≥ 10 g/dL
• Absolute neutrophil count (ANC) ≥1.5 × 10\^9/L
• Total bilirubin ≤ 1.5 mg/dL or ≤ 3 mg/dL with HCC or metastatic liver disease
• Alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 2.5 × upper limit of normal (ULN) or ≤ 5 × ULN with HCC or metastatic liver disease
• Serum creatinine ≤1.5 × ULN

You may not qualify if:

• Previous anti-cancer chemotherapy, radiotherapy, immunotherapy or investigational agents within 4 weeks prior to the first day of study defined treatment with the following exceptions: 1) a prostate cancer patient on androgen deprivation with gonadotropin-releasing hormone (GnRH) agonists can be enrolled while he remains on the immunotherapy; 2) a patient received palliative radiotherapy previous can be enrolled if the therapy was completed 1 week (7 days) prior to the first day of study defined treatment and the patient has recovered from any radiotherapy-related adverse event(s); and 3) patients are currently on sorafenib can be enrolled
• 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 clinically significant bradycardia, other uncontrolled 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 sorafenib (e.g. significant, uncontrolled inflammatory bowel disease or extensive small bowel resection).

Sponsors & Collaborators

• ArQule, Inc., a subsidiary of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (Rahway, NJ USA): lead

Study Sites (4)

Unknown Facility

Boston, Massachusetts, 02111, United States

Location

Roswell Park Cancer Institute

Buffalo, New York, 14263, United States

Location

Unknown Facility

Nashville, Tennessee, 37232, United States

Location

Unknown Facility

Rozzano, 20089, Italy

Location

MeSH Terms

Conditions

Neoplasms; Carcinoma, Hepatocellular; Carcinoma, Renal Cell; Melanoma; Carcinoma, Non-Small-Cell Lung; Breast Neoplasms

Interventions

Therapeutics; ARQ 197; Sorafenib

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Skin Diseases; Skin and Connective Tissue Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases; Breast Diseases

Intervention Hierarchy (Ancestors)

Phenylurea Compounds; Urea; Amides; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Niacinamide; Nicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 21, 2009
• First Posted: January 22, 2009
• Study Start: September 1, 2009
• Primary Completion: September 1, 2012
• Study Completion: May 1, 2013
• Last Updated: January 24, 2014

Record last verified: 2014-01

Locations

IT (1); US (3)