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Trial of ARQ 197 in Patients With Unresectable Hepatocellular Carcinoma (HCC) Who Have Failed One Prior Systemic Therapy

Primary Purpose

Unresectable Hepatocellular Carcinoma

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
ARQ 197
Placebo
Sponsored by
ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Unresectable Hepatocellular Carcinoma focused on measuring Unresectable, Hepatocellular, Carcinoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Written informed consent granted prior to initiation of any study-specific screening procedures
  • 18 year of age or older
  • Histologically or cytologically confirmed HCC
  • Archival, fresh core needle biopsy or fine needle aspiration (FNA) tumor samples
  • Received at least one cycle of prior systemic therapy (at least 3 weeks for continuously administered drugs) and experienced radiographic disease progression or was unable to tolerate therapy. If intolerance was manifested by a Grade 3 or 4 event of such nature that re-challenge is not acceptable, less than 3 weeks of continuous administration will be allowed
  • Discontinued prior treatment for at least 4 weeks, or at least 2 weeks (14 days) if drug was administered continuously and orally (e.g. sorafenib or sunitinib), prior to the study randomization
  • Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤1
  • Local or loco-regional therapy (i.e., surgery, radiation therapy, hepatic arterial embolization, chemoembolization, radiofrequency ablation, percutaneous ethanol injection, or cryoablation) must have been completed ≥4 weeks prior to randomization
  • Measurable disease as defined by a modified version of the revised Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (see section 9). Tumor lesions previously treated with local therapy should demonstrate clear dimensional increase by radiographic assessment in order to be selected as target lesion(s) at baseline. (Radiological assessment needs to be redone within 7 days prior to randomization if the pre-study AFP level has increased by more than 30% since the last AFP level taken one to four months prior to randomization)
  • Adequate bone marrow, liver, and renal functions at Pre-Study Visit, defined as:

    • Platelet count ≥ 60 × 10^9/L
    • Hemoglobin ≥ 9.0 g/dL
    • Absolute neutrophil count (ANC) ≥1.5 × 10^9/L
    • Total bilirubin ≤ 2 mg/dL
    • Alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 5 × upper limit of normal (ULN)
    • Serum creatinine ≤1.5 × ULN
    • International normalized ratio (INR) 0.8 to 1.4 or ≤3 for patients receiving anticoagulant such as coumadin or heparin. Patients who are therapeutically anticoagulated are allowed to participate provided that no prior evidence of underlying abnormality exists in these parameters
    • Albumin ≥ 2.8 g/dL
  • Women of childbearing potential must have a negative pregnancy test performed within ten 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:

  • More than 1 prior systemic regimen
  • Child-Pugh B-C cirrhotic status
  • Previous or concurrent cancer that is distinct from HCC in primary site or histology, EXCEPT cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta, Tis & T1). Any cancer curatively treated >3 years prior to enrollment is permitted
  • History of congestive heart failure defined as Class II to IV per New York Heart Association (NYHA) classification within 6 months prior to study entry; active coronary artery disease (CAD); clinically significant bradycardia or other uncontrolled, cardiac arrhythmia defined as ≥Grade 3 according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, or uncontrolled hypertension; myocardial infarction occurring within 6 months prior to study entry (myocardial infarction occurring >6 months prior to study entry is permitted)
  • Active clinically serious infections defined as ≥ Grade 3 according to NCI CTCAE, version 4.0.
  • 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
  • History of liver transplant
  • Inability to swallow oral medications
  • Clinically significant gastrointestinal bleeding occurring ≤4 weeks prior to randomization

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

ARQ 197

placebo

Arm Description

Outcomes

Primary Outcome Measures

Evaluate time to progression among all patients treated with ARQ 197 compared to placebo

Secondary Outcome Measures

Evaluate progression-free survival, overall survival, objective response rate and disease control rate among all patients treated with ARQ 197 compared to placebo.
Evaluate objective response rate in crossover population following radiographic disease progression on placebo.
Further characterize the safety of ARQ 197 in patients with unresectable HCC
Further evaluate pharmacokinetics of ARQ 197.

Full Information

First Posted
September 30, 2009
Last Updated
February 22, 2013
Sponsor
ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)
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1. Study Identification

Unique Protocol Identification Number
NCT00988741
Brief Title
Trial of ARQ 197 in Patients With Unresectable Hepatocellular Carcinoma (HCC) Who Have Failed One Prior Systemic Therapy
Official Title
A Randomized Controlled Phase 2 Trial of ARQ 197 in Patients With Unresectable Hepatocellular Carcinoma (HCC) Who Have Failed One Prior Systemic Therapy
Study Type
Interventional

2. Study Status

Record Verification Date
February 2013
Overall Recruitment Status
Completed
Study Start Date
September 2009 (undefined)
Primary Completion Date
October 2011 (Actual)
Study Completion Date
March 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
This is a global randomized, placebo-controlled, double-blinded Phase 2 study designed to compare treatment of ARQ 197 versus placebo in patients with unresectable HCC who had radiographic disease progression after systemic first line therapy or were unable to tolerate the therapy.
Detailed Description
Patients will be randomly assigned in a 2:1 ratio to receive ARQ 197 or placebo. The treatment assignment will be stratified based on Eastern Cooperative Oncology Group (ECOG) performance status (PS), and vascular invasion status. The treatment with ARQ 197 or placebo will be continued until progression of disease, unacceptable toxicity, or another discontinuation criterion listed in this protocol is met. After radiographic disease progression is documented, treatment assignment will be unblinded. Patients who were assigned to placebo arm and had documented radiographic disease progression will have the option to receive ARQ 197 and will be evaluated for objective response rate and disease control rate continuously. The study will continue until 78 total time to progression events are reached. At the end of study, all remaining patients still on treatment will have the option to be rolled over to another study to continue their treatment.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Unresectable Hepatocellular Carcinoma
Keywords
Unresectable, Hepatocellular, Carcinoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
107 (Actual)

8. Arms, Groups, and Interventions

Arm Title
ARQ 197
Arm Type
Experimental
Arm Title
placebo
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
ARQ 197
Other Intervention Name(s)
Tivantinib
Intervention Description
The investigational drug ARQ 197 is supplied as capsules. A dose of 360 mg (3 capsules of 120 mg each) of ARQ 197 will be administered by mouth BID, once in the morning and once in the evening with meals, for a total daily dose of 720 mg. Under Amendment 2, a dose of 240 mg (2 capsules of 120 mg each) of ARQ 197/placebo will be administered by mouth BID, once in the morning and once in the evening with meals, for a total daily dose of 480 mg. A treatment cycle is defined as 4 weeks for both treatment arms. Cycles will be repeated every 4 weeks (28 days) based on toxicity and response.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
The placebo is provided in a capsule form.
Primary Outcome Measure Information:
Title
Evaluate time to progression among all patients treated with ARQ 197 compared to placebo
Time Frame
Patients will be evaluated every 6 weeks until unacceptable toxicity, disease progression or another discontinuation criterion is met
Secondary Outcome Measure Information:
Title
Evaluate progression-free survival, overall survival, objective response rate and disease control rate among all patients treated with ARQ 197 compared to placebo.
Time Frame
Patients will be evaluated for these endpoints every 6 weeks
Title
Evaluate objective response rate in crossover population following radiographic disease progression on placebo.
Time Frame
Patients will be evaluated for these endpoints every 6 weeks
Title
Further characterize the safety of ARQ 197 in patients with unresectable HCC
Time Frame
While on therapy, patients will be evaluated for safety every 4 weeks
Title
Further evaluate pharmacokinetics of ARQ 197.
Time Frame
Patients will be evaluated monthly for the first 3 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Written informed consent granted prior to initiation of any study-specific screening procedures 18 year of age or older Histologically or cytologically confirmed HCC Archival, fresh core needle biopsy or fine needle aspiration (FNA) tumor samples Received at least one cycle of prior systemic therapy (at least 3 weeks for continuously administered drugs) and experienced radiographic disease progression or was unable to tolerate therapy. If intolerance was manifested by a Grade 3 or 4 event of such nature that re-challenge is not acceptable, less than 3 weeks of continuous administration will be allowed Discontinued prior treatment for at least 4 weeks, or at least 2 weeks (14 days) if drug was administered continuously and orally (e.g. sorafenib or sunitinib), prior to the study randomization Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤1 Local or loco-regional therapy (i.e., surgery, radiation therapy, hepatic arterial embolization, chemoembolization, radiofrequency ablation, percutaneous ethanol injection, or cryoablation) must have been completed ≥4 weeks prior to randomization Measurable disease as defined by a modified version of the revised Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (see section 9). Tumor lesions previously treated with local therapy should demonstrate clear dimensional increase by radiographic assessment in order to be selected as target lesion(s) at baseline. (Radiological assessment needs to be redone within 7 days prior to randomization if the pre-study AFP level has increased by more than 30% since the last AFP level taken one to four months prior to randomization) Adequate bone marrow, liver, and renal functions at Pre-Study Visit, defined as: Platelet count ≥ 60 × 10^9/L Hemoglobin ≥ 9.0 g/dL Absolute neutrophil count (ANC) ≥1.5 × 10^9/L Total bilirubin ≤ 2 mg/dL Alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 5 × upper limit of normal (ULN) Serum creatinine ≤1.5 × ULN International normalized ratio (INR) 0.8 to 1.4 or ≤3 for patients receiving anticoagulant such as coumadin or heparin. Patients who are therapeutically anticoagulated are allowed to participate provided that no prior evidence of underlying abnormality exists in these parameters Albumin ≥ 2.8 g/dL Women of childbearing potential must have a negative pregnancy test performed within ten 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: More than 1 prior systemic regimen Child-Pugh B-C cirrhotic status Previous or concurrent cancer that is distinct from HCC in primary site or histology, EXCEPT cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta, Tis & T1). Any cancer curatively treated >3 years prior to enrollment is permitted History of congestive heart failure defined as Class II to IV per New York Heart Association (NYHA) classification within 6 months prior to study entry; active coronary artery disease (CAD); clinically significant bradycardia or other uncontrolled, cardiac arrhythmia defined as ≥Grade 3 according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, or uncontrolled hypertension; myocardial infarction occurring within 6 months prior to study entry (myocardial infarction occurring >6 months prior to study entry is permitted) Active clinically serious infections defined as ≥ Grade 3 according to NCI CTCAE, version 4.0. 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 History of liver transplant Inability to swallow oral medications Clinically significant gastrointestinal bleeding occurring ≤4 weeks prior to randomization
Facility Information:
City
Los Angeles
State/Province
California
ZIP/Postal Code
90048
Country
United States
City
Tampa
State/Province
Florida
ZIP/Postal Code
33612
Country
United States
City
Galveston
State/Province
Texas
ZIP/Postal Code
77555
Country
United States
City
Brussels
ZIP/Postal Code
1070
Country
Belgium
City
Brussels
ZIP/Postal Code
1200
Country
Belgium
City
Gent
ZIP/Postal Code
9000
Country
Belgium
City
Toronto
ZIP/Postal Code
M5G 2N2
Country
Canada
City
Vancouver
ZIP/Postal Code
V5Z 1M9
Country
Canada
City
Essen
ZIP/Postal Code
45123
Country
Germany
City
Frankfurt am Main
ZIP/Postal Code
D-60594
Country
Germany
City
Hamburg
ZIP/Postal Code
20099
Country
Germany
City
Munchen
ZIP/Postal Code
81337
Country
Germany
City
Munchen
ZIP/Postal Code
81657
Country
Germany
City
Avellino
ZIP/Postal Code
83100
Country
Italy
City
Benevento
ZIP/Postal Code
82100
Country
Italy
City
Bologna
ZIP/Postal Code
40138
Country
Italy
City
Padova
ZIP/Postal Code
35128
Country
Italy
City
Parma
ZIP/Postal Code
43126
Country
Italy
City
Pavia
ZIP/Postal Code
27100
Country
Italy
City
Pisa
ZIP/Postal Code
56100
Country
Italy
City
Reggio Emilia
ZIP/Postal Code
42100
Country
Italy
City
Roma
ZIP/Postal Code
00168
Country
Italy
City
Rozzano Milano
ZIP/Postal Code
20089
Country
Italy

12. IPD Sharing Statement

Citations:
PubMed Identifier
23182627
Citation
Santoro A, Rimassa L, Borbath I, Daniele B, Salvagni S, Van Laethem JL, Van Vlierberghe H, Trojan J, Kolligs FT, Weiss A, Miles S, Gasbarrini A, Lencioni M, Cicalese L, Sherman M, Gridelli C, Buggisch P, Gerken G, Schmid RM, Boni C, Personeni N, Hassoun Z, Abbadessa G, Schwartz B, Von Roemeling R, Lamar ME, Chen Y, Porta C. Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebo-controlled phase 2 study. Lancet Oncol. 2013 Jan;14(1):55-63. doi: 10.1016/S1470-2045(12)70490-4. Epub 2012 Nov 20.
Results Reference
derived

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Trial of ARQ 197 in Patients With Unresectable Hepatocellular Carcinoma (HCC) Who Have Failed One Prior Systemic Therapy

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