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Study Summary
No. 2009-0990:.......Colorectum......Cathy Eng......Gastrointestinal Medical Oncology
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Study Summary Title
Study Summary
Number:
2009-0990
Study Title:A Randomized, Placebo-Controlled, Phase I/2 Study of ARQ 197 in Combination with Irinotecan and Cetuximab in Subjects with Metastatic Colorectal Cancer with Wild-Type KRAS Who Have Received Front-Line Systemic Therapy (ARQ 197-A-U252)
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Physician New Patient Referral
Name:Cathy EngPatients Call:800-392-1611 (in U.S.A.) 713-792-6161 (outside U.S.A.)
Dept:Gastrointestinal Medical OncologyReferring MD
Call:
800-392-1611 (in U.S.A.) 713-792-6161 (outside U.S.A.)
Phone:713-792-2828
Contact us about clinical trials
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General Information
Disease Group:ColorectumSupported By:Daiichi Sankyo Pharma Development
Phase of Study:Phase I/Phase IIReturn
Visit:
Every 2 weeks.
Treatment
Agents:
ARQ-197
Cetuximab
Irinotecan
Home Care:ARQ 197 is administered orally and patients may self-administer it.
Treatment Loc:Both at MDACC & outside MDACC at one or more Collaborating Sites or Institutions
Estimated
Length of Stay
in Houston:
Hospitalization is not required
Description/
Intervention:
The goal of this clinical research study is to find the highest tolerable dose
of the combination of ARQ 197, Camptosar® (irinotecan), and ERBITUX®
(cetuximab) that can be given to patients with metastatic colorectal cancer.
The safety of this drug combination will also be studied.

Optional Procedures: You are being asked to allow blood left over from a test
performed on this study to be stored in a research blood bank for use in future
research related to cancer.
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Study Objectives / Outcomes
    Study Objectives

    Phase 1 Primary Objectives
    • To evaluate the safety and tolerability of ARQ 197 when administered with irinotecan and cetuximab in subjects with colorectal cancer (CRC) with wild-type v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) who have received front-line systemic therapy.
    • To define the recommended dose of ARQ 197, in combination with irinotecan and cetuximab, for Phase 2 study.

    Phase 2
    Primary Objective
    • To estimate the difference in progression-free survival (PFS) between the study and control arms in subjects with CRC with wild-type KRAS who have received front-line systemic therapy.

    Secondary Objectives
    • To estimate the difference between control and study arms in overall survival (OS) and objective response rate (ORR).
    • To evaluate the safety profile of ARQ 197 in combination with irinotecan and cetuximab.

    Exploratory Objectives
    • To evaluate the changes in epidermal growth factor receptor (EGFR) mutations, v-raf murine sarcoma viral oncogene homolog B1(BRAF) mutations, EGFR fluorescence in-situ hybridization (FISH), mesenchymal-epithelial transition factor (c-MET FISH), immunohistochemistry (IHC) for total c-MET, phosphatase and tensin homolog (PTEN) in tumors and explore their correlation with the effects of study treatment.
    • To evaluate the changes in hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), s-c-MET, and sVEGF receptor (VEGFR) in plasma.
    • To evaluate additional biomarkers, using these tumor and blood samples, as new data suggest.
    • To explore the relationship between common genetic variants in CYP2C19 and UGT1A1 on primary and secondary endpoints as well as pharmacokinetic (PK) and pharmacodynamic measurements.
    • To evaluate the PK/pharmacodynamic relationship of ARQ 197. Population PK/pharmacodynamic analysis will be conducted separately with possible pooling of data from other clinical studies of ARQ 197. This analysis will not be part of the statistical analysis plan (SAP) for this study.
    • To evaluate the population PK of irinotecan and the active metabolite SN-38. This will be conducted separately. This analysis will not be part of the SAP for this study.
    • To evaluate health-related quality of life (HRQOL), based on the Functional Assessment of Cancer Therapy-Colorectal (FACT-C) scale, in the control and study arms.
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Study Status Information
Study Activation / Registration Date:05/28/2010
IRB Review and Approval Date:05/28/2010
Study Type:Phase Ii Or Phase I/Ii
Recruitment Status:Closed
Projected Accrual:168
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Enrollment Eligibility
If you do not meet the enrollment eligibility, there may be other treatment options for you. Please Contact the Referral Office for more information.

Inclusion Criteria:1) Subjects with surgically unresectable locally advanced or metastatic disease who have received one prior line of chemotherapy, including irinotecan-based chemotherapy. Subjects who received only adjuvant treatment will be eligible if disease progressed less than 6 months after completion of adjuvant therapy. (The Phase 1 portion of the study will be open for enrollment for subjects who received 1 or more prior therapies). Both relapsed and refractory CRC are allowed. Subjects must have radiologically documented disease progression prior to enrollment.

2) All subjects must express the wild-type form of the gene KRAS.

3) Measurable disease according to RECIST criteria, Version 1.1.

4) Male or female >/= 18 years of age.

5) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

6) Resolution of any toxic effects of prior therapy (except alopecia) to NCI CTCAE, Version 4.0, grade </= 1.

7) Adequate bone marrow, liver, and renal functions, defined as: Hemoglobin >/= 9.0 g/dL (transfusion and/or growth factor support allowed); Absolute neutrophil count (ANC) >/= 1.5 x 10^9/L; Platelet count >/= 75 x 10^9/L; Serum creatinine </= 1.5 x upper limit of normal (ULN) or creatinine clearance >/= 60 mL/min; Alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase </= 2.5 x ULN in subjects with no liver metastasis and </= 5.0 x ULN in subjects with liver metastasis;

8) (continued from # 7) Total bilirubin </= 1.5 x ULN (</= 4 x ULN and direct bilirubin </= 1.5 x ULN is acceptable for subjects with Gilbert's syndrome).

9) 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.

10) All female subjects of childbearing potential must each have a negative pregnancy test (serum or urine) result before initiating study treatment.

11) Subjects must be fully informed about their illness and the investigational nature of the study protocol (including foreseeable risks and possible side effects) and must sign and date an Independent Ethics Committee (IEC) or Institutional Review Board (IRB)-approved informed consent form (ICF) [including Health Insurance Portability and Accountability Act (HlPAA) authorization, if applicable] before performance of any study-specific procedures or tests.

Exclusion Criteria:1) Prior therapy with an EGFR inhibitor.

2) History of malignancy other than CRC, unless there is an exception that the malignancy has been cured and no tumor-specific treatment for the malignancy has been administered within the 5 years prior to initiation of study treatment (subjects with a history of basal cell carcinoma or benign tumor of cervix can be enrolled if diagnosis and treatment occurred < 3 years prior to randomization).

3) Anticipation of need for a major surgical procedure or radiation therapy (RT) during the study.

4) Treatment with chemotherapy, radiotherapy, surgery, immunotherapy, biological therapy, or any other investigational anticancer agent within 4 weeks prior to start of study treatment.

5) 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 or higher according to NCI CTCAE, version 4.0, or uncontrolled hypertension; Myocardial infarction that occurred within 6 months prior to start of study treatment (myocardial infarction that occurred > 6 months before the start of study treatment is permitted).

6) Malabsorption syndrome, chronic diarrhea (lasting > 4 weeks), inflammatory bowel disease, or partial bowel obstruction.

7) Known metastatic brain or meningeal tumors, unless the subject is > 6 months from definitive therapy, has a negative imaging study within 4 weeks of first dose of study treatment, and is clinically stable (no concomitant therapy, including supportive therapy with steroids or anticonvulsant medications) with respect to the tumor at the time of first dose of study treatment.

8) Uncontrolled seizure disorder, spinal cord compression, or carcinomatous meningitis.

9) Pericardial or pleural effusion (eg, requiring drainage) or pericardial involvement with the tumor. Subjects with minimal pleural effusion may be eligible upon request by Investigator and approval by Sponsor.

10) Clinically significant active infection that requires antibiotic therapy.

11) Previous administration of ARQ 197 (or other known c-MET inhibitor).

12) Substance abuse or medical, psychological or social conditions that may, in the opinion of the Investigator, interfere with the subject's participation in the clinical trial or evaluation of the clinical trial results.

13) Any condition that is unstable or that could jeopardize the safety of the subject and the subject's protocol compliance, including known human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.

14) Inability to swallow oral medications.

15) Pregnant or nursing females.

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Links
Registration Number: NCT01075048
Study Information on Clinical Trials Registry (clinicaltrials.gov)

Other Links:
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Results


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