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Study of Tivantinib (ARQ 197) Plus Cetuximab in EGFR Inhibitor-Resistant MET High Subjects

Primary Purpose

Colorectal Cancer Metastatic, C-met Overexpression

Status
Completed
Phase
Phase 2
Locations
Italy
Study Type
Interventional
Intervention
Tivantinib (ARQ197)
Sponsored by
Armando Santoro, MD
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Colorectal Cancer Metastatic focused on measuring Colorectal Cancer Metastatic, wild type KRAS, C-met overexpression, Tivantinib, Cetuximab

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:Subjects must satisfy all of the following criteria to be included in the study:

  1. Subjects with surgically unresectable locally advanced or metastatic disease who have received ≥ 1 prior line of systemic therapies for advanced or metastatic disease. The last treatment regimen must include EGFR inhibitor (cetuximab or panitumumab) on which the patient had a best response as CR or PR or SD, and must have either progressed on or after EGFR inhibitor based therapy within 3 months before enrollment. Subjects must have radiologically documented disease progression prior to enrollment.
  2. All subjects must express the wild-type form of the gene KRAS. Previously existing KRAS mutation status from an accredited local laboratory will be accepted.
  3. Fresh tumor biopsy tissue must be available for molecular sequencing and biomarker expression in >70% of patients. If prior radiotherapy, tissue biopsy must be outside radiotherapy field. In a minor percentage of patients (<30%) archival tumor tissue could be considered acceptable for molecular sequencing and biomarker expression.
  4. Patients must be MET High testing by IHC (IHC 2+ or 3+ in ≥50% of tumor cells) analyzed by Ventana Test Kit.
  5. Measurable disease according to RECIST criteria, Version 1.1.
  6. Male or female ≥ 18 years of age.
  7. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.
  8. Resolution of any toxic effects of prior therapy to NCI CTCAE, Version 4.0, grade ≤ 1 (with the exception of alopecia and grade ≤ 2 neuropathy).
  9. 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 × 109/L. Platelet count ≥ 75 × 109/L. Serum creatinine ≤ 1.5 × upper limit of normal (ULN) or creatinine clearance ≥ 60 mL/min. Alanine transaminase (ALT), and aspartate transaminase (AST) ≤ 2.5 x ULN in subjects with no liver metastasis and ≤ 5.0 x ULN in subjects with liver metastasis. Total bilirubin ≤ 1.5 x ULN (≤ 4 x ULN and direct bilirubin ≤ 1.5 x ULN is acceptable for subjects with Gilbert's syndrome).

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

12. 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 IEC- or IRB-approved ICF (including HIPAA authorization, if applicable) before performance of any study-specific procedures or tests.

Exclusion Criteria:

Subjects who meet any of the following criteria will be disqualified from entering the study:

  1. 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 3 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 enrollment).
  2. Anticipation of need for a major surgical procedure or radiation therapy (RT) during the study.
  3. Treatment with chemotherapy, radiotherapy, surgery, immunotherapy, biological therapy, or any other investigational anticancer agent within 3 weeks prior to start of study treatment.
  4. 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 (subjects with asymptomatic bradycardia and hear rate above 50 bpm are allowed) 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 prior the start of study treatment is permitted).
  5. Malabsorption syndrome, chronic diarrhea (lasting > 4 weeks), inflammatory bowel disease, or partial bowel obstruction.
  6. 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.
  7. Uncontrolled seizure disorder, spinal cord compression, or carcinomatous meningitis.
  8. Pericardial or pleural effusion (requiring drainage) or pericardial involvement with the tumor. Subjects with minimal pleural effusion may be eligible upon request by Investigator and approval by Sponsor.
  9. Clinically significant active infection that requires antibiotic therapy.
  10. Previous administration of any MET inhibitor (including tivantinib) or EGFR inhibitor (except cetuximab or panitumumab).
  11. 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.
  12. Any condition that is unstable or that could jeopardize the safety of the subject and the subject's protocol compliance.
  13. Inability to swallow oral medications.
  14. Pregnant or nursing females.

Sites / Locations

  • Istituto Clinico Humanitas

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Tivantinib plus Cetuximab

Arm Description

Single arm

Outcomes

Primary Outcome Measures

Study of Tivantinib (ARQ 197) plus Cetuximab in EGFR inhibitor-Resistant MET High Subjects with Locally Advanced or Metastatic Colorectal Cancer with Wild-Type KRAS
To determine objective response rate (ORR).

Secondary Outcome Measures

Tivantinib (ARQ 197) plus Cetuximab in EGFR inhibitor-Resistant MET High Subjects
To estimate progression-free survival (PFS).

Full Information

First Posted
May 6, 2013
Last Updated
September 8, 2022
Sponsor
Armando Santoro, MD
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1. Study Identification

Unique Protocol Identification Number
NCT01892527
Brief Title
Study of Tivantinib (ARQ 197) Plus Cetuximab in EGFR Inhibitor-Resistant MET High Subjects
Official Title
A Single-Arm Phase II Study of Tivantinib (ARQ 197) Plus Cetuximab in EGFR Inhibitor-Resistant MET High Subjects With Locally Advanced or Metastatic Colorectal Cancer With Wild-Type KRAS
Study Type
Interventional

2. Study Status

Record Verification Date
September 2022
Overall Recruitment Status
Completed
Study Start Date
March 2013 (undefined)
Primary Completion Date
May 2016 (Actual)
Study Completion Date
March 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Armando Santoro, MD

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a single-arm, Simon 2-stage, phase 2 clinical study conducted in subjects with advanced or metastatic colorectal cancer who have previously received ≥ 1 prior line of systemic therapies and are resistant to EGFR inhibitor (cetuximab or panitumumab). This trial will be conducted to determine objective response rate (ORR), progression-free survival (PFS) and overall-survival (OS) of cetuximab plus tivantinib in patients with wild-type KRAS CRC that is resistant to anti-EGFR antibody treatment (cetuximab or panitumumab) and shows overexpression of cMET.
Detailed Description
This is a single-arm, Simon 2-stage, phase 2 clinical study conducted in subjects with advanced or metastatic colorectal cancer who have received ≥1 prior line of systemic therapies and are resistant to EGFR inhibitor (cetuximab or panitumumab). Fresh tumor tissue is needed for the MET testing, thus a biopsy will be required to participate in this trial. In a minor percentage of subjects archival tumor tissue could be acceptable for this analysis.Eligible subjects will be treated with tivantinib (ARQ 197) at a dose of 360 mg twice daily (a total daily dose of 720 mg) orally in a continuous manner and cetuximab (Erbitux) at a dose of 500 mg/mq i.v. every 2 weeks. The overall treatment period will be divided into continuous 28 days cycles without treatment interruption. Disease status and tumor response will be assessed per modified Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.1 at screening (within 4 weeks before the first scheduled dose of study drug), in 8 weeks intervals while the subjects are on treatment or as clinically indicated until progression of disease, withdrawal of consent, death, or lost to follow-up. Tumor measurement will also be performed during the end of treatment visit if not done within the previous 8 weeks. Subjects with progressive disease at any time during the treatment period will discontinue study treatment. Subjects with stable disease (SD), complete response (CR) and partial response (PR) will stay on treatment until disease progression and/or unacceptable toxicity and/or withdrawal of consent is documented. CR and PR must be confirmed no sooner than 4 weeks after the initial observation. After discontinuation from study treatment during the follow-up period, survival status will be obtained by phone every 3 months until the subject dies, withdraws consent from study, or is lost to follow-up, for a maximum of 12 months.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Colorectal Cancer Metastatic, C-met Overexpression
Keywords
Colorectal Cancer Metastatic, wild type KRAS, C-met overexpression, Tivantinib, Cetuximab

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
43 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Tivantinib plus Cetuximab
Arm Type
Experimental
Arm Description
Single arm
Intervention Type
Drug
Intervention Name(s)
Tivantinib (ARQ197)
Other Intervention Name(s)
Cetuximab
Intervention Description
Eligible subjects will be treated with tivantinib (ARQ 197) at a dose of 360 mg twice daily (a total daily dose of 720 mg) orally in a continuous manner and cetuximab (Erbitux) at a dose of 500 mg/mq i.v. every 2 weeks.
Primary Outcome Measure Information:
Title
Study of Tivantinib (ARQ 197) plus Cetuximab in EGFR inhibitor-Resistant MET High Subjects with Locally Advanced or Metastatic Colorectal Cancer with Wild-Type KRAS
Description
To determine objective response rate (ORR).
Time Frame
36 months
Secondary Outcome Measure Information:
Title
Tivantinib (ARQ 197) plus Cetuximab in EGFR inhibitor-Resistant MET High Subjects
Description
To estimate progression-free survival (PFS).
Time Frame
36months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:Subjects must satisfy all of the following criteria to be included in the study: Subjects with surgically unresectable locally advanced or metastatic disease who have received ≥ 1 prior line of systemic therapies for advanced or metastatic disease. The last treatment regimen must include EGFR inhibitor (cetuximab or panitumumab) on which the patient had a best response as CR or PR or SD, and must have either progressed on or after EGFR inhibitor based therapy within 3 months before enrollment. Subjects must have radiologically documented disease progression prior to enrollment. All subjects must express the wild-type form of the gene KRAS. Previously existing KRAS mutation status from an accredited local laboratory will be accepted. Fresh tumor biopsy tissue must be available for molecular sequencing and biomarker expression in >70% of patients. If prior radiotherapy, tissue biopsy must be outside radiotherapy field. In a minor percentage of patients (<30%) archival tumor tissue could be considered acceptable for molecular sequencing and biomarker expression. Patients must be MET High testing by IHC (IHC 2+ or 3+ in ≥50% of tumor cells) analyzed by Ventana Test Kit. Measurable disease according to RECIST criteria, Version 1.1. Male or female ≥ 18 years of age. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. Resolution of any toxic effects of prior therapy to NCI CTCAE, Version 4.0, grade ≤ 1 (with the exception of alopecia and grade ≤ 2 neuropathy). 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 × 109/L. Platelet count ≥ 75 × 109/L. Serum creatinine ≤ 1.5 × upper limit of normal (ULN) or creatinine clearance ≥ 60 mL/min. Alanine transaminase (ALT), and aspartate transaminase (AST) ≤ 2.5 x ULN in subjects with no liver metastasis and ≤ 5.0 x ULN in subjects with liver metastasis. Total bilirubin ≤ 1.5 x ULN (≤ 4 x ULN and direct bilirubin ≤ 1.5 x ULN is acceptable for subjects with Gilbert's syndrome). 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. 11. All female subjects of childbearing potential must each have a negative pregnancy test (serum or urine) result before initiating study treatment. 12. 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 IEC- or IRB-approved ICF (including HIPAA authorization, if applicable) before performance of any study-specific procedures or tests. Exclusion Criteria: Subjects who meet any of the following criteria will be disqualified from entering the study: 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 3 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 enrollment). Anticipation of need for a major surgical procedure or radiation therapy (RT) during the study. Treatment with chemotherapy, radiotherapy, surgery, immunotherapy, biological therapy, or any other investigational anticancer agent within 3 weeks prior to start of study 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 (subjects with asymptomatic bradycardia and hear rate above 50 bpm are allowed) 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 prior the start of study treatment is permitted). Malabsorption syndrome, chronic diarrhea (lasting > 4 weeks), inflammatory bowel disease, or partial bowel obstruction. 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. Uncontrolled seizure disorder, spinal cord compression, or carcinomatous meningitis. Pericardial or pleural effusion (requiring drainage) or pericardial involvement with the tumor. Subjects with minimal pleural effusion may be eligible upon request by Investigator and approval by Sponsor. Clinically significant active infection that requires antibiotic therapy. Previous administration of any MET inhibitor (including tivantinib) or EGFR inhibitor (except cetuximab or panitumumab). 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. Any condition that is unstable or that could jeopardize the safety of the subject and the subject's protocol compliance. Inability to swallow oral medications. Pregnant or nursing females.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Lorenza Rimassa, MD
Organizational Affiliation
Istituto Clinico Humanitas
Official's Role
Study Chair
Facility Information:
Facility Name
Istituto Clinico Humanitas
City
Rozzano
State/Province
Milano
ZIP/Postal Code
20089
Country
Italy

12. IPD Sharing Statement

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Study of Tivantinib (ARQ 197) Plus Cetuximab in EGFR Inhibitor-Resistant MET High Subjects

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