Metastatic Non-Small Cell Lung Cancer
Conditions
Keywords
KRAS mutation, metastatic NSCLC
Brief summary
The purpose of this study is to evaluate progression-free survival among subjects with KRAS mutation positive Non-Small Cell Lung Cancer (NSCLC) treated with erlotinib plus tivantinib (ARQ 197) compared to single agent chemotherapy.
Detailed description
This is a randomized, open-label Phase 2 study designed to compare treatment with erlotinib plus tivantinib (ARQ 197) versus single agent chemotherapy in subjects with previously treated KRAS mutation positive NSCLC. Eligible subjects are randomly assigned to receive erlotinib plus tivantinib or one of three (based on Investigator's choice) single-agent chemotherapy agents including pemetrexed, docetaxel, or gemcitabine.
Interventions
DRUGARQ 197 plus erlotinib
Eligible subjects will be randomly assigned to receive erlotinib plus ARQ 197.
DRUGPemetrexed, docetaxel or gemcitabine
Investigator's choice of a single agent chemotherapy (pemetrexed, docetaxel, or gemcitabine) administered according to the approved label.
Sponsors
ArQule, Inc., a subsidiary of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (Rahway, NJ USA)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Provide signed and dated informed consent prior to study-specific screening procedures 2. Male or female at least 18 years of age 3. Histologically or cytologically confirmed inoperable locally advanced or metastatic (stage IVA/IVB) NSCLC 4. Documented KRAS mutation positive status (per Lung Cancer Mutation Consortium \[LCMC\] guidelines; see www.golcmc.com) 5. At least one prior chemotherapy regimen for advanced NSCLC 6. Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, Version 1.1 7. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 8. Male or female subjects of child-producing potential must agree to use double barrier contraception, oral contraceptives or avoidance of pregnancy measures during the study and for 90 days after the last day of treatment 9. Females of childbearing potential must have a negative serum pregnancy test 10. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 × upper limit of normal (ULN) or ≤ 5 × ULN with metastatic liver disease 11. Total bilirubin ≤ 1.5 × ULN 12. Serum creatinine ≤ 1.5 × ULN 13. Absolute neutrophil count (ANC) ≥ 1.5 x 10\^9/L 14. Platelets ≥ 100 x 10\^9/L 15. Hemoglobin ≥ 10 g/dL (transfusion is allowed at least 7 days prior to randomization) 16. Subjects must agree to allow testing for c-Met status if archival and/or fresh tissue biopsy samples are available.
Exclusion criteria
1. Previous receipt of erlotinib or other epidermal growth factor receptor (EGFR) inhibitors 2. Previous receipt of any c-MET inhibitor (a receptor tyrosine kinase) or other c-MET-targeted therapy, including ARQ 197, MetMab, crizotinib 3. Prior receipt of chemotherapy agent selected for administration in this study (e.g., if subject was treated with gemcitabine, he is not eligible to receive gemcitabine in this study but eligible to receive pemetrexed or docetaxel). 4. Inability or unwillingness to receive ARQ 197, erlotinib, docetaxel, gemcitabine, and/or pemetrexed including contraindications, hypersensitivity, or prior administration 5. Receipt of any anti-tumor treatment for NSCLC within 3 weeks (2 weeks for radiotherapy) prior to randomization 6. Pregnant or breastfeeding 7. Significant gastrointestinal disorder that could, in the opinion of the Investigator, interfere with the absorption of ARQ 197 and/or erlotinib 8. Any other significant co-morbid conditions that in the opinion of the Investigator would impair study participation or cooperation 9. Other malignancies within the last three years, with the exception of adequately treated intraepithelial carcinoma of the cervix uteri, prostate carcinoma with a prostate-specific antigen (PSA) value \< 0.2 ng/mL or basal or squamous cell carcinoma of the skin 10. Known human immunodeficiency virus (HIV), or active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection 11. Major surgical procedure within 4 weeks prior to randomization 12. History of cardiac disease: Congestive heart failure defined as Class II to IV per New York Heart Association classification; Active coronary artery disease; Previously diagnosed bradycardia or other cardiac arrhythmia defined as ≥ Grade 2 according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, or uncontrolled hypertension; Myocardial infarction that occurred within 6 months prior to study entry (myocardial infarction that occurred \> 6 months prior to study entry is permitted) 13. Clinically unstable central nervous system metastasis (to be enrolled in the study, subjects must have confirmation of stable disease by MRI or CT scan within 4 weeks of randomization and have central nervous system \[CNS\] metastases well controlled by steroids, anti-epileptics or other symptom-relieving medications) 14. Known EGFR-mutation positive status
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) Among Subjects With KRAS Mutation Positive NSCLC (ITT Population) Treated With Erlotinib Plus Tivantinib Compared to Single Agent Chemotherapy. | Date of randomization until disease progression per RECIST (v 1.1) or death from any cause, whichever came first, assessed up to 24 months. | Progression is defined using Response Evaluation Criteria in Solid Tumors (RECIST v 1.1) criteria as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions or progression of existing non-target lesions are also considered progression. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) Among All Eligible Subjects (ITT Population) Treated With Erlotinib Plus Tivantinib Compared to Chemotherapy. | Date of randomization to the date of death from any cause, assessed up to 24 months | OS is calculated from the date of randomization until death from any cause. |
| Objective Response Rate (ORR) Among All Eligible Subjects (ITT Population) Treated With Erlotinib Plus Tivantinib Compared to Chemotherapy. | Date of randomization to the date of death from any cause or to the date that the subject discontinues from the study, assessed up to 24 months | Per RECIST v1.1, Complete Response (CR) = disappearance of all lesions and Partial Response (PR) = at least 30% decrease in the sum of diameters of target lesions. ORR = (CR+PR)/# subjects. |
| ORR Among Subjects in the Crossover Period Treated With Erlotinib Plus Tivantinib | Date of randomization to the date of death from any cause or to the date that the subject discontinues from the study, assessed up to 24 months. | Per RECIST v1.1, CR = disappearance of all lesions and PR = at least 30% decrease in the sum of diameters of target lesions. ORR = (CR+PR)/# subjects. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tivantinib Plus Erlotinib Arm Tivantinib 360 mg BID (total daily dose 720 mg) plus erlotinib 150 mg QD, tablets, orally in 3-week cycles until disease progression or unacceptable toxicity | 51 |
| Chemotherapy Arm Investigator's choice of single agent chemotherapy (pemetrexed, docetaxel, or gemcitabine) administered in 3-week cycles according to the approved label until disease progression or unacceptable toxicity. Subjects who discontinued chemotherapy could be switched to the crossover arm (tivantinib plus erlotinib) and continue treatment until disease progression or unacceptable toxicity. | 45 |
| Total | 96 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Open-label Treatment Period | Withdrawal by Subject | 4 | 0 | 0 |
Baseline characteristics
| Characteristic | Tivantinib Plus Erlotinib Arm | Chemotherapy Arm | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 23 Participants | 29 Participants | 52 Participants |
| Age, Categorical Between 18 and 65 years | 28 Participants | 16 Participants | 44 Participants |
| Age, Continuous | 62.6 years STANDARD_DEVIATION 9.23 | 65.2 years STANDARD_DEVIATION 9.55 | 63.8 years STANDARD_DEVIATION 9.43 |
| Cigarette Use No | 5 Participants | 3 Participants | 8 Participants |
| Cigarette Use Yes | 46 Participants | 42 Participants | 88 Participants |
| Confirmation of Kirsten rat sarcoma (KRAS) Mutation No | 0 Participants | 0 Participants | 0 Participants |
| Confirmation of Kirsten rat sarcoma (KRAS) Mutation Yes | 51 Participants | 45 Participants | 96 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Score Grade 0 | 12 Participants | 8 Participants | 20 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Score Grade 1 | 32 Participants | 33 Participants | 65 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Score Grade 2 | 7 Participants | 4 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 50 Participants | 45 Participants | 95 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Height | 166.38 centimeters STANDARD_DEVIATION 10.28 | 164.88 centimeters STANDARD_DEVIATION 9.42 | 165.68 centimeters STANDARD_DEVIATION 9.86 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 47 Participants | 41 Participants | 88 Participants |
| Region of Enrollment United States | 51 participants | 45 participants | 96 participants |
| Sex: Female, Male Female | 33 Participants | 30 Participants | 63 Participants |
| Sex: Female, Male Male | 18 Participants | 15 Participants | 33 Participants |
| Weight | 72.50 kilograms STANDARD_DEVIATION 17.31 | 68.86 kilograms STANDARD_DEVIATION 15.19 | 70.79 kilograms STANDARD_DEVIATION 16.37 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 51 | 4 / 45 |
| other Total, other adverse events | 51 / 51 | 45 / 45 |
| serious Total, serious adverse events | 19 / 51 | 25 / 45 |
Outcome results
Primary
Progression-free Survival (PFS) Among Subjects With KRAS Mutation Positive NSCLC (ITT Population) Treated With Erlotinib Plus Tivantinib Compared to Single Agent Chemotherapy.
Progression is defined using Response Evaluation Criteria in Solid Tumors (RECIST v 1.1) criteria as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions or progression of existing non-target lesions are also considered progression.
Time frame: Date of randomization until disease progression per RECIST (v 1.1) or death from any cause, whichever came first, assessed up to 24 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tivantinib Plus Erlotinib Arm | Progression-free Survival (PFS) Among Subjects With KRAS Mutation Positive NSCLC (ITT Population) Treated With Erlotinib Plus Tivantinib Compared to Single Agent Chemotherapy. | 7.3 weeks |
| Chemotherapy Arm | Progression-free Survival (PFS) Among Subjects With KRAS Mutation Positive NSCLC (ITT Population) Treated With Erlotinib Plus Tivantinib Compared to Single Agent Chemotherapy. | 18.6 weeks |
p-value: 0.5017Log Rank
Secondary
Objective Response Rate (ORR) Among All Eligible Subjects (ITT Population) Treated With Erlotinib Plus Tivantinib Compared to Chemotherapy.
Per RECIST v1.1, Complete Response (CR) = disappearance of all lesions and Partial Response (PR) = at least 30% decrease in the sum of diameters of target lesions. ORR = (CR+PR)/# subjects.
Time frame: Date of randomization to the date of death from any cause or to the date that the subject discontinues from the study, assessed up to 24 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tivantinib Plus Erlotinib Arm | Objective Response Rate (ORR) Among All Eligible Subjects (ITT Population) Treated With Erlotinib Plus Tivantinib Compared to Chemotherapy. | 0 Participants |
| Chemotherapy Arm | Objective Response Rate (ORR) Among All Eligible Subjects (ITT Population) Treated With Erlotinib Plus Tivantinib Compared to Chemotherapy. | 4 Participants |
Secondary
ORR Among Subjects in the Crossover Period Treated With Erlotinib Plus Tivantinib
Per RECIST v1.1, CR = disappearance of all lesions and PR = at least 30% decrease in the sum of diameters of target lesions. ORR = (CR+PR)/# subjects.
Time frame: Date of randomization to the date of death from any cause or to the date that the subject discontinues from the study, assessed up to 24 months.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tivantinib Plus Erlotinib Arm | ORR Among Subjects in the Crossover Period Treated With Erlotinib Plus Tivantinib | 2 Participants |
Secondary
Overall Survival (OS) Among All Eligible Subjects (ITT Population) Treated With Erlotinib Plus Tivantinib Compared to Chemotherapy.
OS is calculated from the date of randomization until death from any cause.
Time frame: Date of randomization to the date of death from any cause, assessed up to 24 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tivantinib Plus Erlotinib Arm | Overall Survival (OS) Among All Eligible Subjects (ITT Population) Treated With Erlotinib Plus Tivantinib Compared to Chemotherapy. | 6.8 months |
| Chemotherapy Arm | Overall Survival (OS) Among All Eligible Subjects (ITT Population) Treated With Erlotinib Plus Tivantinib Compared to Chemotherapy. | 8.5 months |
p-value: 0.4356Log Rank