E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Non-squamous, non–small-cell lung cancer |
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E.1.1.1 | Medical condition in easily understood language |
Non-small cell lung cancer (NSCLC) is a general term for the most common form of solid cancer which affects the lungs. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10029514 |
E.1.2 | Term | Non-small cell lung cancer NOS |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061873 |
E.1.2 | Term | Non-small cell lung cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to evaluate overall survival (OS) in the intent-to-treat (ITT) subject population defined by this protocol. |
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E.2.2 | Secondary objectives of the trial |
Key secondary objectives are to evaluate OS in the epidermal growth factor receptor (EGFR) wild type subpopulation; and progression-free survival (PFS) in the ITT population, and to further characterize the safety of ARQ 197 in combination with erlotinib.
Additional exploratory objectives include patient-reported outcomes (PROs), population pharmacokinetics, pharmacodynamics, pharmacogenomics, and analyses of efficacy measures in subgroups of subjects predefined in the Statistical Analysis Plan (SAP).
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female at least 18 years of age.
2. Histologically or cytologically confirmed surgically unresectable locally advanced or metastatic (stage IIIB/IV) non-squamous NSCLC.
3. Measurable disease and documented disease progression following last prior therapy according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, Version 1.1.
4. Have received one or two prior lines of systemic anti-cancer therapy therapy for advanced or metastatic disease, one of which must be a platinum-doublet therapy. Patients who received only adjuvant treatment will be eligible only if disease progression occurred <6 months after completion of adjuvant therapy. Prior maintenance therapy is allowed and will be considered as the same line of therapy when continued without discontinuation after initiation of a treatment regimen.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6. Resolution of any toxic effects of prior therapy (including radiotherapy) according to NCI CTCAE, Version 4.0, Grade ≤1 (with the exception of alopecia and ≤ Grade 2 neuropathy). Subject must have recovered from significant surgery-related complications.
7. Demonstrate adequate bone marrow, liver, and renal functions, defined as:
• ALT, AST, and alkaline phosphatase ≤ 2.5 × upper limit of normal (ULN) in subjects with no liver metastasis and ≤5.0 x ULN in subjects with liver metastasis.
• Total bilirubin ≤ 1.5 × ULN (≤ 4 × ULN total and ≤1.5 × ULN direct bilirubin is acceptable for subjects with Gilbert’s syndrome).
• ANC ≥1.5 × 10e9/L.
• Platelet count ≥100 × 10e9/L.
• Hemoglobin ≥9.0 g/dL (transfusion and/or growth factor support allowed).
• Serum creatinine ≤1.5 × ULN or creatinine clearance ≥ 60 mL/min.
8. Archival and/or fresh biopsy tissue sample must be available for biomarker determination. The status of the following biomarkers will be collected in this study: EGFR and KRAS mutation status prior to randomization, and MET status post randomization:
a. Previously existing documentation for EGFR and KRAS mutation status from an accredited local laboratory (ie, certified by CLIA, CAP and/or similar agencies) will be accepted.
b. If documented results are not available, then archival and/or fresh tissue biopsy samples (approximately 10 unstained, unbaked, uncharged, paraffinembedded slides) or a tissue block suitable for biomarker analysis must be available.
c. If EGFR and KRAS data from local laboratories are utilized, tissue samples for MET IHC and FISH analysis must be provided to the central lab. Refer to the lab manual for further details on sample requirements.
d. If a subject does not have previous documentation or adequate tissue for EGFR status determination, the subject is not eligible for the study.
9. If of child-bearing/reproductive potential (female or male), 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. If female and of childbearing potential, must have a negative result of a pregnancy test (serum or urine) within 72 hours prior to initiating study treatment.
11. Must have signed and dated an IEC or IRB approved ICF (Including HIPAA authorization, if applicable) before performance of any study-specific procedures or tests. Subjects must be fully informed about their illness and the investigational nature of the study protocol (including forseeable risks and possible side effects)
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E.4 | Principal exclusion criteria |
1. Prior therapy with an EGFR inhibitor and/or ARQ 197 (or other known c-MET inhibitor).
2. Receipt of any systemic anti-tumor treatment for NSCLC within 3 weeks prior to randomization.
3. Receipt of palliative radiotherapy within 2 weeks or radiotherapy for curative intent of target lesions within 3 weeks prior to randomization. (Lesions subjected to radiotherapy within 3 weeks prior to randomization may not be used as target lesions.)
4. Major surgical procedure within 3 weeks prior to randomization (brain
metastases treated with sterotactic gamma knife radiosurgery within 3 weeks prior to randomization will be allowed).
5. 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 symptomatic bradycardia (subjects with asymptomatic bradycardia and heart rate above 50 bpm are allowed) or other cardiac arrhythmia defined as ≥Grade 2 according to NCI 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).
6. Clinically unstable CNS metastasis (to be enrolled in the study, subjects must have confirmation of stable disease by MRI or computed tomography (CT) scan within 4 weeks of randomization and have CNS metastases well controlled by steroids, anti-epileptics or other symptom-relieving medications).
7. Need to breastfeed a child during or within 12 weeks of completing the study.
8. Significant gastrointestinal disorder that, in the opinion of the investigator, could interfere with absorption of ARQ 197 and/or erlotinib (eg, Crohn’s disease, small or large bowel resection, malabsorption syndrome).
9. Inability or unwillingness to swallow the complete doses of ARQ 197 or erlotinib.
10. Any known contraindication to treatment with, including hypersensitivity to, ARQ 197 or erlotinib.
11. History of malignancy other than NSCLC within the 5 years prior to randomization, with the exceptions of adequately treated intraepithelial carcinoma of the cervix uteri; prostate carcinoma with a prostate-specific antigen value <0.2 ng/mL; or basal or squamous-cell carcinoma of the skin.
12. Known infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV).
13. Any other significant co-morbid condition that, in opinion of the investigator, would impair study participation or cooperation.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint of the study is OS in the ITT population. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
· OS in subjects with EGFR wild type (WT)
NSCLC
· Progression-free survival (PFS) in the ITT
population |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 100 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Belgium |
Canada |
Denmark |
France |
Germany |
Hungary |
India |
Italy |
Austria |
Netherlands |
Poland |
Romania |
Russian Federation |
Czech Republic |
Spain |
Sweden |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |