| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced NSCLC harbouring EGFR mutations (del19 or L858R). |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced non-small-cell lung cancer (NSCLC) harbouring epidermal growth factor receptor (EGFR) mutations (exon 19 deletion (del19) or exon 21 mutation (L858R)). |
|
| 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 | 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) |
|
| 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 |
To determine progression free survival (PFS) of patients with advanced non-squamous NSCLC harbouring at diagnosis EGFR mutations with and without T790M mutation, treated with the combination of erlotinib and bevacizumab.
Hypotheses of interest:
When treated with bevacizumab and erlotinib
a. Median PFS increases to 18 months for patients with EGFR T790M mutation
b. Median PFS is approximately 18 months or more in patients without EGFR T790M mutation. |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate secondary measures of clinical efficacy including overall survival (OS), time to treatment failure (TTF), objective response rate (ORR), disease control rate (DCR) and duration of response (DR).
- To assess the safety and the tolerability of the erlotinib and bevacizumab combination.
- To evaluate the correlation of BRCA1 mRNA and AEG-1 mRNA expression and T790M with progression-free survival.
- To monitor EGFR mutations (including T790M) in serum longitudinally.
- To evaluate molecular biomarkers related to EGFR TKI and bevacizumab.
- To determine the feasibility of re-biopsies at the time of progression and geneexpression arrays for decision-making for second-line treatment
- To study the feasibility of recommending customized second-line chemotherapy based on BRCA1 and AEG-1 mRNA levels. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Age ≥ 18 years
- ECOG performance status 0-2
- Adequate haematological function: haemoglobin > 9 g/dL, neutrophils count >1.5×109/L, platelet count > 100 × 109/L
- Adequate coagulation: INR ≤ 1.5
- Adequate liver function: Total bilirubin < 1.5 × ULN, ALT and/or AST < 2.5 ×ULN, alkaline phosphatase < 5 ULN, except in the presence of exclusive bone metastases and in the absence of any liver disorder.
- Adequate renal function: Calculated creatinine clearance ≧ 50 mL/min (Cockroft-Gault) and proteinuria < 2+ (dipstick).
- Oral swallowing capability, patient capable of proper therapeutic compliance, and accessible for correct follow-up.
- Life expectancy of at least 2 months.
- Women of childbearing age, including women who had their last menstrual period in the last 2 years, must have a negative serum or urine pregnancy test within 7 days before beginning treatment.
- All sexually active men and women of childbearing age must use an effective contraceptive method during the study treatment and for a period of at least 12 months following the last administration of trial drugs.
- Written Informed Consent (IC) must be signed and dated by the patient and the investigator prior to any trial-related intervention for
a) trial treatment
b) tissue submission for central review and central EGFR testing
Disease characteristics
- Pathological diagnosis of predominantly non-squamous, non-small-cell lung cancer (NSCLC).
- TNM version 7 stage IV disease including M1a (malignant effusion) or M1b (distant metastasis), or locally advanced disease not amenable to curative treatment (including patients progressing after radio-chemotherapy for stage III disease).
- Measurable or evaluable disease (according to RECIST 1.1 criteria).
- Centrally confirmed EGFR exon 19 deletion (del19) or exon 21 mutation (L858R).
- Patients with asymptomatic and stable cerebral metastases |
|
| E.4 | Principal exclusion criteria |
- Patients with increased risk of bleeding, defined by:
- major surgery or significant traumatic injury within 28 days prior to inclusion
- minor surgery (including permanent catheter insertion) within 24 hours prior to first treatment with bevacizumab
- history or evidence of bleeding diathesis or hereditary coagulopathy
- history of haemoptysis (defined as at least half a teaspoon’s emission of red blood) in the 3 months prior to inclusion)
- evidence by CT of tumor cavitations, or tumours invading or abutting major blood vessels
- uncontrolled hypertension (systolic blood pressure > 150 mm Hg and / or diastolic > 100 mm Hg)
- Patients with clinically significant cardiovascular diseases, including
- cerebral vascular accident (<6 months before inclusion)
- acute myocardial infarction (<6 months before inclusion)
- unstable angina
- congestive heart failure class > NYHA II
- serious cardiac arrhythmia requiring medication during the study and which could interfere with regularity of study treatment or is not controlled with medication.
- Patients with a history of thrombosis or thromboembolism in the 6 months prior to treatment
- Patients with gastrointestinal problems including
- intestinal transit problems (such as malabsorption syndrome, chronic intestinal inflammatory disease, or other pathologies that can alter absorption of the medication
- history of abdominal fistula, intestinal perforation or intra-abdominal abscess within 6 months prior to inclusion
- uncontrolled active peptic ulcer
- presence of trachea-oesophageal fistula.
- Patients with neurologic problems, including
- evidence of spinal cord compression
- significant neurological or psychiatric disorders (including dementia and epileptic seizures).
- Patients who have had in the past 5 years any previous or concomitant malignancy EXCEPT adequately treated basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix or bladder, in situ breast carcinoma.
- Patients with any known significant ophthalmologic anomaly of the ocular surface.
- Patients with other serious diseases or clinical conditions, including but not limited to uncontrolled active infection and any other serious underlying medical processes that could affect the patient’s capacity to participate in the study.
- Known hypersensitivity to bevacizumab or erlotinib or any of its excipients.
- Patients who received prior chemotherapy for metastatic disease.
- Patients who received previous treatment for lung cancer with drugs targeting EGFR or VEGF.
- Patients who received treatment with an investigational drug agent during the 3 weeks before enrolment in the study.
- Patients with current or recent use (within the last 10 days) of full doses of anticoagulants or thrombolytics, either orally or parenterally. Use of anticoagulant prophylaxis is permitted (low dose heparin or aspirin <=325 mg, prophylactic FXa inhibitors).
- Patients with concurrent use of CYP3A4 inducers/inhibitors (such as, but not limited to, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin (TAO), voriconazole, or grapefruit or grapefruit juice). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| - Progression-free survival (PFS is defined as the time from the date of enrolment until documented progression or death, whichever occurs first) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The final evaluation will be done within 6 months after the last visit of the last patient, approximately 54 months after the inclusion of the first patient. |
|
| E.5.2 | Secondary end point(s) |
- Overall survival (OS)
- Time to treatment failure (TTF)
- Objective response (OR)
- Adverse events graded according to CTCAE V4.0
- Disease control (DC)
- Duration of response (DR) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The final evaluation will be done within 6 months after the last visit of the last patient, approximately 54 months after the inclusion of the first patient. |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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 | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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 |
| Denmark |
| France |
| Germany |
| Greece |
| Ireland |
| Italy |
| Netherlands |
| Portugal |
| Spain |
| Switzerland |
| United Kingdom |
|
| 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
|
Patient accrual is expected to be completed within 12 months.
Patients will be followed until death – thus follow-up estimated up to 3 years following the enrolment of the last patient. The trial will end with the preparation of the final report, scheduled for month 54 after the inclusion of first patient. |
|
| 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 | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| 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 |
Print
