| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| patients with EGFR mutated advanced non squamous non small cell lung cancer |
| pazienti affetti da carcinoma del polmone non a piccole cellule ad istotipo non squamoso e mutazione attivante di EGFR |
|
| E.1.1.1 | Medical condition in easily understood language |
| patients with EGFR mutated advanced non squamous non small cell lung cancer |
| pazienti affetti da carcinoma del polmone non a piccole cellule ad istotipo non squamoso e mutazione attivante di EGFR |
|
| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10064049 |
| E.1.2 | Term | Lung adenocarcinoma metastatic |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 test whether the combination of bevacizumab plus erlotinib can prolong investigatorassessed
(IA-PFS) and blinded-independent centrally-reviewed progression-free survival
(BICR-PFS) as compared with erlotinib alone as first-line treatment in patients with EGFRmutated
NSCLC.
Note: CT (or other pertinent) scans performed at baseline and during follow-up will be
collected and reviewed by an independent central panel of radiologists who will be blinded
to the assigned treatment. |
To test whether the combination of bevacizumab plus erlotinib can prolong investigatorassessed
(IA-PFS) and blinded-independent centrally-reviewed progression-free survival
(BICR-PFS) as compared with erlotinib alone as first-line treatment in patients with EGFRmutated
NSCLC.
Note: CT (or other pertinent) scans performed at baseline and during follow-up will be
collected and reviewed by an independent central panel of radiologists who will be blinded
to the assigned treatment. |
|
| E.2.2 | Secondary objectives of the trial |
· To compare the two arms in terms of
o overall survival
o quality of life (EORTC C30 + LC13)
o centrally-reviewed objective response rate (RECIST1.1)
o investigator assessed objective response rate (RECIST1.1)
o adverse events (CTCAE 4.03 version)
· To test whether an interaction exists between treatment arms and type of EGFR
mutation (exon 19del vs exon 21 L858R vs other)
· To explore other possible predictive factors and their interaction with treatment arms
· To explore prognostic factors
· To explore the usefulness of liquid biopsy at baseline and during the follow-up for
testing mutational status of the EGFR gene and of a panel of other genes putatively
involved in NSCLC prognosis and behavior.
|
· To compare the two arms in terms of
o overall survival
o quality of life (EORTC C30 + LC13)
o centrally-reviewed objective response rate (RECIST1.1)
o investigator assessed objective response rate (RECIST1.1)
o adverse events (CTCAE 4.03 version)
· To test whether an interaction exists between treatment arms and type of EGFR
mutation (exon 19del vs exon 21 L858R vs other)
· To explore other possible predictive factors and their interaction with treatment arms
· To explore prognostic factors
· To explore the usefulness of liquid biopsy at baseline and during the follow-up for
testing mutational status of the EGFR gene and of a panel of other genes putatively
involved in NSCLC prognosis and behavior.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age =18 years
2. Histological documentation of primary non squamous lung carcinoma
3. Stage IV or IIIB disease with supraclavear metastatic nodes (according to TNM 7th
edition)
4. Activating epidermal growth factor receptor mutation (exon19 deletion or exon 21
L858R mutation or other activating/sensitizing mutations, such as exon 21 L861Q,
exon 18 G719S, G719A and G719C, exon 20 S768I and V769L). EGFR mutation
testing must be performed at participating centres in a certified lab (AIOM-SIAPEC
program or other European Quality Assurance [EQA] schemes)
5. Clinical or radiologic evidence of disease (at least one target or non target lesion
according to RECIST 1.1)
6. ECOG performance status 0 to 2
7. Life expectancy > 3 months
8. Use of an acceptable mean of contraception for men and women of childbearing
potential
9. Written informed consent. |
1. Age =18 years
2. Histological documentation of primary non squamous lung carcinoma
3. Stage IV or IIIB disease with supraclavear metastatic nodes (according to TNM 7th
edition)
4. Activating epidermal growth factor receptor mutation (exon19 deletion or exon 21
L858R mutation or other activating/sensitizing mutations, such as exon 21 L861Q,
exon 18 G719S, G719A and G719C, exon 20 S768I and V769L). EGFR mutation
testing must be performed at participating centres in a certified lab (AIOM-SIAPEC
program or other European Quality Assurance [EQA] schemes)
5. Clinical or radiologic evidence of disease (at least one target or non target lesion
according to RECIST 1.1)
6. ECOG performance status 0 to 2
7. Life expectancy > 3 months
8. Use of an acceptable mean of contraception for men and women of childbearing
potential
9. Written informed consent.
|
|
| E.4 | Principal exclusion criteria |
Cancer related
1. EGFR T790M mutation and exon 20 insertions
2. Tumors with a squamous component
Prior, current or planned treatment related
3. Prior chemotherapy or any other medical treatment for advanced NSCLC (previous
neoadjuvant or adjuvant chemotherapy is allowed if > 6 months before
randomisation)
4. Radiotherapy to any site for any reason within 28 days prior to randomization
(palliative radiotherapy to bone lesions is allowed if = 14 days before randomization)
5. Full-dose anticoagulation with warfarin
6. Current or recent (within 10 days of enrolment) use of aspirin (>325 mg/day) or
chronic use of other full-dose nonsteroidal anti-inflammatory drugs (NSAIDs) with
anti-platelet activity
7. Receiving any medications or substances that are strong or moderate inhibitors of
cytochrome P450 3A4 (CYP3A4) are prohibited =< 7 days prior to registration
8. Receiving any medications or substances that are inducers of CYP3A4 use of
inducers are prohibited =< 7 days prior to registration
Laboratory related
9. Inadequate coagulation parameters:
o activated partial thromboplastin time (APTT) >1.5 x the upper limit of normal
(ULN) or
o INR >1.5
10. Inadequate liver function, defined as:
o serum (total) bilirubin >1.5 x ULN
o AST/SGOT or ALT/SGPT >2.5 x ULN
11. Inadequate renal function, defined as:
o serum creatinine >2.0 mg/dl or >177 mmol/l
o urine dipstick for proteinuria >2+. Patients with ³1+ proteinuria at baseline
dipstick analysis must undergo a 24-hour urine collection and must demonstrate
=1g of protein in their 24-hour urine collection.
Prior or concomitant conditions or procedures related
12. Pregnancy or breast-feeding
13. Inadequately controlled hypertension (defined as systolic blood pressure >150
and/or diastolic blood pressure >100 mmHg on antihypertensive medications)
14. History of gross hemoptysis within 3 months prior to randomization unless
definitively treated with surgery or radiation
15. History of any of the following within 6 months prior to randomisation: serious
systemic disease, unstable angina, New York Heart Association (NYHA) Grade 2 or
greater Congestive Heart Failure (CHF), unstable symptomatic arrhythmia requiring
medication, clinically significant peripheral vascular disease, abdominal fistula,
gastrointestinal perforation, or intra-abdominal abscess
16. Serious, non-healing wound, ulcer, or bone fracture
17. Evidence of bleeding diathesis or coagulopathy or other serious or acute internal
bleeding within 6 months prior to randomization
18. Central Nervous System (CNS) bleeding; history or clinical evidence of CNS stroke
(hemorrhagic or thrombotic) within the last 6 months
19. In-patient surgical procedure, open biopsy, or significant traumatic injury within 28
days prior to randomization
20. Minor surgical procedure, fine needle aspirations or core biopsy within 7 days prior
to randomization
21. Anticipation of need for a major surgical procedure during the course of the study
22. Inability to take oral medication or requirement for intravenous (IV) alimentation or
total parenteral nutrition with lipids, or prior surgical procedures affecting absorption
23. Evidence of confusion or disorientation, or history of major psychiatric illness that
may impair the patient's understanding of the Informed Consent Form or his/her
ability to comply with study requirements
24. Any other invasive malignancies within 5 years (except for adequately treated
carcinoma in situ of the cervix or basal or squamous cell skin cancer or surgically
resected prostate cancer with normal PSA)
25. Brain metastasis
26. Patients who have had radiotherapy = 4 weeks prior to the first dose of study
treatment, but who are still experiencing acute toxic effects of radiotherapy
27. Known HIV positive patients (patients with both acute or chronic infection are
excluded)
28. Active HBV or HCV infection (patients with chronic non-active infection are eligible)
29. Any already known inflammatory changes of the surface of the eye at baseline
30. Any other concomitant pathologies or laboratory alterations that prevent or
contraindicate the use of erlotinib or bevacizumab.
|
Cancer related
1. EGFR T790M mutation and exon 20 insertions
2. Tumors with a squamous component
Prior, current or planned treatment related
3. Prior chemotherapy or any other medical treatment for advanced NSCLC (previous
neoadjuvant or adjuvant chemotherapy is allowed if > 6 months before
randomisation)
4. Radiotherapy to any site for any reason within 28 days prior to randomization
(palliative radiotherapy to bone lesions is allowed if = 14 days before randomization)
5. Full-dose anticoagulation with warfarin
6. Current or recent (within 10 days of enrolment) use of aspirin (>325 mg/day) or
chronic use of other full-dose nonsteroidal anti-inflammatory drugs (NSAIDs) with
anti-platelet activity
7. Receiving any medications or substances that are strong or moderate inhibitors of
cytochrome P450 3A4 (CYP3A4) are prohibited =< 7 days prior to registration
8. Receiving any medications or substances that are inducers of CYP3A4 use of
inducers are prohibited =< 7 days prior to registration
Laboratory related
9. Inadequate coagulation parameters:
o activated partial thromboplastin time (APTT) >1.5 x the upper limit of normal
(ULN) or
o INR >1.5
10. Inadequate liver function, defined as:
o serum (total) bilirubin >1.5 x ULN
o AST/SGOT or ALT/SGPT >2.5 x ULN
11. Inadequate renal function, defined as:
o serum creatinine >2.0 mg/dl or >177 mmol/l
o urine dipstick for proteinuria >2+. Patients with ³1+ proteinuria at baseline
dipstick analysis must undergo a 24-hour urine collection and must demonstrate
=1g of protein in their 24-hour urine collection.
Prior or concomitant conditions or procedures related
12. Pregnancy or breast-feeding
13. Inadequately controlled hypertension (defined as systolic blood pressure >150
and/or diastolic blood pressure >100 mmHg on antihypertensive medications)
14. History of gross hemoptysis within 3 months prior to randomization unless
definitively treated with surgery or radiation
15. History of any of the following within 6 months prior to randomisation: serious
systemic disease, unstable angina, New York Heart Association (NYHA) Grade 2 or
greater Congestive Heart Failure (CHF), unstable symptomatic arrhythmia requiring
medication, clinically significant peripheral vascular disease, abdominal fistula,
gastrointestinal perforation, or intra-abdominal abscess
16. Serious, non-healing wound, ulcer, or bone fracture
17. Evidence of bleeding diathesis or coagulopathy or other serious or acute internal
bleeding within 6 months prior to randomization
18. Central Nervous System (CNS) bleeding; history or clinical evidence of CNS stroke
(hemorrhagic or thrombotic) within the last 6 months
19. In-patient surgical procedure, open biopsy, or significant traumatic injury within 28
days prior to randomization
20. Minor surgical procedure, fine needle aspirations or core biopsy within 7 days prior
to randomization
21. Anticipation of need for a major surgical procedure during the course of the study
22. Inability to take oral medication or requirement for intravenous (IV) alimentation or
total parenteral nutrition with lipids, or prior surgical procedures affecting absorption
23. Evidence of confusion or disorientation, or history of major psychiatric illness that
may impair the patient's understanding of the Informed Consent Form or his/her
ability to comply with study requirements
24. Any other invasive malignancies within 5 years (except for adequately treated
carcinoma in situ of the cervix or basal or squamous cell skin cancer or surgically
resected prostate cancer with normal PSA)
25. Brain metastasis
26. Patients who have had radiotherapy = 4 weeks prior to the first dose of study
treatment, but who are still experiencing acute toxic effects of radiotherapy
27. Known HIV positive patients (patients with both acute or chronic infection are
excluded)
28. Active HBV or HCV infection (patients with chronic non-active infection are eligible)
29. Any already known inflammatory changes of the surface of the eye at baseline
30. Any other concomitant pathologies or laboratory alterations that prevent or
contraindicate the use of erlotinib or bevacizumab.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Investigator-assessed
(IA-PFS) and blinded-independent centrally-reviewed progression-free survival
(BICR-PFS) |
Investigator-assessed
(IA-PFS) and blinded-independent centrally-reviewed progression-free survival
(BICR-PFS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| week 9th and 18nd from randomization and thereafter every 12 weeks |
| week 9th and 18nd from randomization and thereafter every 12 weeks |
|
| E.5.2 | Secondary end point(s) |
| overall survival; quality of life(EORTC C30 + LC13); toxicity; Investigator assessed objective response rate; Centrally reviewed objective response rate |
| overall survival; quality of life(EORTC C30 + LC13); toxicity; Investigator assessed objective response rate; Centrally reviewed objective response rate |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| death; At the end of cycles 1,2,3,4,5,6,(on day 1 of the next cycle before receiving treatment) and every 12 weeks thereafter until progression; At the end of each cycle (on day 1 of the next cycle before receiving treatment) and 30days after the end of treatment; week 9th and 18nd from randomization and thereafter every 12 weeks; week 9th and 18nd from randomization and thereafter every 12 weeks |
| death; At the end of cycles 1,2,3,4,5,6,(on day 1 of the next cycle before receiving treatment) and every 12 weeks thereafter until progression; At the end of each cycle (on day 1 of the next cycle before receiving treatment) and 30days after the end of treatment; week 9th and 18nd from randomization and thereafter every 12 weeks; week 9th and 18nd from randomization and thereafter every 12 weeks |
|
| 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) | 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| stesso farmaco in monoterapia |
| the same drug as monotherapy |
|
| 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 | 72 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 72 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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
|
|
| 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 | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
