E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastatic Non-Squamous Non-Small Cell Lung Cancer |
Μεταστατικός Μη-Πλακώδης Μη-Μικροκυτταρικός Καρκίνος του Πνεύμονα |
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E.1.1.1 | Medical condition in easily understood language |
Lung Cancer |
Καρκίνος του Πνεύμονα |
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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 | 16.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10059515 |
E.1.2 | Term | Non-small cell lung cancer metastatic |
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 |
laboratory abnormalities defined as dose-limiting toxicity in subjects with metastatic non-squamous nonsmall cell lung cancer
(NSCLC) treated with AMG 386 in combination with pemetrexed and carboplatin
Part 2:
To estimate the treatment effect of AMG 386 as measured by progression free survival (PFS) of AMG 386 versus AMG 386 placebo in combination with pemetrexed and carboplatin induction
therapy followed by pemetrexed and AMG 386 or AMG 386 placebo as maintenance therapy in subjects with metastatic non-squamous NSCLC |
Η αξιολόγηση της συχνότητας εμφάνισης ανεπιθύμητων συμβάντων και κλινικών εργαστηριακών ανωμαλιών που ορίζονται ως δοσοπεριοριστική τοξικότητα σε ασθενείς με μεταστατικό μη- πλακώδη μη-μικροκυτταρικό καρκίνο του πνεύμονα (ΜΜΚΠ) που λαμβάνουν AMG 386 σε συνδυασμό με πεμετρεξίδη και καρβοπλατίνη.
Μέρος 2:
Η εκτίμηση της θεραπευτικής επίδρασης του AMG 386 προσδιοριζόμενης με βάση την επιβίωση χωρίς εξέλιξη της νόσου (PFS) που θα παρατηρηθεί κατά την εισαγωγική θεραπεία με AMG 386 έναντι πανομοιότυπου με το AMG 386 εικονικού φαρμάκου σε συνδυασμό με πεμετρεξίδη και καρβοπλατίνη ακολουθούμενη από πεμετρεξίδη και AMG 386 ή πανομοιότυπο με το AMG 386 εικονικό φάρμακο ως θεραπεία συντήρησης σε ασθενείς με μεταστατικό μη-πλακώδη ΜΜΚΠ.
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E.2.2 | Secondary objectives of the trial |
Estimate OS of AMG386 vs AMG386 placebo in combination with
pemetrexed & carboplatin induction therapy followed by pemetrexed & AMG386 or AMG386 placebo as maintenance therapy in subjects with metastatic non-squamous NSCLC
Evaluate:
- other measures of efficacy including objective response
rate,tumor burden change,& duration of response
- safety & tolerability of AMG386 in combination with
pemetrexed & carboplatin as induction therapy & AMG386 & pemetrexed as maintenance therapy Evaluate pharmacokinetics of AMG386 when administered with pemetrexed & carboplatin
- AMG386 exposure-efficacy & exposure-safety relationships
- anti-AMG386 antibody formation
Estimate the effect of AMG386 vs AMG386 placebo when given in
combination with pemetrexed & carboplatin induction therapy followed by pemetrexed & AMG386 or AMG 86 placebo maintenance therapy on NSCLC-related symptoms & health-related quality of life (Functional Assessment of Cancer Therapy- Lung [FACT-L],EQ-5D) |
Due to space limitations please check above |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Disease related
• Histologically confirmed (cytological specimens obtained by bronchial washing or brushing, or fine-needle aspiration are acceptable), unresectable stage IV non-squamous NSCLC
• Radiographically evaluable disease (measurable or non-measurable) per RECIST 1.1 with modifications (Appendix G)
General
• Men or women aged ≥ 18 years old
• ECOG Performance Status of 0 or 1 (see Appendix J)
• Life expectancy ≥ 3 months (per investigator opinion)
• Generally well-controlled blood pressure with systolic blood pressure ≤ 140 mmHg AND diastolic blood pressure ≤ 90 mmHg prior to enrolment or randomization. The use of anti-hypertensive medications to control hypertension is permitted
Laboratory
• Adequate organ and hematological function as evidenced by the
following laboratory studies
- Hematological function:
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
Platelet count ≥ 100 x 109/L and ≤ 850 x 109/L
Hemoglobin ≥ 9 g/dL
- Coagulation function:
partial thromboplastin time (PTT) or activated prothrombin
time (aPTT) ≤ 1.5 x ULN per institutional laboratory range
International normalized ratio (INR) ≤ 1.5
- Renal function:
Urinary protein of ≤ 30 mg/dL in urinalysis or ≤ 1+ on dipstick,
unless quantitative protein is ≤ 1000 mg in a 24-hour urine
sample
Creatinine clearance (CrCl) ≥ 45 mL/min per 24-hour urine
collection or calculated according to the Cockcroft-Gault formula:
CrCl (mL/min) =
(140-age) x actual body weight (kg)
(x 0.85) for females
72 x serum creatinine (mg/dL)
− Or
CrCl (mL/min) =
(140-age) x actual body weight (kg)
(x 0.85) for females
0.8136 x serum creatinine (μmol/L)
- Hepatic function:
AST and ALT ≤ 2.5 x ULN per institutional laboratory range
(or≤ 5 x ULN if liver metastases are present)
Total bilirubin < 1.2 mg/dL
- Nutritional:
Albumin ≥ 2.8 g/dL |
Σχετιζόμενα με τη νόσο
• Ιστολογικά επιβεβαιωμένος (θα γίνουν αποδεκτά τα κυτταρολογικά δείγματα που ελήφθησαν με βρογχική έκπλυση ή βρογχική ψήκτρα ή με αναρρόφηση με λεπτή βελόνα), ανεγχείρητος, μη-πλακώδης ΜΜΚΠ σταδίου IV
• Ακτινολογικά αξιολογήσιμη νόσος (μετρήσιμη ή μη μετρήσιμη) βάσει των κριτηρίων RECIST, έκδοση 1.1, με τροποποιήσεις (ΈΝΤΥΠΟ ΓΝΩΣΤΟΠΟΙΗΣΗΣ ΓΑΛΟΥΧΙΑΣ
• Παράρτημα Ζ)
Γενικά
• Άνδρες ή γυναίκες ηλικίας ηλικίας 18 ετών.
• Κατάσταση απόδοσης κατά ECOG 0 ή 1 (βλ. Παράρτημα .)
• Προσδόκιμο επιβίωσης 3 μήνες (σύμφωνα με την κρίση του ερευνητή).
• Σε γενικές γραμμές, καλά ελεγχόμενη αρτηριακή πίεση με συστολική αρτηριακή πίεση ≤ 140 mmHg ΚΑΙ διαστολική αρτηριακή πίεση ≤ 90 mmHg πριν από την ένταξη στη μελέτη ή την τυχαιοποίηση. Επιτρέπεται η χρήση αντιυπερτασικών φαρμάκων για τον έλεγχο της υπέρτασης.
Εργαστηριακά
• Επαρκής οργανική και αιματολογική λειτουργία όπως καταδεικνύεται από τις ακόλουθες εργαστηριακές εξετάσεις:
- Αιματολογική λειτουργία:
Απόλυτος αριθμός ουδετερόφιλων (ANC) 1,5 x 109/L
Αριθμός αιμοπεταλίων 100 x 109/L και 850 x 109/L
Αιμοσφαιρίνη 9 g/dL
- Πηκτική λειτουργία:
χρόνος μερικής θρομβοπλαστίνης (PTT) ή χρόνος ενεργοποιημένης μερικής θρομβοπλαστίνης (aPTT) 1,5 x ULN σύμφωνα με τις φυσιολογικές τιμές του εργαστηρίου του νοσοκομείου.
Διεθνής ομαλοποιημένη σχέση (INR) ≤ 1,5.
- Νεφρική λειτουργία:
Λεύκωμα ούρων 30 mg/dL στην ανάλυση ούρων ή 1+ στο stick ούρων, εκτός και αν η ποσοτική πρωτεΐνη είναι 1000 mg σε δείγμα ούρων 24ώρου.
Κάθαρση κρεατινίνης (CrCl) ≥ 45 mL/min ανά συλλογή ούρων 24ώρου ή υπολογιζόμενη σύμφωνα με τον τύπο Cockcroft- Gault:
CrCl (mL/min) =
(140-ηλικία) x πραγματικό σωματικό βάρος (kg)
(x 0,85) για τις γυναίκες
72 x κρεατινίνη ορού (mg/dL)
Ηπατική λειτουργία:
AST και ALT ≤ 2,5 x ULN σύμφωνα με τις φυσιολογικές τιμές του εργαστηρίου του νοσοκομείου (ή ≤ 5 x ULN αν υπάρχουν ηπατικές μεταστάσεις).
Ολική χολερυθρίνη < 1,2 mg/dL
- Θρεπτική λειτουργία:
Λευκωματίνη 2,8 g/dL
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E.4 | Principal exclusion criteria |
• Any prior chemotherapy or targeted therapy for non-squamous NSCLC
• Subjects with adenosquamous histology or any histology subtype containing greater than 10% squamous cells
• Subjects with a known epidermal growth factor receptor (EGFR)
mutation sensitive to treatment with a tyrosine kinase inhibitor (TKI)
• Subjects with known anaplastic lymphoma kinase (EML4-ALK)
translocations
• History or presence of central nervous system metastases.
Central (chest) radiation therapy within 28 days, or radiation therapy to any other site within 14 days prior to enrollment/ randomization.
• Subjects must have recovered from all radiotherapy related toxicity
- If all sites of disease have been irradiated, documented progression must have occurred in at least 1 site of disease subsequent to the radiation therapy
• History of pulmonary hemorrhage or gross hemoptysis (approximately 3 mL of bright red blood or more) within 6 months prior to enrollment/randomization
• History of arterial or venous thromboembolism within 12 months prior to enrollment/randomization
• History of clinically significant bleeding within 6 months prior to
enrollment/randomization
Medications
• Enrolled in or has not yet completed a 30-day washout period prior to enrollment/randomization for an investigational device or drug trial, or is currently receiving other investigational treatment
• Known active or ongoing infection (except uncomplicated urinary tract infection) within 14 days prior to enrollment/randomization
• Currently or previously treated with AMG 386, or other molecules that inhibit the angiopoietins or Tie2 receptor
• Treatment within 30 days prior to enrollment/randomization with
strong immune modulators including but not limited to systemic cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil, methotrexate, azathioprine, rapamycin, thalidomide, and lenalidomide
General Medical
• Clinically significant cardiovascular disease within 12 months prior to enrollment/randomization, including myocardial infarction, unstable angina, grade 2 or greater peripheral vascular disease, cerebrovascular accident, transient ischemic attack, congestive heart failure, or arrhythmias not controlled by outpatient medication, or placement of percutaneous transluminal coronary angioplasty/stent
• History of prior malignancy, except:
- Malignancy treated with curative intent and with no known active
disease present for ≥ 3 years before enrollment/randomization and felt to be at low risk for recurrence by the treating physician
- Adequately treated non-melanoma skin cancer or lentigo maligna
without evidence of disease
- Adequately treated cervical carcinoma in situ without evidence of
disease
- Prostatic intraepithelial neoplasia without evidence of prostate cancer
• Major surgery within 28 days prior to enrollment/randomization or still recovering from prior surgery
• Minor surgical procedures, except placement of tunneled central
venous access device within 3 days prior to enrollment/ randomization
• History of allergic reactions to bacterially produced proteins
• Pregnant (ie, positive beta-human chorionic gonadotropin test) or is breast feeding or planning to become pregnant within 6 months after the end of treatment
• Subject not willing to use highly effective methods of birth control during treatment and for 6 months after the end of treatment
• Known positive test(s) for human immunodeficiency virus (HIV)
infection, hepatitis C virus, acute or chronic active hepatitis B infection
• Any condition, which, in the investigator's opinion, makes the subject unsuitable for study participation
• Any uncontrolled concurrent illness or history of any medical condition that may interfere with the interpretation of the study results
• Non-healing wound, ulcer (including gastrointestinal) or fracture
Other
• Subject has previously been enrolled onto this study
• Subject will not be available for protocol-required study visits or
procedures, to the best of the subject and investigator's knowledge
• Subject has known sensitivity to any of the products to be
administered during dosing
• Subject has any kind of disorder that, in the opinion of the
investigator, may compromise the ability of the subject to give written informed consent and/or to comply with all required study procedures |
Due to space limitations please check above |
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E.5 End points |
E.5.1 | Primary end point(s) |
• Part 1: Incidence of adverse events and clinical laboratory
abnormalities defined as a
DLT
• Part 2: PFS |
• 1ο Μέρος: Συχνότητα εμφάνισης ανεπιθύμητων συμβάντων και κλινικών εργαστηριακών ανωμαλιών που ορίζονται ως δοσοπεριοριστική τοξικότητα (DLT)
• 2ο Μέρος: PFS |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
174 PFS events among the 3 arms have been observed |
Όταν θα έχουν παρατηρηθεί τουλάχιστον 174 συμβάντα που υποδηλώνουν PFS μεταξύ των 3 σκελών |
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E.5.2 | Secondary end point(s) |
Part 1 :
PFS
• Incidence of adverse events and significant laboratory abnormalities not defined as DLTs
• Intensive pharmacokinetics of pemetrexed and carboplatin (total and unbound carboplatin) with or without AMG 386
Part 2:
• Incidence of adverse events and significant laboratory abnormalities
• Patient reported outcomes using FACT-L and EQ-5D
• Sparse pharmacokinetics of pemetrexed with and without AMG 386
• Exposure-response relationship of AMG 386
Part 1 and 2:
• Overall survival (OS), objective response rate (ORR) duration of
response (DOR), change in tumor burden
• Pharmacokinetics of AMG 386 (eg, AUC, Cmax and Cmin)
• Incidence of anti-AMG 386 antibody formation |
1ο Μέρος
• PFS
• Συχνότητα εμφάνισης ανεπιθύμητων συμβάντων και σημαντικών εργαστηριακών ανωμαλιών που δεν ορίζονται ως δοσοπεριοριστικές τοξικότητες (DLT)
• Βασισμένη σε εντατική δειγματοληψία φαρμακοκινητική της πεμετρεξίδης και της καρβοπλατίνης (ολικής και αδέσμευτης καρβοπλατίνης) σε συνδυασμό με ή χωρίς AMG 386
2ο Μέρος
• Συχνότητα εμφάνισης ανεπιθύμητων συμβάντων και σημαντικών εργαστηριακών ανωμαλιών
• Έκβαση της θεραπείας όπως αναφέρθηκε από τους ασθενείς χρησιμοποιώντας τα ερωτηματολόγια FACT-L και EQ-5D
• Βασισμένη σε αραιή δειγματοληψία φαρμακοκινητική της πεμετρεξίδης σε συνδυασμό με ή χωρίς AMG 386
• Σχέση έκθεσης-ανταπόκρισης στο AMG 386
1ο και 2ο Μέρος
• Συνολική επιβίωση (OS), ποσοστό αντικειμενικής ανταπόκρισης (ORR), διάρκεια ανταπόκρισης (DOR) και μεταβολή του φορτίου όγκου
• Φαρμακοκινητική του AMG 386 (π.χ., AUC, Cmax και Cmin)
• Συχνότητα σχηματισμού αντισωμάτων έναντι του AMG 386
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Please advise |
Όταν θα έχουν παρατηρηθεί τουλάχιστον 174 συμβάντα που υποδηλώνουν PFS μεταξύ των 3 σκελών |
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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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
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 | 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 | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 26 |
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 |
Australia |
Canada |
Russian Federation |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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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The time when the last subject is assessed or receives an intervention for evaluation in the study inclusive of the safety follow up and survival assessment beyond the Primary Completion. |
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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 | 6 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 4 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 4 |