E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastatic Non-Squamous Non-Small Cell Lung Cancer |
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E.1.1.1 | Medical condition in easily understood language |
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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 |
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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) |
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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 |
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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 |
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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 |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
174 PFS events among the 3 arms have been observed |
|
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 |
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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 | 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
| 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 | 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 |