E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Subjects with unresectable stage IIIB with pericardial or pleural effusion or stage IV or recurrent Non Small Cell Lung Cancer (NSCLC)
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E.1.1.1 | Medical condition in easily understood language |
Non-Small Cell Lung Cancer |
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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 | 14.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029522 |
E.1.2 | Term | Non-small cell lung cancer stage IV |
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 | 14.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029521 |
E.1.2 | Term | Non-small cell lung cancer stage IIIB |
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 | 14.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029515 |
E.1.2 | Term | Non-small cell lung cancer recurrent |
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 |
To determine if treatment with AMG 706 in combination with paclitaxel and carboplatin improves overall survival compared to treatment with placebo in combination with paclitaxel and carboplatin in subjects with advanced non-squamous NSCLC and in subjects with adenocarcinoma histology (adenocarcinoma subpopulation). |
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E.2.2 | Secondary objectives of the trial |
∙ To evaluate PFS time, objective tumor response rate (only in
subjects with measurable disease) and duration of response in subjects with non-squamous NSCLC histology and in subjects with adenocarcinoma histology
- To evaluate the association of AMG 706 treatment-induced PlGF increase with OS in subjects with non-squamous NSCLC and in subjects with adenocarcinoma histology
∙ To evaluate the safety and tolerability of AMG 706 in combination with paclitaxel
and carboplatin compared to placebo in combination with paclitaxel and carboplatin in subjects with non-squamous NSCLC histology and adenocarcinoma histology
∙ To evaluate OS, PFS, AMG 706 treatment-induced PlGF increase association with OS, ORR (only in subjects with measurable disease) and duration of response in subjects with non-squamous, non-adenocarcinoma histology
∙ To evaluate the PK of AMG 706 & metabolites when administered with paclitaxel and carboplatin ... Reference is made to the protocol for complete list. |
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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 IIIB with pericardial or pleural effusion or stage IV or recurrent non-squamous NSCLC.
Evaluation of effusions (ie, with cytology) is not required if diagnosis of
non-squamous NSCLC has been otherwise histologically confirmed.
∙ Measurable or non-measurable disease per modified RECIST criteria
∙ ECOG performance status of 0 or 1
∙ Life expectancy of ≥ 3 months as documented by the investigator.
Demographic
∙ Men or women aged ≥ 18 years old.
Laboratory
∙ Hematological function, as follows:
- Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
- Platelet count ≥ 100 x 109/L and ≤ 850 x 109/L
- Hemoglobin ≥ 9 g/dL
∙ Renal function, as follows:
- Creatinine clearance (GFR) > 40 mL/min (calculated by Cockcroft-Gault formula, see Section 6.2.2.2).
- Urinary protein quantitative value of ≤ 30 mg in urinalysis or ≤ 1+ on
dipstick unless total quantitative protein is < 500 mg in a 24-hour urine sample.
∙ Hepatic function, as follows:
- Aspartate aminotransferase (AST) ≤ 2.5 x upper limit of normal ULN OR AST < 5 x ULN if liver metastases are present.
- Alanine aminotransferase (ALT) ≤ 2.5 x ULN OR ALT < 5 x ULN if liver
metastases are present.
- Alkaline phosphatase ≤ 2.0 x ULN OR alkaline phosphatase < 5 x ULN if liver or bone metastases are present.
- Total bilirubin < 1.5 x ULN OR if total bilirubin < 3 X ULN if subject has UGT1A1 promoter polymorphism (ie, Gilbert syndrome) confirmed by genotyping or Invader® UGT1A1 Molecular Assay prior to randomization.
- Partial thromboplastin (PTT) or activated partial thromboplastin (aPTT)
≤ 1 x ULN and international normalized ratio (INR) ≤ 1.5 x ULN.
Ethical
∙ Competency to give written informed consent.
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E.4 | Principal exclusion criteria |
Disease Related
• Subjects with adenosquamous histology or an unclear histology subtype (eg, not otherwise specified) containing greater than 10% squamous cells
• Untreated or symptomatic central nervous system metastases. Subjects with a history of brain metastases are eligible if definitive therapy has been administered (surgery and/or radiation therapy), there is no planned treatment for brain metastasis, and the subject is clinically stable and is off corticosteroids for at least 2 weeks prior to randomization.
• Prior chemotherapy as follows:
- Any prior chemotherapy for advanced non-squamous NSCLC
- Any prior adjuvant chemotherapy for non-squamous NSCLC within
52 weeks prior to randomization. Adjuvant chemotherapy completed
> 52 weeks prior to randomization is permitted
- Any prior chemoradiation for locally advanced stage III disease
• Central (chest) radiation therapy within 28 days prior to randomization, radiation therapy within 14 days prior to randomization for peripheral lesions.
• History of pulmonary hemorrhage or gross hemoptysis (approximately 3 mL of bright red blood or more) within 6 months prior to randomization.
Medications
• Prior targeted therapies, including but not limited to:
- AMG 706, inhibitors of VEGF (eg, SU5416, SU6668, ZD6474, SU11248, PTK787, AZD2171, AEE-788, sorafenib, bevacizumab), or EGFr
(eg, panitumumab, cetuximab, gefitinib, erlotinib)
• Any anticoagulation therapy within 7 days prior to randomization. The use of low-dose warfarin [≤ 2 mg daily] or low molecular weight heparin or heparin flushes for prophylaxis against central venous catheter thrombosis is allowed.
• Known history of allergy or hypersensitivity reaction to paclitaxel or carboplatin.
General
• Prior (within 30 days of randomization) yellow fever vaccination
• History of arterial or venous thrombosis within 12 months prior to randomization.
• History of bleeding diathesis or bleeding within 14 days prior to randomization.
• Peripheral neuropathy > grade 1 per Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0.
• Clinically significant cardiac disease within 12 months of randomization, including myocardial infarction, unstable angina, grade 2 or greater peripheral vascular disease, cerebrovascular accident, transient ischemic attack, percutaneous transluminal coronary angioplasty/stent, congestive heart failure or ongoing arrhythmias requiring medication.
• Any kind of disorder that compromises the ability to comply with the study procedures.
• Open wound, ulcer or fracture.
• Active infection requiring systemic treatment or any uncontrolled systemic infection ≤ 14 days prior to randomization.
• Uncontrolled hypertension as defined by resting blood pressure > 150/90 mm Hg.
Anti-hypertensive medications are allowed if the subject is stable on their current dose at the time of randomization.
• History of other primary cancer unless:
- Curatively resected non-melanomatous skin cancer
- Curatively treated cervical carcinoma in situ
- Other primary solid tumor curatively treated with no known active disease present and no curative treatment administered for the last 3 years
• Surgery:
- Major surgical procedures within 28 days prior to randomization.
- Minor surgical procedures within 14 days prior to randomization.
- Failure to recover from prior surgery.
- Placement of a central venous access device (including ports and
tunneled or non- tunneled catheters) within 7 days prior to randomization.
- Planned elective surgery while on study treatment.
- Core needle biopsy within 7 days prior to randomization.
• Not recovered from all previous therapies (ie, radiation, surgery and
medications). Adverse events related to previous therapies must be CTCAE grade ≤ 1 at screening or returned to the subject’s baseline prior to their most recent previous therapy.
• Participation in therapeutic clinical trials or currently receiving other
investigational treatment(s) within 30 days prior to randomization.
• Pregnant (eg, positive HCG test-urine or serum) or breast feeding woman.
• Any subject not consenting to use adequate contraceptive precautions
(eg, hormonal, barrier or abstinence) during the course of the study and for 6 months after the last treatment.
• Known to be human immunodeficiency virus (HIV), hepatitis B surface antigen or hepatitis C positive.
• Known chronic hepatitis.
• History of any medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risks associated with the study participation or investigational product(s) administration or may interfere with the
interpretation of the results.
• Previously randomized to this study.
• Not available for follow-up assessments or unable to comply with study requirements. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Overall survival time: Overall survival time is calculated as the number of days from randomization to death (date of death - date of randomization + 1). Subjects who have not died (no record of death) will be censored at their
last contact date. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
One formal interim analysis of OS will be performed when approximately 370 deaths have occurred in non-squamous population. The primary efficacy analysis will be performed when approximately 742 non-squamous deaths have ccurred (target event goal) and approximately 593 deaths have occurred in the adenocarcinoma subpopulation. An updated survival analysis will be performed at the end of the study. |
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E.5.2 | Secondary end point(s) |
• Progression-free survival time (PFS): Progression-free survival time is calculated as the number of days from randomization to the date of radiological evidence of disease progression (date of CT or MRI scan, whichever indicates disease progression) or death, regardless of cause (date of progressive disease or death - date of randomization + 1). Subjects who are alive without a disease response assessment of progressive disease will be censored at the last disease assessment date. In the case where there are 2 or more missing tumor assessments followed by disease progression at the next assessment or death, PFS will be censored at the last complete tumor assessment date prior to the missing assessment. Subjects who withdraw from treatment prior to progression without withdrawing consent will be followed for disease status whenever possible. Subjects who have no response assessments after baseline will be censored on the randomization date. All tumor assessment dates will be based on the actual date of the CT or MRI scans.
• Overall survival time in the PlGF analysis set
• Objective tumor response rate (ORR) (complete [CR] and partial response [PR]) according to modified RECIST criteria in subjects with measurable disease at baseline: The incidence of either a confirmed CR or PR per modified RECIST criteria (responder). Any complete response or partial response will be confirmed with a subsequent CT or MRI scan no less than 4 weeks after the criteria for response are first met
• Duration of response (calculated for only those subjects who respond): The number of days between the date of first tumor response assessment of objective response (including complete response and partial response), which is subsequently confirmed, to the time of the first tumor response assessment of progressive disease or death due to any cause (date of first progressive disease assessment or death - date of first objective response assessment + 1). This will be calculated only for those subjects who have a confirmed objective response based on a review of CT or MRI scans. Subjects who respond and have not progressed while on study will be censored at the date of assessment of the last CT or MRI scan. Subjects who withdraw consent to participate in the study prior to progression will be censored at the date of their last evaluable assessment of response. Subjects who withdraw from treatment prior to progression without withdrawing consent will be followed for disease status whenever possible.
• Pharmacokinetics of AMG 706 (eg, Cmin, Cmax) and metabolite concentrations when administered in combination with paclitaxel and carboplatin (in approximately 250 subjects at selected centers).
• Pharmacokinetics (eg, Cmax) of carboplatin (total and unbound platinum concentrations) when administered in combination with paclitaxel and AMG 706 or placebo (in approximately 20 to 30 subjects at selected centers outside of the European Union).
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary endpoints will be evaluated as part of the primary analysis. The primary efficacy analysis will be performed when approximately 742 non-squamous deaths have occurred (target event goal) and approximately 593 deaths have occurred in the adenocarcinoma subpopulation. |
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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 | Yes |
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 | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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 | 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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 52 |
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 |
Australia |
Brazil |
Canada |
Chile |
Hong Kong |
India |
Japan |
Korea, Republic of |
Mexico |
New Zealand |
Philippines |
Russian Federation |
Singapore |
Taiwan |
Turkey |
Ukraine |
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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Reference is made to the protocol. |
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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 | 5 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |