| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Subjects with Previously Untreated Stage IIIb/IV Non-Small Cell Lung Cancer (NSCLC) Treated with Chemotherapy with or without Bevacizumab |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10029521 |
| E.1.2 | Term | Non-small cell lung cancer stage IIIB |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10029522 |
| E.1.2 | Term | Non-small cell lung cancer stage IV |
|
| 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 |
Phase 1b Primary Objective:
To determine the maximum tolerated dose (MTD) (up to 8 mg/kg/day for 5 days treatment and up to 20mg/kg/day for 2 days treatment) through safety and tolerability of multiple doses of AMG 951 administered by intravenous (IV) infusion to subjects with NSCLC in combination with chemotherapy and bevacizumab.
Phase 2 Primary Objective:
To evaluate the objective response rate (CR and PR) by modified RECIST for AMG 951 at varying dose schedules in combination with carboplatin / paclitaxel + bevacizumab for subjects with NSCLC. |
|
| E.2.2 | Secondary objectives of the trial |
Phase 1b Secondary Objective:
To characterize the pharmacokinetics of AMG 951 (to include but not limited to AUC, Cmax, t1/2, clearance, and volume of distribution).
Phase 2 Secondary Objectives:
To evaluate overall response rate (CR, PR and SD), progression-free survival, time to response, duration of response, time to progression and overall survival for AMG 951 at varying dose schedules.
To evaluate the safety profile of AMG 951 at varying dose schedules.
To evaluate the formation of anti-AMG 951 antibodies.
To characterize the pharmacokinetics of AMG 951. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Disease related
-Histologically or cytologically confirmed Non-Small Cell Lung Cancer (NSCLC).
Mixed tumors will be categorized by the predominant cell type unless small cell
elements are present in which case the patient is ineligible. Cytologic or histologic elements can be established on metastatic tumor aspirates or biopsy.
-Subjects must have advanced NSCLC defined as stage IIIb with malignant pleural effusion or Stage IV or recurrent disease. Subjects with non-measurable but evaluable disease can be included in the phase 1b study, but disease must be measurable to be included in the phase 2 study
-Planning to receive up to 6 cycles of chemotherapy
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 (see
Appendix F)
• Life expectancy greater than 3 months
Demographic:
• ≥18 years old and of legal age for informed consent
• Subjects must sign and date a written Independent Ethics Committee (IEC)-
approved Informed Consent Form
Laboratory
• International Normalization Ratio (INR) ≤ 1.2 and PTT ≤ ULN within 1 week
prior to enrollment |
|
| E.4 | Principal exclusion criteria |
-Prior malignancy other than NSCLC, unless have been treated with curative intent with no evidence of disease for ≥3yrs
-Untreated or unstable central nervous system (CNS) metastases.
Subjects with CNS metastases that are both definitively treated and stably controlled are eligible for cohorts A and B of the phase 2 part of the study if all of the following apply:1) definitive therapy has been administered (surgery and/or radiation therapy);2) there is no additional treatment planned for brain metastases;3) the subject is clinically stable;4) the subject is off corticosteroids or on a stable dose of corticosteroids for at least 2wks prior to enrollment
-Myocardial infarction, or unstable or uncontrolled disease or condition related to
or impacting cardiac function (e.g., unstable angina, congestive heart failure) within 1yr of enrollment
-Uncontrolled hypertension defined as: systolic blood pressure ≥150mm Hg OR
diastolic blood pressure ≥100mm Hg (antihypertensive therapy to achieve these
parameters is allowable)
-History of arterial thrombosis, pulmonary embolus, deep vein thrombosis or hemorrhagic disorders within 1yr of enrollment
-Recent major surgical procedure within 28dys prior to enrollment or not yet recovered from prior major surgery
-Recent minor surgical procedure or core biopsy ≤ 7 days prior to enrollment or not yet recovered from prior minor surgery. (Insertion vascular access device is not considered major or minor surgery).
-Subjects must not have serious non-healing wound ulcer, or bone fracture within
21dys prior to enrollment
-Persistent history of gross hemoptysis (defined as bright red blood of a ½tspn or more) relating to subject’s NSCLC
-Known (documented in medical notes) HIV infection
-Active infection on day of enrollment
-Known to be hep C positive OR hep B surface antigen positive
-Subjects with Gilbert’s syndrome
Within 7 days prior to enrollment the following test results must be obtained,
unless otherwise specified:
-Absolute neutrophil count (ANC) <1.5x109/L (without granulocyte-colony stimulating factor support within 2wks of enrollment)
-Platelet count <100x109 L (without transfusion within 2wks of enrollment)
-Hemoglobin <9g/dL (subjects may be transfused or receive erythropoietic treatment to meet criterion)
-Urine protein quantitative value of >1+ on dipstick or >30mg/dL in urinalysis. If
quantitative protein is <500mg in 24hr urine collection then subject can be included
-Significant liver dysfunction as defined by aspartate aminotransferase (AST) or alanine aminotransferase (ALT)>2.5xupper limits of normal (ULN)
-Alkaline phosphatase >2.5xULN, or alkaline phosphatase >5xULN in the presence of bone or liver metastasis
-Total bilirubin >1.5XULN
-Calculated creatinine clearance <50mL/min.
-Hypercalcemia (serum calcium ≥12.0mg/dL or symptomatic)
-Prior chemotherapy (except for adjuvant chemotherapy, provided the last dose of adjuvant therapy was received at least one year prior to enrollment), hormonal therapy, radiotherapy (except palliative radiotherapy for bone metastases or radiation therapy for CNS metastases) or immunotherapy for treatment of advanced NSCLC
-Prior drug treatment or therapy with investigational agents for advanced NSCLC
-Therapeutic anticoagulation treatment. Prophylactic anticoagulation of venous access devices (e.g., with low-dose warfarin [1-2mg/day] or lowdose heparin) is allowed providing INR≤1.2 and PTT≤ULN within 1 wk prior to randomization
-Chronic daily treatment with aspirin (>325mg/day) or non-steroidal antiinflammatory agents known to inhibit platelet function. Treatment with
dipyridamole, ticlopidine, clopidogrel and/or cilostazol is also not allowed
-Participation in clinical trials or undergoing other investigational procedures
within 30dys before study enrollment
-Subject is evidently pregnant (eg, + HCG test) or is breast feeding.
-Woman or man with partner of childbearing potential not consenting to use adequate contraceptive precautions i.e. double barrier contraceptive methods (eg diaphragm plus condom), or abstinence during the course of the study and for 5 mths after the last study drug administration for women, and 7mths for men
-Subject has known sensitivity to any of the products to be administered during study.
-Subject has any kind of disorder that compromises the ability of the subject to
give written informed consent and/or to comply with study procedures.
-Any condition which in the investigator’s opinion makes the subject unsuitable
for study participation
-Subjects enrolled and dosed in phase1b will be excluded from phase2
Excl criteria for phase1b and bevacizumab treatment (cohorts C, D and E) in phase 2
-Subjects with central nervous system tumor involvement
-Subjects with squamous NSCLC
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Incidence of dose-limiting toxicities (DLTs)
Incidence and severity of adverse events (Phase 1b)
Objective response rate (complete or partial response) (Phase 2)
|
|
| 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 | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| 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 | 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 59 |
| 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
|
End of study will be defined as the date when the last subject completes the safety
follow up visit (approximately 4 weeks after the final dose of AMG 951). |
|
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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