E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Previously Untreated Extensive Stage Small Cell Lung Cancer (SCLC) |
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E.1.1.1 | Medical condition in easily understood language |
Lung Cancer
Small Cell Lung Cancer
Solid Tumour
Small Cell Lung Cancer Extensive Stage
|
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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 | LLT |
E.1.2 | Classification code | 10041067 |
E.1.2 | Term | Small cell lung cancer |
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 |
Part 1:
To identify a dose of AMG 479 in combination with etoposide plus carboplatin and/or etoposide plus cisplatin and of AMG 102 in combination with etoposide plus carboplatin and/or etoposide plus cisplatin that can be administered safely and is tolerated as determined by the incidence of dose-limiting toxicity (DLT)
Part 2:
To estimate the relative treatment effect of AMG 479 (at the dose selected in Part 1) in combination with chemotherapy (etoposide plus carboplatin and/or etoposide
plus cisplatin, as determined in part 1), and of AMG 102 (at the dose selected in
Part 1) in combination with chemotherapy, compared with placebo plus
chemotherapy, as measured by the respective hazard ratios (HR) for overall survival
(OS). |
|
E.2.2 | Secondary objectives of the trial |
Part 1:
To evaluate safety as assessed by the incidence of adverse events and laboratory abnormalities not defined as DLT
To evaluate safety as assessed by the incidence of anti-AMG 479 antibody formation and anti-AMG 102 antibody formation
To evaluate pharmacokinetics (PK) as assessed by the maximum observed serum concentration (Cmax) and the minimum observed serum concentration (Cmin) for AMG 479 and for AMG 102
Part 2:
To evaluate clinical benefit as assessed by the objective response rate (ORR) as measured by modified Response Evaluation Criteria in Solid Tumors (RECIST), duration of response (DOR), time to progression (TTP), progression-free survival (PFS), median OS (mOS), and OS rates at 10, 12, 24 and 36 months
To evaluate safety as assessed by the incidence of adverse events and laboratory abnormalities
For remaining secondary objectives and for exploratory objectives please see the protocol |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Disease related
• Histologically or cytologically confirmed SCLC
Extensive disease, defined by at least one of the following criteria:
− No limited disease (ie, no disease confined to the ipsilateral hemithorax, which can be safely encompassed within a tolerable radiation field)
− Extrathoracic metastases − Malignant pericardial or pleural effusion
− Contralateral hilar adenopathy
Measurable or non-measurable disease, as defined by modified RECIST (see
Appendix E)
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (see
Appendix I)
Life expectancy (with therapy) ≥ 3 months
Demographic
Woman or man ≥ 18 years old
Ethical
Before any study-specific procedure, the appropriate written informed consent must
be obtained (see Section 12.1)
Laboratory
Hematological function (within 3 days prior to enrollment), as follows:
− Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
− Platelet count ≥ 100 x 109/L
− Hemoglobin ≥ 9 g/dL
Partial thromboplastin time (PTT) ≤ 1.3 x upper limit of normal (ULN) and
international normalized ratio (INR) ≤ 1.3
Renal function, as follows:
− Creatinine (Cr) clearance (CrCl) ≥ 60 mL/minute (min); calculated by Cockcroft-
Gault formula (see Appendix D) as follows:
������ Male CrCl = (140 - age) x (weight in Kg) / (serum Cr x 72)
������ Female CrCl = (140 - age) x (weight in Kg) x 0.85 / (serum Cr x 72)
Hepatic function, as follows:
− Aspartate aminotransferase (AST) ≤ 2.5 x ULN
(≤ 5 x ULN if attributable to liver metastases)
− Alanine aminotransferase (ALT) ≤ 2.5 x ULN
(≤ 5 x ULN if attributable to liver metastases)
− Alkaline phosphatase ≤ 2.5 x ULN
(≤ 5 x ULN if attributable to bone and/or liver metastases)
− Total bilirubin ≤ 1.5 x ULN
(≤ 3 x ULN for subjects with UGT1A1 promoter polymorphism ie, Gilbert
syndrome, confirmed by genotyping or Invader UGT1A1 molecular assay prior to
enrollment)
Fasting blood glucose ≤ 160 mg/dL (Fasting will require subjects to refrain
from all food and beverage [except water] for at least 8 hours)
Negative pregnancy test (urine or serum) within 7 days prior to enrollment (women of child-bearing potential only)
General
• Plan to begin protocol specific therapy ≤ 7 days after enrollment |
|
E.4 | Principal exclusion criteria |
Disease Related
Symptomatic or untreated CNS metastasis − Subjects with CNS metastases that are both treated and stably controlled are
eligible if all of the following apply:
1. 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; and
4. the subject is off corticosteroids or on a stable dose of corticosteroids for at least 2 weeks prior to enrollment
Any prior or synchronous malignancy, except:
− Malignancy treated with curative intent and with no known active disease present
for ≥ 3 years prior to enrollment 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
Cancer Therapy • Prior chemotherapy, chemo-radiation or investigational agent for the treatment of SCLC
− Prior palliative radiotherapy to sites of distant metastasis is allowed (if completed
≥ 7 days prior to enrollment)
− Prior treatment of CNS metastasis is allowed (as defined in Section 4.2.1)
• Currently or previously treated with biological, immunological or other anti-tumor
therapies for SCLC
• Prior radiotherapy to > 25% of the bone marrow
Medications/Treatments
• Recent infection requiring systemic anti-infective treatment that was completed ≤ 14 days prior to enrollment (with the exception of uncomplicated urinary tract infection or upper respiratory tract infection)
Currently being treated with full dose anti-coagulation therapy (ie coumadin
with a goal INR between 2 to 3, or full dose low molecular weight heparin)
Medical Conditions
History of bleeding diathesis
Current serious or non-healing wound or ulcer
Known positive test for human immunodeficiency virus, hepatitis C, chronic or active
hepatitis B
Any clinically significant medical or psychiatric condition, co-morbid disease,
addictive disorder, or laboratory abnormality (eg, cardiovascular disease or chronic
obstructive pulmonary disease), which may increase the risks associated with study
participation or study treatments or could interfere with the safe delivery of study
treatment or increase risk of toxicity
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
Major surgical procedure within 28 days prior to enrollment, or not yet recovered
from major surgery
Minor surgical procedures within 7 days prior to enrollment, or not yet recovered from
minor surgery
Note: uncomplicated placement of vascular access device ≥ 1 day prior to first
administration of study treatment, and fine needle aspiration, thoracocentesis
or paracentesis ≥ 3 days prior to first administration of study treatment is
acceptable
Thrombosis or vascular ischemic events within the last twelve months, such as deep venous thrombosis, pulmonary embolism, transient ischemic attack, cerebral infarction, or myocardial infarction.
General
Inability to tolerate IV drug administration
Subject is currently enrolled in or has not yet completed at least 30 days prior to
enrollment since ending other investigational device or clinical study(s)
Subject of child-bearing potential is evidently pregnant (eg, positive human chorionic
gonadotropin test) or is breast feeding
Woman or man with partner of childbearing potential not consenting to use adequate contraceptive precautions ie, double barrier contraceptive methods (eg, diaphragm
plus condom), or abstinence during the course of the study and for 3 months after
the last study drug administration for women, and 6 months for men
Subject has known sensitivity to any of the products to be administered during the
study
Subject is not able to tolerate IV drug infusions
Subject unwilling or unable to comply with study requirements
Subject will not be available for follow-up assessments
Subject previously enrolled in this study |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Part 1: ▪ The incidence of adverse events and clinical laboratory abnormalities defined as DLT
Part 2: ▪ OS |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
On treatment, 10,12 and 24 months After stopping study treatment, every 3 months for up to 36 months |
|
E.5.2 | Secondary end point(s) |
Part 1
• The incidence of adverse events and laboratory abnormalities not defined as DLT :
• The incidence of anti-AMG 479 and anti-AMG 102 antibody formation
• PK (Cmax and Cmin for AMG 479 and AMG 102)
Part 2
• ORR, DOR, TTP, PFS, mOS, and OS rates at 10,12, 24, and 36 months :
• The incidence of adverse events and laboratory abnormalities
• The incidence of anti-AMG 479 and anti-AMG 102 antibody formation
• PK (Cmax and Cmin) for AMG 479 and AMG 102
• EORTC QLQ-C30 and EORTC QLQ-LC13 scores |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
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 | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
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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 | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Part 1 is open label, Part 2 is double blind placebo controlled |
|
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 36 |
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 |
Belgium |
Czech Republic |
France |
Hungary |
India |
Italy |
Korea, Republic of |
Netherlands |
Philippines |
Poland |
Romania |
Russian Federation |
Spain |
Taiwan |
United Kingdom |
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
|
The end of the clinical study is when all subjects have completed the study treatment and long term follow up (up to a maximum of 36 months from the date the last subject is randomised). This will allow long term assessment of disease status and survival. |
|
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 | 6 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |