| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced Non-Small Cell Lung Cancer (NSCLC) |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 evaluate the efficacy of mapatumumab in combination with paclitaxel and carboplatin in subjects with Stage IIIB/IV NSCLC. |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the safety and tolerability of mapatumumab in combination with
paclitaxel and carboplatin
- To determine serum mapatumumab concentrations |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Exploratory Biomarker Sub-study (Appendix E of study protocol; amendment 01; 05Oct07)
2. Study Objectives and Design
2.1. Indicators of Response
2.1.1. Serum-Based Markers of Response
Induction of cell death in tumor cells can elicit the release of certain biomarkers into the serum. These markers can be quantified to evaluate treatment effect. To assess release of biomarkers associated with cell death, serum-based assays will be conducted, including, but not limited to, assessments of M30, a fragment of cytokeratin 18 that is generated by induction of programmed cell death in epithelial
tissues. Other examples of markers of tumor cell death that will be examined include the cytokines TRAIL, TNFα and IFNγ. The levels of these factors will be examined before and after treatment to see if they correlate with response to treatment. To achieve this, a blood sample (10 mLs) will be collected predose on Day 1, and on Day 15 of Cycles 1 and 2. Serum will be isolated and the level of cytokines and other markers like M30 will be characterized. Collection, processing and handling of these samples are described in the SPM. Samples collected in this study will be stored for up to 15 years and may be analyzed with samples collected in other studies, but will only be used for mapatumumab-related research.
2.2. Modifiers of Response
2.2.1. Neoplastic Modifiers of Response
Historically collected tumor biopsy material, if available, will be collected from subjects during Cycle 1. Samples will also be obtained from subjects who undergo a biopsy during the treatment period. Samples of resected tumor tissue that has been formalin-fixed and embedded in paraffin is acceptable; either tissue blocks or slides may be provided. Frozen samples of tumor tissue may also be provided. Biopsy material collected from FNAs may be provided; either cell pellets or cytological slides are acceptable. Levels of TRAIL receptors will be assessed in biopsy material using immunohistochemical techniques if samples are available as formalin-fixed/paraffin-embedded tissue blocks or slides. Historically obtained biopsy material or biopsy material obtained during the treatment period that is in the form of fresh frozen tissue or cell pellet samples will be utilized to isolate RNA for analysis of TRAIL
receptor gene expression. Similar techniques will be used to evaluate other potential biomarkers and factors that may influence mapatumumab response. These may include but are not limited to caspase 8, AKT and Mcl-1. See the SPM for collection, processing and handling of these samples. Samples collected in this study will be stored for up to 15 years and may be analyzed with samples collected in other studies, but will only be used for mapatumumab-related research.
2.2.2. Somatic Modifiers of Response
Inherited differences in the genes that code for drug targets or components of signaling pathways related to the target can dramatically influence the effect of pharmacotherapy. Variations in genes that could potentially impact mapatumumab’s activity, including polymorphic changes in the Fc gamma receptor and K-Ras gene mutations, will be examined to see if they correlate with response to treatment.
To achieve this, a blood sample (10 mLs) will be collected predose in Cycle 1. DNA will be isolated from the blood and polymorphisms and mutations in specific response-related genes will be characterized. Collection, processing and handling of these samples are described in the SPM. Samples collected in this study will be stored for up to 15 years and may be analyzed with samples collected in other studies, but will only be used for mapatumumab-related research. |
|
| E.3 | Principal inclusion criteria |
1. Histologically or cytologically confirmed Stage IIIB (T4 due to malignant pericardial or pleural effusions as indicated by positive cytology, exudative effusion and LDH > 200IU with effusion/serum LDH ratio 0.6 [“Wet IIIB”] or any N3, M0 who are not candidates for standard combined modality therapy) or Stage IV advanced primary non-small cell lung carcinoma.
2. Measurable disease according to RECIST. Measurable lesions must be outside a previous radiotherapy field if they are the sole site of disease unless disease progression has been documented. Pleural/pericardial effusions, ascites or laboratory parameters are not acceptable as the only evidence of disease.
3. Adequate hematologic function and bone marrow reserve:
-Absolute neutrophil count (ANC) ≥ 1.5 x 109/L.
-Platelet (PLT) count ≥ 100 x 109/L without a transfusion within 14 days before randomization.
-Hemoglobin ≥ 9 g/dL without a transfusion or growth factor support within 14 days before randomization.
4. Adequate hepatic and renal function:
-Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x upper limit of normal (ULN) in the absence of liver metastases and ≤ 5.0 x ULN in the presence of liver metastases.
-Creatinine clearance ≥ 50 mL/min using the Cockcroft-Gault formula.
-Serum creatinine ≤ 1.5 mg/dL or ≤ 132.6 µmol/L.
5. Performance status of 0 to 1 on the Eastern Cooperative Oncology Group (ECOG) Scale.
6. Age 18 years or older.
7. Have the ability to understand the requirements of the study, provide written informed consent (including consent for the use and disclosure of research-related health information), and comply with the study and follow-up procedures. |
|
| E.4 | Principal exclusion criteria |
1. Any co-morbid condition that in the judgment of the investigator renders the subject at high risk of treatment complication or reduces the probability of assessing clinical effect.
2. Received prior investigational or non-investigational cytotoxic chemotherapy, hormonal therapy, or biological therapy (including but not limited to monoclonal antibodies, small molecules or other immunotherapy) as 1st-line therapy for advanced NSCLC. Chemotherapy administered as a radiosensitizing agent will be allowed provided it was administered at least 4 weeks before randomization and all toxicities are resolved. Adjuvant chemotherapy administered for the treatment of NSCLC will be allowed provided it was completed at least 24 months prior to randomization. Subjects who completed cancer therapy for a cancer other than NSCLC greater than 5 years before randomization and who are documented disease free at the time of randomization will be allowed in study.
3. Need for concomitant anticancer therapy (radiation therapy, chemotherapy,
immunotherapy, radiofrequency ablation) or other investigational agents. Subjects who need palliative radiation therapy within 4 weeks before randomization or during Cycle 1 to lesions identified at baseline that are not designated for follow-up as target lesions are not excluded.
4. Received radiation therapy (with or without chemosensitization), photodynamic therapy or radiofrequency ablation to any lesion identified as a target lesion within 4 weeks before randomization.
5. Major surgery (ie, the opening of a major body cavity, requiring the use of general
anesthesia) within 4 weeks before randomization; minor surgery (except for insertion of vascular access device) within 2 weeks before randomization; or not yet recovered from the effects of such surgery. Invasive percutaneous procedures (eg, thoracentesis) require no washout period prior to randomization if there are no adverse effects of the procedure present.
6. Systemic steroids within 1 week before randomization except steroids used as part of an antiemetic regimen or maintenance-dose steroids for non-cancerous disease.
7. Small cell histology.
8. Any Grade 2 or greater neuropathy.
9. History of severe (Grade 4) hypersensitivity reaction to products containing Cremophor EL (cyclosporine, teniposide).
10. History of any infection requiring hospitalization or systemic anti-infectives within
2 weeks before randomization. Topical anti-infectives and oral antibiotics for standard of care prophylactic indications (for example, but not limited to, subacute bacterial endocarditis during dental procedures) will be permitted.
11. Known symptomatic brain or spinal cord metastases unless adequately treated (surgery or radiotherapy) with no evidence of progression and neurologically stable off anticonvulsants and steroids. Asymptomatic brain or spinal cord metastases which are stable and do not require treatment will be allowed.
12. History of other cancers within 5 years before randomization except for basal cell
carcinoma or squamous cell carcinoma of the skin and in situ cancers of the cervix.
13. Known human immunodeficiency virus (HIV) infection.
14. Have a history of, or test positive at screening for Hepatitis B surface antigen, or Hepatitis C antibody.
15. Unstable angina, myocardial infarction, cerebrovascular accident, or ≥ Class III congestive heart failure (CHF) according to the New York Heart Association Classification for CHF (see Appendix 2) within 6 months before randomization.
16. Pregnant or breast-feeding women. Women with an intact uterus (unless amenorrheic for the 24 months before randomization) must have a negative serum pregnancy test at screening. All non-sterile or non-postmenopausal females must agree to use a medically approved method of contraception during the study and for 60 days following the final dose of study agent.
17. Males who do not agree to use effective contraception during the study and for a period of 60 days following the final dose of study agent.
18. Subject is currently enrolled in or has not yet completed at least 30 days since ending other investigational device or drug study(s) or subject is receiving other investigational agents.
19. Subject previously treated with mapatumumab.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Objective response (complete response + partial response [CR+PR])
- Progression free survival (PFS) |
|
| 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 | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| 2 arms with Mapatumumab given in combination with chemotherapy SOC versus chemotherapy SOC alone. |
|
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 9 |
| 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 |
| Germany |
| Hungary |
| Romania |
| United States |
|
| 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
| |
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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