| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally Advanced or Metastatic Non-Small Cell Lung Cancer (Stage IIIB or IV) other than Predominantly Squamous Cell Histology |
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| MedDRA Classification |
| 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 | 10025055 |
| E.1.2 | Term | Lung cancer non-small cell stage IV |
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| 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 | 10025054 |
| E.1.2 | Term | Lung cancer non-small cell stage IIIB |
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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 estimate the objective response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. |
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| E.2.2 | Secondary objectives of the trial |
• To estimate progression-free survival (PFS)
• To estimate 1-year survival rate
• To examine the safety and toxicity profile of study treatment
• To assess biomarkers relevant for pemetrexed and cetuximab
• To explore the correlation between biomarkers and clinical outcome
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients with Stage IIIB or Stage IV nonsquamous NSCLC will be eligible to be included in the study only if they meet all of the following criteria:
[1] they or their legal representative must have signed an informed consent document (ICD) for clinical and translational research;
[2] have a histological diagnosis of Stage IIIB (not amenable to curative treatment) or IV NSCLC other than predominantly squamous cell histology (will subsequently be referred to as "nonsquamous" NSCLC for ease of reference);
[3] have biological tissue available for detection of EGFR expression on tumor tissue; [4] have not received any prior systemic chemotherapy, immunotherapy, targeted therapy, or biological therapy for NSCLC. Previous adjuvant chemotherapy is allowed if terminated at least 1 year prior to enrollment;
[5] prior chest irradiation is allowed provided it was terminated at least 12 weeks prior to study entry;
[6] prior radiation therapy is allowed to <25% of the bone marrow; however, prior radiation to the whole pelvis is not allowed. Prior radiation therapy must be completed at least 2 weeks prior to Day 1 of Cycle 1. Patients must have recovered from the acute toxic effects of radiation therapy prior to Day 1 of Cycle 1;
[7] have measurable disease as defined by RECIST criteria. Target lesions must not be in an irradiated area;
[8] males and females at least 18 years of age;
[9] have a performance status of 0 or 1 on the ECOG scale;
[10] have adequate organ function as follows: Adequate bone marrow reserve:
white blood cell count > or = to 3x109/L, absolute neutrophil (segmented and bands) count > or = to 1.5x109/L, platelet count > or = to 100x109/L, and hemoglobin > or = to 9.0 g/dL
Hepatic: bilirubin < or = to 1.5 x upper limit of normal (ULN); alkaline phosphatase, alanine transaminase, and aspartate transaminase < or = to 2.5 x ULN (< or = to 5 x ULN with liver metastases)
Renal: creatinine ≤1.5 x ULN, and calculated creatinine clearance > or = to 45mL/min based on the Cockcroft-Gault formula (Cockcroft and Gault 1976)
These tests must be performed within 7 days prior to Day 1 of Cycle 1.
[11] male patients must agree to use a reliable method of birth control during the study and for 6 months following the last dose of study drug;
[12] eligible female patients: are women of childbearing potential who test negative for pregnancy at the time of enrollment based on a serum or urine pregnancy test within 7 days prior to Day 1 of Cycle 1, and agree to use a reliable method of birth control during the study and for 6 months following the last dose of study drug;
are women not of childbearing potential due to surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are postmenopausal;
are postmenopausal women, defined as women age > or = to 45 with an intact uterus who have not taken hormones or oral contraceptives within the last 6 months/year who have had either cessation of menses for at least 1 year, or 6 to 12 months of spontaneous amenorrhea with follicle stimulating hormone) (FSH) >40 mIU/mL;
[13] have an estimated life expectancy of at least 12 weeks;
[14] are able to comply with study and/or follow-up procedures.
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| E.4 | Principal exclusion criteria |
Patients will be excluded from the study if they meet any of the following criteria:
[15] have symptomatic central nervous system (CNS) metastases;
[16] have a serious concomitant systemic disorder (for example, tuberculosis or active infection including human immunodeficiency [HIV] syndrome) that, in the opinion of the investigator, would compromise the patient’s ability to adhere to the protocol;
[17] have a serious cardiac condition, such as myocardial infarction, angina, or heart disease, as defined by the New York Heart Association Class II, III, or IV, within 6 months prior to Day 1 of Cycle 1;
[18] have another active malignancy, other than superficial basal cell and superficial squamous (skin) cell, or carcinoma in situ of the cervix within the last 5 years;
[19] have a history of significant neurologic or psychiatric disorders including dementia, seizures, and bipolar disorder;
[20] have peripheral neuropathy of CTCAE Grade 1 or higher;
[21] have received treatment within 30 days prior to Day 1 of Cycle 1 with any drug that has not received regulatory approval for any indication at the time of study entry;
[22] have had major surgery within 4 weeks prior to study entry;
[23] have previously received treatment with transduction inhibitors or EGFR-targeting therapy;
[24] are receiving concurrent chronic systemic immune therapy, or chemotherapy for a disease other than cancer;
[25] have prior known allergic/hypersensitivity reaction to any of the components of study treatment;
[26] are pregnant or breastfeeding;
[27] are unable to interrupt aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), other than aspirin < or = to 1.3 grams per day, for a 5-day period (8-day period for long-acting agents, such as piroxicam);
[28] are unable or unwilling to take folic acid, vitamin B12, or corticosteroid supplementation;
[29] have clinically significant third-space fluid collections, for example, ascites or pleural effusions that cannot be controlled by drainage or other procedures prior to Day 1 of Cycle 1;
[30] known drug abuse;
[31] recent (within 30 days before enrollment) or concurrent yellow fever vaccination.
[32] are investigator site personnel directly affiliated with this study and/or their immediate families. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted;
[33] are Lilly employees;
[34] are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an off-label use of an investigational drug or device (other than the study drug/device used in this study), or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary objective of this study is to assess the antitumor activity of the combination therapy of pemetrexed and cisplatin plus cetuximab, as measured by the objective response rate (ORR), in patients with Stage IIIB or IV nonsquamous NSCLC.
The primary outcome measure for this trial is ORR, based on the patient’s best response across all study treatment cycles. Investigators will determine the cycle response using RECIST criteria. The ORR will be the proportion of the PQ patient population having a confirmed response of PR or CR. The ORR will be estimated for the PQ patient population using unadjusted, large-sample, normal approximation for binomial proportions (z approximation). The RR will be compared to historical control data on pemetrexed and cisplatin without cetuximab administered to a similar patient population.
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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 | No |
| 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 | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Patient outcomes and resource utilization |
|
| 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 | No |
| E.8.1.1 | Randomised | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 22 |
| 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 | 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 data cutoff date for the final analysis will occur at the earlier of the following dates: (a) when the last patient completes 1-year survival follow-up or (b) at the time of last patient death or lost to follow-up.
After the final analysis, if patients are continuing to benefit from study treatment, they will be allowed to continue receiving study treatment. |
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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 | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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