| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| advanced, unresectable, or metastatic (stage IIIB or IV) non-small cell lung cancer |
|
| MedDRA Classification |
| 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 |
The study will be conducted in 2 parts:
• Part 1: a single-arm, unblinded, safety lead in.
• Part 2: a multiple-site, randomized, double-blind, placebo-controlled study.
The objective of the Safety lead in, Part1, is to evaluate the safety of enzastaurin plus pemetrexed and cisplatin in the first-line treatment of patients with advanced, unresectable (stage IIIB) or metastatic (Stage IV) NSCLC
The objective of Part 2 (randomized, double-blind, placebo-controlled, phase 2 study) is to compare first-line treatment with pemetrexed and cisplatin plus enzastaurin versus pemetrexed and cisplatin plus placebo, followed by maintenance enzastastaurin or placebo, in terms of progression-free survival (PFS) |
|
| E.2.2 | Secondary objectives of the trial |
Those objectives are applicable to Part 2 only:
o Compare the response rates (RR) and the disease control rates (DCR) between treatment arms according to Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines
o overall survival (OS)
o duration of disease control (DDC)
o duration of response (CR, PR)
o time to worsening of symptoms (TWS) using the Lung Cancer Symptom Scale (LCSS)
o safety and toxicity profile of study treatments
o to assess biomarkers relevant to enzastaurin, pemetrexed and the disease state, as well as their correlation to clinical outcome |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients are eligible to be included from the study if they meet all of the following criteria:
[1] Have histologic or cytologic diagnosis of advanced NSCLC (Stage IIIB disease with pleural effusion and/or positive supraclavicular nodes, or Stage IV disease) not amenable to curative treatment
[2] No prior systemic chemotherapy, pleurodesis, immunotherapy, targeted or biological therapy for this disease
[3] Have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >20 mm with conventional techniques or as >10 mm with spiral CT scan, OR nonmeasurable disease, defined according to RECIST
[4] Prior radiation therapy is allowed to <25% of the bone marrow; however prior radiation to the whole pelvis is not allowed. Prior radiotherapy must be completed at least 2 weeks before study enrollment. Patients must have recovered from the acute toxic effects prior to study enrollment
[5] Have a performance status of 0 or 1 on the Eastern Cooperative Oncology group (ECOG) scale
[6] Must sign an informed consent document (or legal representative has given informed consent)
[7] Male or female patients at least 18 years of age
[8] Females of child-bearing potential (not surgically sterilized and between menarche and 1 year post menopause) must test negative for pregnancy within 7 days prior to or at the time of enrollment based on a serum pregnancy test. Both males and females of reproductive potential must agree to use a reliable method of birth control, as determined by the patient and his or her health care team, during the study and for 6 months following the last dose of study treatment
[9] Have adequate organ function as follows:
• Hepatic: total bilirubin ≤1.5 times the upper limit of normal (× ULN); alanine transaminase (ALT) alkaline phosphatase (AP) and aspartate transaminase (AST) ≤2.5 ×ULN (≤5 × ULN, with hepatic metastases).
• Renal: serum creatinine ≤1.5 × ULN; creatinine clearance ≥45mL/min (calculated according to Cockcroft and Gault 1976
• Adequate bone marrow reserve: platelet count ≥100 × 109/L, absolute neutrophil count (ANC) ≥1.5 x 109/L, and hemoglobin ≥9.0 g/dL |
|
| E.4 | Principal exclusion criteria |
Patients will be excluded from the study if they meet any of the following criteria:
[10] Have received treatment within the last 30 days with any drug that has not received regulatory approval for any indication at the time of study entry
[11] Have active infection that, in the opinion of the investigator, would compromise the patient’s ability to tolerate therapy
[12] Have a second primary malignancy that is clinically detectable at the time of consideration for study enrollment
[13] Have documented central nervous system (CNS) metastases (unless the patient has completed successful local therapy for CNS metastases and has been off corticosteroids for at least 4 weeks before starting study treatment). A screening CT or MRI before enrollment in the absence of a clinical suspicion of brain metastases is not required.
[14] Have had myocardial infarction occurring <6 months before inclusion, uncontrolled arrhythmia, symptomatic angina pectoris, or cardiac failure not controlled by medications (refer to the New York Heart Association Class III or IV)
[15] Have peripheral neuropathy of NCI CTCAE Grade 2 or above
[16] Are unable or unwilling to discontinue use of carbamazepine, phenobarbital, or phenytoin at least 14 days prior to study therapy
[17] Are pregnant or breast feeding
[18] Are unable to swallow tablets.
[19] Recent (within 30 days before enrollment) or concurrent yellow fever vaccination.
[20] Presence of clinically significant third-space fluid collections (for example, ascites or pleural effusions) that cannot be controlled by drainage or other procedures prior to study enrollment.
[21] Inability to interrupt aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), other than an aspirin dose < or =1.3 g per day, for a 5-day period (8 day period for long-acting agents, such as piroxicam).
[22] Inability or unwillingness to take folic acid or vitamin B12 supplementation or corticosteroids.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint for Part 1 (Safety lead in) is to evaluate the safety of the combination of enzastaurin plus pemetrexed and cisplatin.
The primary endpoint for Part 2 is to compare progression-free survival (PFS) between the two arms of treatment. PFS is defined as the time from the date of study enrolment to the first date of objectively determined progressive disease or death from any cause. |
|
| 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 | No |
| 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 | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | 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) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Yes |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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
| |
| 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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