E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced and inoperable Non-sqamous Non-small-cell lung cancer |
Fortgeschrittener und inoperabler, Nicht-Kleinzelliger Lungenkrebs |
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E.1.1.1 | Medical condition in easily understood language |
Advanced and inoperable Non-sqamous Non-small-cell lung cancer |
Fortgeschrittener und inoperabler, Nicht-Kleinzelliger Lungenkrebs |
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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 | 18.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029522 |
E.1.2 | Term | Non-small cell lung cancer stage IV |
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 |
To evaluate and compare objective response rates in both arms while defining toxicity profiles of both application schedules.
Additionally, evaluation of biologically validated, potentially predictive biomarkers and identification of new biomarkers for therapy response, therapy resistance, and course of disease in formalin-fixed paraffin-embedded (FFPE) and fresh tumour specimens as well as circulating tumour cells (CTCs), obtained before treatment and, if applicable, during and after study treatment. |
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E.2.2 | Secondary objectives of the trial |
• Overall survival
• Time to progression (TTP)
• Treatment compliance
• Treatment toxicity
• Duration of treatment administration in both arms
• Life quality analysis (by means of EORTC QLQ-C30 version 3.0)
• Received dose-intensity cisplatinum (RDI)
• Received dose intensity (RDI) pemetrexed
• Cumulative dose cisplatinum
• Documentation of outpatient or inpatient administration of treatment
• Evaluation of predictive biomarkers for response or resistance to pemetrexed/cisplatin-based chemotherapy in NSCLC, in tumour specimens and in circulating tumour cells (CTCs)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Histologically or cytologically confirmed diagnosis of non-squamous-cell non-small cell lung cancer (NSCLC) Stage IV
2. No prior systemic chemotherapy for lung cancer
3. At least one unidimensionally measurable lesion meeting Response Evaluation Criteria in Solid Tumours (RECIST; version 1.1, Eisenhauer et al. 2009), longest diameter ≥10 mm with computed tomography (CT) scan [CT scan slice thickness no greater than 5 mm] , or ≥ 20 mm with chest x-ray. Positron emission tomography (PET) scans and ultrasounds should not be used
4. ECOG performance status of 0 or 1
5. ≥ 18 years of age < 75 years
6. Adequate organ function, including the following:
• Adequate bone marrow reserve: absolute neutrophil (segmented and bands) count (ANC) ≥ 1.5 x 10^9/L, platelets ≥ 100 x 10^9/L, and hemoglobin ≥ 9 g/dL
• Hepatic: bilirubin ≤ 1.5 times the upper limit of normal (ULN), alkaline phosphatase (AP), aspartate transaminase (AST), and alanine transaminase (ALT) ≤ 3.0 x ULN (AP, AST, and ALT ≤ 5 x ULN is acceptable if the liver has tumour involvement)
• Renal: calculated creatinine clearance (CrCl) ≥ 45 mL/minute based on the standard Cockcroft and Gault formula, and creatinine ≤ 1.5 mg/dL
7. Prior radiation therapy allowed to <25% of the bone marrow. Prior radiation to the whole pelvis is not allowed. Prior radiotherapy must be completed at least 4 weeks before study enrollment. Patients must have recovered from the acute toxic effects of the treatment prior to study enrollment.
8. Patient must understand and sign an informed consent document before the start of specific protocol procedures.
9. A pretreatment FFPE tumour biopsy must be available for central biomarker analysis. If consented by the patient and clinically feasible, a fresh pretreatment biopsy is obtained and submitted for central biomarker analysis.
10. Female patients with childbearing potential must use highly effective methods of contraception (combined oral contraceptives, hormon-releasing intrauterine contraceptive device, hormonal contraceptive implants, hormonal contraceptive injectables)
or have sexual intercourse with a vasectomised partner only
during and for 6 months after the study
and their pregnancy test must be negative within 7 days prior to study enrollment.
A female subject is considered to be of childbearing potential unless she is age ≥ 50 years and naturally amenorrhoeic for ≥ 2 year or unless she is surgically sterile.
Male patients must agree to use condoms during the study and for 6 months after the study if their partner is of childbearing potential and does not use highly effective method of contraception
11. Estimated life expectancy of ≥ 12 weeks.
12. Patient compliance and geographic proximity that allow adequate follow up.
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E.4 | Principal exclusion criteria |
1. Active participation in other clinical studies or treatment with any experimental drug within 30 days prior to study enrollment or during study participation
2. Patients with known somatic activating mutations of EGFR, as these patients should be offered EGFR-TKI treatment as first-line therapy. Detection of EGFR mutations and additional somatic mutations with relation to treatment will be performed centrally at the Universitätsklinikum Essen. In case immediate treatment initiation is required for medical reasons (such as superior vena cava syndrome, severely symptomatic disease) patients may be enrolled before results from EGFR testing are available. As EGFR-TKI treatment is equally effective in second-line therapy, such patients may remain on study treatment if a clinical benefit is derived.
3. Peripheral neuropathy of ≥ CTCAE Grade 1
4. Inability to comply with protocol or study procedures
5. A serious concomitant systemic disorder that, in the opinion of the investigator, would compromise the patient’s ability to complete the study.
6. A serious cardiac condition, such as myocardial infarction within 6 months prior to study enrollment, symptomatic coronary artery disease, cardiac arrhythmia, or other heart disease, as defined by the New York Heart Association Class III or IV (functional capacity)
7. Second primary malignancy that is clinically detectable at the time of consideration for study enrollment
8. Documented brain metastases unless the patient has completed successful local therapy for central nervous system metastases and has been off of corticosteroids for at least 4 weeks before enrollment. Brain imaging is required in symptomatic patients to rule out brain metastases,but is not required in asymptomatic patients.
9. The effect of third space fluid, such as pleural effusion and ascites, on pemetrexed is unknown. In patients with clinically significant third space fluid, consideration should be given to draining the effusion prior to pemetrexed administration.
10. Significant weight loss (that is, ≥ 10%) over the previous 6 weeks before study entry
11. Significant hearing function impairment, especially high-frequency hearing function impairment
12. Any active or uncontrolled infection
13. Concurrent administration of any other antitumour therapy
14. Inability to interrupt aspirin or other nonsteroidal anti-inflammatory agents, other than an aspirin dose <1.3 grams per day, for a 5-day period (8-day period for long-acting agents, such as piroxicam)
15. Inability or unwillingness to take folic acid or vitamin B12 supplementation
16. Inability to take corticosteroids
17. Hypersensitivity to cisplatinum or to any other platinum compound
18. Hypersensitivity to pemetrexed or to any of the excipients of ALIMTA®
19. Pregnant or breast-feeding patient
20. Yellow fever vaccination within the 30 days previous to study entry.
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E.5 End points |
E.5.1 | Primary end point(s) |
• Objective response rate in both treatment arms
Response will be assessed in all patients who achieve six cycles of chemotherapy or less in case of prior tumour progression or trial termination due to toxicity.
Treatment response will be analyzed according to RECIST 1.1 with standard computed tomography (CT) scans, chest x-ray, or chest MRI as done routinely also outside of clinical trials situations for survey of chemotherapy in patients with NSCLC.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
tumour assessment every second cycle |
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E.5.2 | Secondary end point(s) |
• Overall survival
• Time to progression (TTP)
• Treatment compliance
• Treatment toxicity
• Duration of treatment administration in both arms
• Life quality analysis (by means of EORTC QLQ-C30 version 3.0)
• Received dose-intensity cisplatinum (RDI)
• Received dose intensity (RDI) pemetrexed
• Cumulative dose cisplatinum
• Documentation of outpatient or inpatient administration of treatment
• Evaluation of predictive biomarkers for response or resistance to pemetrexed/cisplatin-based chemotherapy in NSCLC, in tumour specimens and in circulating tumour cells (CTCs)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• During treatment cycles:
- D1 and end of study visit: Life quality analysis
- D1, D8 and D15 and end of study visit: overall survival, treatment compliance, treatment toxicity, duration of treatment administration in both arms, received dose intensity cisplatinum and pemetrexed, cumulative dose cisplatinum, documentation of outpatient or inpatient administration of treatment
- every second cycle and end of study visit: time to progression
• During Follow Up (every 6 to 8 weeks): overall survival, time to progression, treatment toxicity (until 30 days after last application of study medication, relevant late toxicities)
• Evaluation of predictive biomarkers: tumour specimens at baseline and optional in case of progression, CTCs on D1 and D8 cycle 1 and D1 cycle 2
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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 | 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 | 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) | Information not present in EudraCT |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Vergleich von Behandlungsschemata |
comparison of treatment schemes |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 10 |
E.8.5 | The trial involves multiple Member States | No |
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 | No |
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
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last visit last subject |
Letzte Visite des Letzten Patienten |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |