E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with pathologically confirmed, R0 resected non-small cell lung cancer (NSCLC), pathologic stage IB, IIA, IIB, T3N1 (without need for further radiotherapy); systematic lymph node dissection is required with resection. |
Patienten mit pathologisch bestätigtem, RO-resiziertem nicht-kleinzelligem Lungenkarzinom (NSCLC), pathologische Stadien IB, IIA, IIB und T3N1 (ohne Indikation zu einer Radiotherapie); systemische Lymphknotendissektion is erforderlich bei der Resektion |
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E.1.1.1 | Medical condition in easily understood language |
Patients with confirmed and surgically removed lung cancer including removal of lymph nodes which not require irradiation |
Patienten mit bestätigtem und operativ entferntem Lungenkrebs incl. Lymphknotenentfernung, die keine Bestrahlung benötigen |
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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 | 15.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10025044 |
E.1.2 | Term | 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 |
The primary objective is to determine the clinical feasibility rate (CFR) of 4 cycles of adjuvant chemotherapy with Pemetrexed and Cisplatin vs. Vinorelbine and Cisplatin in patients with NSCLC stage IB, IIA, IIB and T3N1 (without need for further radiotherapy).
Treatment is considered to have clinical feasibility if DLT as defined in the protocol in chapter 13.2 will not be observed, and no non-acceptance by the patient leading to premature withdrawal, and no death due to cancer or cancer therapy will occur.
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E.2.2 | Secondary objectives of the trial |
To determine and compare the drug delivery between both treatment arms
To determine the Time To Treatment Failure (TTTF)
To determine the Relapse Free Survival (RFS)
To determine the Overall Survival (OS)
To determine the Distant Metastases Free Survival (DMFS)
To determine the Local Relapse Free Survival (LRFS)
To determine the Localization of Relapse
To determine Dose Delivery
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Histopathologically confirmed diagnosis of non-small cell lung cancer (NSCLC), pathologic stage IB, IIA, IIB or T3N1 (without need for further radiotherapy)
Complete tumor resection without detectable residual tumor including negative margins (R0) [R-classifaction according to Wittekind et al 2002] and systematic intraoperative dissection of mediastinal lymph nodes according to the guidelines of the British thoracic society (British thoracic society, 2001; Hoffmann et al., 1999); of course lymph node dissection has to comprise all lymph node levels removed with standard right or left sided resection. The dissection has to assure the removal of mediastinal lymph nodes > 1,5 cm on the preoperative CT scan.
The following histological tumor types are eligible:
- Squamous Cell Carcinoma
- Adenocarcinoma (including adenocarcinomas with bronchioloalveolar differentiation)
- Large Cell Carcinoma (excluding tumors with slight areas of small cell carcinoma
with neuroendocrine differentiation)
- Mixed Cell Carcinoma without small cell fraction
- Provision of informed consent according to local regulatory requirements for
participation in the study
- Age between 18 – 75 years
- Karnofsky Performance Status ≥ 80% or ECOG performance status less or equal 1
- Adequate hematological laboratory parameters
- Hemoglobin ≥ 10 g/dl
- ANC ≥ 1,500 /µl
- Platelets ≥ 100000 /µl
- Adequate hepatic laboratory parameters:
- Bilirubin less or equal 1.5 x UNL
- ASAT/ALAT less or equal 2 x UNL
- Adequate renal laboratory parameters
- Creatinine less or equal 1,5 mg/dl and
- Calculated Creatinine Clearance ≥ 60 ml/min
- Cardiac function allowing Cisplatin chemotherapy (in case of doubt
echocardiography is mandatory documenting LVEF > 49%)
- 12-lead Electrocardiogram without significant cardiac arrhythmia
- FEV1 ≥ 1.2 l post-operatively
- Respiratory function not impeding Cisplatin-based chemotherapy assessed by
either absolute DLCO or capillary / arterial BGA in resting condition (absolute DLCO
> 40 % or pO2 >60 mmHg in resting condition
- Agreement by the patient to use an effective method of contraception
- Negative pregnancy test for women of childbearing potential or women who are
postmenopausal at baseline. (Postmenopausal women must have been
amenorrheic at least for 12 month to be considered of non child-bearing potential) |
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E.4 | Principal exclusion criteria |
- Presence of a Pancoasttumor
- The following histological tumor types are excluded
- Pure Bronchioloalveolar carcinoma
- Mixed cell carcinoma with small cell fractions
- Large cell carcinoma with areas of small cell carcinoma
- Involvement of N2/N3 lymph nodes
- Distant metastases
- Pregnancy or lactation period
- Other co-existing malignancies or malignancies diagnosed within the last 5 years
with the exception of basal cell carcinoma of cervical cancer in situ or non-
melanomatous skin cancer. Patients curatively treated and free of disease for at
least 5 years will be discussed with the Principal Investigator (LKP) before inclusion
- Radio- and/or chemotherapy within the last five years
- Concurrent administration of any other antitumor therapy
- Patients who are not compliant with vitamin (folic acid and vitamin B12) intake or to
whom administration is not possible
- Treatment with an investigational new drug, currently or within the last 30 days,
and/or participation in another clinical trial, currently or during the last 12 weeks,
and/or previous participation in this study
- Patient has previously completed or withdrawn from this study or any other study
with the respective medication in this study
- History of a psychological illness or condition such as to interfere with the patient's
ability to understand the requirements of the study
- Patients with any clinically significant disease that in the opinion of the investigator
is likely to put the patient at risk or to interfere with the evaluation of the patient's
safety and of the study outcome. This includes, but is not limited to:
- Clinically significant cardiac disease (e.g. congestive heart failure, symptomatic
coronary artery disease and cardiac arrhythmia not well controlled with medication)
or myocardial infarction within the last 6 months
- Uncontrolled hypertension
- Interstitial pneumonia, or extensive or symptomatic interstitial fibrosis of the lung.
- Pleural effusion or ascites, which cause respiratory compromise. Patients with sero
(pneumo)-thorax after hemi-pneumonectomy will not be excluded. Those patients
must be monitored for toxicity closely.
- Any other active or uncontrolled infection
- Organ allografts
- A serious concomitant systemic disorder (e.g. active infection including HIV) that in
the opinion of the investigator would compromise the patient’s ability to complete
the study
- Post-operative complications or other surgery-related conditions that could
interfere with a study participation
- Patients with neurologic disorders
- A history or presence of any CNS disorder or psychiatric disability judged by the
Investigator to be clinically significant and/or interfering with compliance
- Hearing function/tinnitus impeding chemotherapy with Cisplatin and/or Vinorelbine
- Alcohol and/or drug abuse
- Patient is unable to interrupt high dose salicylates (like aspirin) or other non-
steroidal anti-inflammatory drugs (NSAID´s) for a 5-day period starting 2 days
before administration of Pemetrexed (8-day period for long-acting agents such as
piroxicam).
- Patients who cannot be regularly observed for psychological, sociological,
geographical reasons or other concomitant conditions not permitting adequate
follow-up and compliance to the protocol |
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E.5 End points |
E.5.1 | Primary end point(s) |
The experimental therapy arm would be rated as unacceptable, if the actual feasibility rate (= 1 – withdrawal/DLT rate) was 65 % or lower.
On the other hand, the therapy would be considered to be a promising candidate for further development (e.g. in a phase III trial), if the true feasibility rate amounted to 80% or more.
Probability to accept the experimental therapy as well tolerable, in spite of a true feasibility rate of < 65% (i.e. withdrawal/DLT rate > 35%): 5% (type I error)
Probability to reject the experimental therapy as not sufficiently feasible (<65%), although the true feasibility rate is promising (> 80%): 20% (type II error, corresponding to a power of 80%).
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Timepoint for Feasibility is after End of Treatment (30 days after last study medication) after completion and/or correction of the according case report forms (Baseline, Treatment, End of Treatments, AEs, SAEs, DLT, Concomitant Mediation) |
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E.5.2 | Secondary end point(s) |
Time to treatment failure will be measured as the time from surgery to the time the patient is withdrawn due to: adverse events, progressive disease/ relapse, death, failure to return, or refused treatment/did not cooperate/withdrew consent. The date of last dose of treatment will be used as the date of event in the case that PD was not recorded earlier.
Relapse free survival (RFS) will be measured as the time from surgery to the time the patient is first recorded as having disease relapse, or the date of death if the patient dies due to causes other than disease progression.
Distant metastasis free survival (DMFS) will be measured as the time from surgery to the time the patient is first recorded as having distant metastatic disease. Local relapse free survival (LRFS) will be measured as the time from surgery to the time the patient is first recorded as having local relapse.
Survival will be measured as the time from surgery to the date of death or the last date the patient was known to be alive.
To determine the Localization of Relapse
Localization of Relapse will be determined by imaging studies initiated upon clinical suspicion and defines the organ where local or distant relapse is first detected.
Dose delivery will be measured as the effectively delivered chemotherapy dose considering all reductions, omissions and withdrawn patients. It will be presented as mean and median and the percentage of the mean and median of the absolute intended dose.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Timepoint for Dose Delivery is at End of Treatment (30 days after last study medication) after completion and/or correction of the according case report forms (Baseline, Treatment, End of Treatments, AEs, SAEs, DLT, Concomitant Mediation)
Timepoint for all other secondary end points is at End of study after completion and/or correction of all case report forms.
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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 | No |
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 | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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 | 15 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 19 |
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 | Yes |
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 Subject randomized: 31-MAR-2010
Last Subject las visit: 31-OCT-2013 |
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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 | 7 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |