E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Non-Small Cell Lung Cancer (Stage IA-T1b, IB, II or IIIA) |
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E.1.1.1 | Medical condition in easily understood language |
Patients with Non-Small cell Lung Cancer |
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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 | 19.0 |
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) |
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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 of this study is to evaluate the clinical efficacy of the PRAME ASCI versus Placebo in terms of Disease-Free Survival (DFS).
As of Amendment 2,
•Recruitment is stopped
•The study is unblinded
•Only patients on active treatment will have the option to continue in the study. Patients randomised to the Placebo group were withdrawn.
•There will no longer be an active follow-up of patients after discontinuation or completion of the treatment. The study will end 30 days after the last dose will be administered.
•No more biological samples planned for protocol research purposes will be collected and samples already collected will not be tested by default except if a scientific rationale remains relevant
• Safety monitoring will continue as initially foreseen for all patients remaining in the study.
As a result, the primary objective will not be assessed as planned. All clinical data collected in the study will be analysed descriptively. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives are to evaluate in the overall study population, in the population of patients who did or did not receive adjuvant chemotherapy and presents or does not present the previously identified MAGE-A3 gene signature (GS):
•The clinical efficacy of the PRAME ASCI versus placebo in terms of OS, NSCLC-specific survival, 2-, 3-, 4- and 5-year DFS rates and DFSS
•The safety of the PRAME ASCI
•The immune humoral response to the PRAME ASCI.
As a result of the changes implemented in Amendment 2, secondary objectives will not be assessed as planned. All clinical and safety data collected will be analysed descriptively. No more serum samples for assessment of immune humoral responses will be collected and serum samples already collected will only be tested if a scientific rationale remains relevant. In this case, testing will be performed according to protocol and ICF signed by the patient. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•The patient has radically resected (R0) NSCLC
•The NSCLC is of pathological stage IA-T1b, IB, II or IIIA NSCLC according to the American Joint Cancer Committee (AJCC) TNM Cancer Staging Manual (7th Edition) (TNM classification)
•The surgical technique for resection of the patient's tumor is anatomical, involving at least a segmentectomy (wedge-resections are not allowed for inclusion in the study)
•The patient's tumor shows expression of PRAME
Note: Analysis will be performed on formalin-fixed paraffin-embedded (FFPE) tissue samples.
•The patient is >= 18 years of age at the time of first consent.
•Written informed consent has been obtained from the patient prior to performance of any study-specific procedure.
Note: all procedures conducted as part of the patient’s routine clinical management and done prior to obtaining the informed consent to screening may be used for screening or baseline assessments, provided these procedures were done as specified in the protocol and within the protocol-defined timeframes.
•The patient is free of disease (no residual tumor, no loco-regional recurrence, no distant metastasis), as confirmed by a post- thoracic surgery contrast-enhanced computed tomography (CT scan) of the chest, upper abdomen and by a contrast-enhanced CT scan or Magnetic Resonance Imaging (MRI) of the brain. Other examinations should be performed as clinically indicated.
Note that post-thoracic surgery contrast-enhanced chest and upper abdomen CT scans performed up to 6 weeks before randomization and contrast-enhanced brain CT scan or brain MRI performed up to 12 weeks before randomization do not have to be repeated unless clinically indicated.
In case a post-thoracic surgery contrast-enhanced CT scan of the chest and upper abdomen cannot be performed, this must be replaced by a post-thoracic surgery chest and upper abdomen MRI performed in addition to a post-thoracic surgery CT scan with no-contrast or a Positron emission tomography (PET)-CT scan.
Note that equivocal findings at imaging should be carefully discussed by the investigator with the radiologist to avoid having ineligible patients entered into the study.
•ECOG performance status of 0, 1 or 2 at the time of randomization
•Adequate bone-marrow reserve, adequate renal, hepatic and adrenal function as assessed by standard laboratory criteria, and defined as:
1. Aboslute neutrophil count- >= 1.0 x 109/L
2. Platelet count- >= 75x 109/L
3. Serum cortisol- >= Lower Limit of Normal (LLN)
4. Serum Creatinine- <= 1.5 times the Upper Limit of Normal (ULN)
5. Total bilirubin-<= 1.5 times the ULN (Except for patients with Gilbert’s syndrome for whom the limit is <=2 x ULN).
6. Alanine transaminase (ALT)- <= 1.5 times the ULN
7. Aspartate aminotransferase (AST)- <= 1.5 times the ULN
8. Alkaline phosphatase (ALP)- <= 2.5 times the ULN
•If the patient is female, she must be of non-childbearing potential, i.e. have a current tubal ligation, hysterectomy, ovariectomy or be post-menopausal, or if she is of childbearing potential, she must practice adequate contraception for 30 days prior to administration of study product, have a negative pregnancy test and continue such precautions during all study treatment period and for 2 months after last treatment administration.
•Patients who the investigator believes can and will comply with the requirements of this protocol (e.g. return for active follow-up visits).
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E.4 | Principal exclusion criteria |
•The patient is diagnosed with a concomitant malignancy AND/OR has a history of malignancy within the past five years OR has had a malignancy that has been in complete remission for less than 5 years. Patients with effectively treated non - melanoma skin cancers or effectively treated carcinoma in situ of the cervix both of which in remission for less than 5 years will be eligible.
•The patient has received any anti-cancer specific treatment, including radiotherapy, immunotherapy, hormonal therapy, chemotherapy or neo-adjuvant chemotherapy, except for:
-Administration of adjuvant platinum-based doublet chemotherapy for the treatment of the current NSCLC allowed between surgery and randomization.
-Treatment of previous malignancies as allowed by the protocol (Please refer to Exclusion criterion 1).
•The patient has been diagnosed with a pIMD. Patients with vitiligo are not excluded from the study.
Note: In the event of a patient presenting with a condition considered by the investigator as pIMD but not listed in Table 13 inclusion should be discussed with the sponsor prior to randomization.
•The patient has a history of confirmed adrenal dysfunction.
•The patient requires concomitant treatment with any immunosuppressive agent, or with systemic corticosteroids prescribed for chronic treatment (more than 7 consecutive days).
Note: The use of prednisone (or equivalent) at <= 0.5 mg/kg/day (absolute maximum 40 mg/day) for more than 7 days or at > 0.5 mg/kg/day but for less than 7 consecutive days is allowed. The use of inhaled corticosteroids or topical steroids is also permitted.
•The patient needs chronic long term oxygen therapy (LTOT), defined as >15hr/day as per the Physicians Consortium for Performance Improvement, American Medical Association (AMA).
•The patient has medically uncontrolled congestive heart failure or hypertension, unstable heart disease (coronary artery disease or myocardial infarction) or uncontrolled arrhythmia at the time of randomization.
•The patient has an uncontrolled bleeding disorder.
•The patient has undergone splenectomy.
•The patient is known to be Human Immunodeficiency Virus (HIV)-positive.
•The patient has psychiatric or addictive disorders that may compromise his/her ability to give informed consent, or to comply with the trial procedures.
•The patient has other concurrent severe medical problems, unrelated to the malignancy, that would significantly limit full compliance with the study or expose the patient to unacceptable risk.
•The patient has a history of allergic disease or reactions likely to be exacerbated by any component of the study investigational product.
•The patient has received any investigational or non-registered product within the 30 days preceding randomization, or planned use during the study period.
•For female patients: the patient is pregnant or lactating or is planning to become pregnant.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint will be Disease-Free Survival (DFS).
As of Amendment 2,
•Recruitment is stopped.
•The study is unblinded.
•Only patients on active treatment will have the option to continue in the study. Patients randomised to the Placebo group were withdrawn.
•There will no longer be an active follow-up of patients after discontinuation or completion of the treatment. The study will end 30 days after the last dose will be administered.
•No more biological samples planned for protocol research purposes will be collected and samples already collected will not be tested by default except if a scientific rationale remains relevant.
• Safety monitoring will continue as initially foreseen for all patients remaining in the study.
As a result, the primary endpoint will not be assessed as planned. All clinical data collected in the study will be analysed descriptively. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Disease Free Survival: When all patients have completed all treatment administrations and the concluding visit. |
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E.5.2 | Secondary end point(s) |
•Overall Survival (OS)
•Lung-cancer-specific survival
•Disease-free specific survival (DFSS)
•DFS at 2, 3, 4 and 5 years after randomization
•The anti-PRAME antibody concentrations
•Occurrence of adverse events, including abnormal hematological and biochemical parameters
•Occurrence of serious adverse events
As a result of the changes implemented in Amendment 2, secondary endpoints will not be assessed as planned. All clinical and safety data collected will be analysed descriptively. No more serum samples for assessment of immune humoral responses will be collected and serum samples already collected will only be tested if a scientific rationale remains relevant. In this case, testing will be performed according to protocol and ICF signed by the patient.. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
•Overall Survival (OS)- at time of the analysis
•Lung-cancer-specific survival- at time of analysis
•Disease-free specific survival (DFSS)- at time of analysis
•DFS at 2, 3, 4 and 5 years after randomization- at time of analysis
•The anti-PRAME antibody concentrations: pre- and post-treatment for each timepoint samples will have been collected.
•Occurrence of adverse events , including abnormal hematological and biochemical parameters- up to 30 days post last dose of study product administration
•Occurrence of serious adverse events- during the whole study duration or up to 30 days after the last study product administration
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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 | Yes |
E.6.13.1 | Other scope of the trial description |
Translational research.
As of Amendment 2,
No more serum samples for translational research will be collected and serum samples already collected will only be tested if a scientific rationale remains relevant. In this case, testing will be performed according to protocol and ICF signed by the patient. |
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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 | Yes |
E.8.1.7.1 | Other trial design description |
As of 18 July 2014, the study was ublinded and stopped for patients assigned to the placebo group |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
As of 18 July 2014, the study was stopped for patients assigned to the placebo group |
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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 | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 23 |
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 |
Japan |
Korea, Republic of |
Russian Federation |
United States |
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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 of the last patient taking part in the trial |
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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 | 2 |
E.8.9.1 | In the Member State concerned days | 19 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 19 |