Page Nct des essais cliniques
Clinical Trial Results:
A multi-centric, open-label, phase II study investigating the combination of Afinitor with paclitaxel and carboplatin in first line treatment of patients with advanced (stage IV) Large Cell Lung Cancer with neuroendocrine differentiation (LC-NEC)
| Summary | |
EudraCT number | 2010-022273-34 |
Trial protocol | DE |
Global end of trial date | 13 Mar 2015 |
| Results information | |
Results version number | v1(current) |
This version publication date | 03 Jul 2016 |
First version publication date | 03 Jul 2016 |
Other versions | |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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| Trial identification | |||
Sponsor protocol code | CRAD001KDE37 | ||
| Additional study identifiers | |||
ISRCTN number | - | ||
US NCT number | - | ||
WHO universal trial number (UTN) | - | ||
| Sponsors | |||
Sponsor organisation name | Novartis Pharm AG | ||
Sponsor organisation address | CH-4002, Basel, Switzerland, | ||
Public contact | Clinical Disclosure Office, Novartis Pharma AG, 41 613241111 x, | ||
Scientific contact | Clinical Disclosure Office, Novartis Pharma AG, 41 613241111 x, | ||
| Paediatric regulatory details | |||
Is trial part of an agreed paediatric investigation plan (PIP) | No | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? | No | ||
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? | No | ||
| Results analysis stage | |||
Analysis stage | Final | ||
Date of interim/final analysis | 13 Mar 2015 | ||
Is this the analysis of the primary completion data? | No | ||
Global end of trial reached? | Yes | ||
Global end of trial date | 13 Mar 2015 | ||
Was the trial ended prematurely? | No | ||
| General information about the trial | |||
Main objective of the trial | The primary endpoint was the proportion of subjects progression-free at Month 3 as assessed by the central reviewer according to RECIST (Version 1.1). | ||
Protection of trial subjects | The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial. | ||
Background therapy | - | ||
Evidence for comparator | - | ||
Actual start date of recruitment | 28 Apr 2011 | ||
Long term follow-up planned | No | ||
Independent data monitoring committee (IDMC) involvement? | No | ||
| Population of trial subjects | |||
Number of subjects enrolled per country | |||
Country: Number of subjects enrolled | Germany: 49 | ||
Worldwide total number of subjects | 49 | ||
EEA total number of subjects | 49 | ||
Number of subjects enrolled per age group | |||
In utero | 0 | ||
Preterm newborn - gestational age | 0 | ||
Newborns (0-27 days) | 0 | ||
Infants and toddlers (28 days-23 months) | 0 | ||
Children (2-11 years) | 0 | ||
Adolescents (12-17 years) | 0 | ||
Adults (18-64 years) | 29 | ||
From 65 to 84 years | 20 | ||
85 years and over | 0 | ||
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| Recruitment | |||||||||||||||||||||
Recruitment details | - | ||||||||||||||||||||
| Pre-assignment | |||||||||||||||||||||
Screening details | This was an open-label, single arm study. | ||||||||||||||||||||
| Period 1 | |||||||||||||||||||||
Period 1 title | Overall Study (overall period) | ||||||||||||||||||||
Is this the baseline period? | Yes | ||||||||||||||||||||
Allocation method | Not applicable | ||||||||||||||||||||
Blinding used | Not blinded | ||||||||||||||||||||
| Arms | |||||||||||||||||||||
| Arm title | RAD001 plus paclitaxel/carboplatin | ||||||||||||||||||||
Arm description | Participants received RAD001 5 mg orally once daily in combination with carboplatin and paclitaxel for a maximum 4 cycles or until discontinuation. | ||||||||||||||||||||
Arm type | Experimental | ||||||||||||||||||||
Investigational medicinal product name | RAD001 | ||||||||||||||||||||
Investigational medicinal product code | RAD001 | ||||||||||||||||||||
Other name | Everolimus | ||||||||||||||||||||
Pharmaceutical forms | Tablet | ||||||||||||||||||||
Routes of administration | Oral use | ||||||||||||||||||||
Dosage and administration details | 5 mg by mouth once daily | ||||||||||||||||||||
Investigational medicinal product name | Carboplatin | ||||||||||||||||||||
Investigational medicinal product code | |||||||||||||||||||||
Other name | |||||||||||||||||||||
Pharmaceutical forms | Solution for infusion | ||||||||||||||||||||
Routes of administration | Intravenous use | ||||||||||||||||||||
Dosage and administration details | Area under the curve (AUC) 5 iv every 21 days for 4 cycles | ||||||||||||||||||||
Investigational medicinal product name | Paclitaxel | ||||||||||||||||||||
Investigational medicinal product code | |||||||||||||||||||||
Other name | |||||||||||||||||||||
Pharmaceutical forms | Solution for infusion | ||||||||||||||||||||
Routes of administration | Intravenous use | ||||||||||||||||||||
Dosage and administration details | 175 mg/m2 intravenously (iv) every 21 days for 4 cycles | ||||||||||||||||||||
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| Baseline characteristics reporting groups | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title | RAD001 plus paclitaxel/carboplatin | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description | Participants received RAD001 5 mg orally once daily in combination with carboplatin and paclitaxel for a maximum 4 cycles or until discontinuation. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| End points reporting groups | |||
Reporting group title | RAD001 plus paclitaxel/carboplatin | ||
Reporting group description | Participants received RAD001 5 mg orally once daily in combination with carboplatin and paclitaxel for a maximum 4 cycles or until discontinuation. | ||
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End point title | Percentage of participants progression-free (PF) [1] | ||||||||
End point description | Tumors were assessed according to Response Evaluation Criteria in Solid tumors (RECIST) to determine PF status. Complete response (CR): disappearance of all lesions (i.e. all evidence of disease, not just the target lesions) determined by 2 observations not less than 4 weeks apart; Partial response (PR): > 30% decrease in the sum of longest diameters of target lesions compared to baseline, with response or stable disease observed in non-target lesions, and no new lesions; Stable disease (SD): neither sufficient shrinkage to qualify for response or sufficient increase to qualify for progressive disease in target lesions, with response or stable disease observed in non-target lesions, and no new lesions; Progressive disease (PD): > 20% increase in the sum of longest diameters of target lesions compared to smallest sum longest diameter recorded. In addition, the sum must also demonstrate an absolute increase of at least 5mm. No statistical analysis was planned for this outcome measure. | ||||||||
End point type | Primary | ||||||||
End point timeframe | 3 months | ||||||||
| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this primary end point. | |||||||||
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| No statistical analyses for this end point | |||||||||
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End point title | Percentage of participants progression-free | ||||||||
End point description | Tumors were assessed according to Response Evaluation Criteria in Solid tumors (RECIST) to determine progression-free status. Complete response (CR) is disappearance of all lesions (i.e. all evidence of disease, not just the target lesions) determined by 2 observations not less than 4 weeks apart; Partial response (PR) is > 30% decrease in the sum of longest diameters of target lesions compared to baseline, with response or stable disease observed in non-target lesions, and no new lesions; Stable disease (SD) is neither sufficient shrinkage to qualify for response or sufficient increase to qualify for progressive disease in target lesions, with response or stable disease observed in non-target lesions, and no new lesions; and Progressive disease (PD is: > 20% increase in the sum of longest diameters of target lesions compared to smallest sum longest diameter recorded. In addition, the sum must also demonstrate an absolute increase of at least 5mm. | ||||||||
End point type | Secondary | ||||||||
End point timeframe | 6 months | ||||||||
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| No statistical analyses for this end point | |||||||||
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End point title | Percentage of participants with Overall Response Rate (ORR) | ||||||||
End point description | ORR was defined as is the proportion of participants with a best overall response of CR or PR. CR is disappearance of all lesions (i.e. all evidence of disease, not just the target lesions) determined by 2 observations not less than 4 weeks apart; Partial response. PR is > 30% decrease in the sum of longest diameters of target lesions compared to baseline, with response or stable disease observed in non-target lesions, and no new lesions. | ||||||||
End point type | Secondary | ||||||||
End point timeframe | 3 months | ||||||||
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| No statistical analyses for this end point | |||||||||
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End point title | Percentage of participants with Disease Control Rate (DCR) | ||||||||
End point description | DCR was defined as is the percentage of participants with a best overall response of CR or PR or SD. Complete response (CR) is disappearance of all lesions (i.e. all evidence of disease, not just the target lesions) determined by 2 observations not less than 4 weeks apart; Partial response (PR) is > 30% decrease in the sum of longest diameters of target lesions compared to baseline, with response or stable disease observed in non-target lesions, and no new lesions; Stable disease (SD) is neither sufficient shrinkage to qualify for response or sufficient increase to qualify for progressive disease in target lesions, with response or stable disease observed in non-target lesions, and no new lesions; and Progressive disease (PD is: > 20% increase in the sum of longest diameters of target lesions compared to smallest sum longest diameter recorded. In addition, the sum must also demonstrate an absolute increase of at least 5mm. | ||||||||
End point type | Secondary | ||||||||
End point timeframe | 3 months | ||||||||
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| No statistical analyses for this end point | |||||||||
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End point title | Progression Free Survival (PFS) | ||||||||
End point description | PFS was defined as the time from the date of start of treatment to date of event defined as the first documented progression or death due to any cause. | ||||||||
End point type | Secondary | ||||||||
End point timeframe | 6 months | ||||||||
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| No statistical analyses for this end point | |||||||||
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End point title | Overall Survival (OS) | ||||||||
End point description | OS was defined as the time from date of start of treatment to date of death due to any cause. | ||||||||
End point type | Secondary | ||||||||
End point timeframe | 12 months | ||||||||
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| No statistical analyses for this end point | |||||||||
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| Adverse events information | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events | Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description | Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type | Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dictionary used for adverse event reporting | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name | MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version | 18.0 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Reporting groups | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title | RAD001 plus paclitaxel/carboplatin | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description | RAD001 plus paclitaxel/carboplatin | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) | |||
| Were there any global substantial amendments to the protocol? Yes | |||
Date | Amendment | ||
15 Jul 2013 | Amendment 1 was primarily written to increase recruitment by updating the inclusion/exclusion criteria in order to better reflect the actual patient population and to enlarge the patient population eligible to be enrolled in this study. Inclusion criterion 2 was changed in a manner that a histological confirmation of LC-NEC diagnosis for relapsing tumors was not necessarily needed anymore at time of recurrence. The histological diagnosis of LC-NEC was still necessary but could also be done during an earlier stage of disease. The diagnosis of LC-NEC depending on neuroendocrine differentiation was specified by including the requirement of non-small cell cytological characteristics (in order to exclude SCLC). The increased proliferation rate had to be demonstrated in histology by microscopic analysis (>11/10 HPF) and, if available, by the Ki67 proliferation marker (>50%). In the exclusion criteria, some ambiguous wordings were specified, especially for allowed prior chemotherapies and for radiotherapies of brain metastases. In addition, some inconsistencies in the protocol were amended: The allowed infusion time of the carboplatin infusion was now consistently 30 to 60 minutes and Figure 6-1 with the study treatment scheme was corrected accordingly. The description of RAD001 maintenance treatment after completion of combination treatment was shifted in a separate paragraph. An error in Table 6-4 was corrected. A wording in the paragraph “End of treatment” was amended. The allowed window for visit scheduling was clarified to +/- 3 days if not otherwise specified. Minor amendments in the visit evaluation schedule were made. Inconsistencies regarding the assessment of the primary and secondary efficacy parameters were corrected: The efficacy endpoints (with exception of overall survival) were assessed by the central imaging reviewer. In the statistical part of the protocol, the definition of the ITT set was corrected and the handling of the ITT set was clarified. | ||
17 Nov 2014 | Amendment 2 was written for the purpose to terminate the enrollment to the trial. The termination was effective with approval of this protocol amendment by the Institutional Review Board (IRBs)/ Independent Ethics Committee (IECs) and Health Authorities. The reason for the termination was the low recruitment rate. Since the first patient was enrolled in April 2011, altogether only 48 patients (cut-off date 17-Nov-2014) could be recruited at 11 active study sites. Several actions were taken to improve the recruitment rate: implementation of protocol amendment 1 which updated the inclusion/exclusion criteria in order to better reflect the actual patient population and to enlarge the patient population eligible to be enrolled in this study; two investigator meetings including the site pathologists; a separate pathologist board; opening of two additional study sites; advertising for the trial in the internet; and several preliminary publications at scientific meetings. However, as the recruitment rate did not improve noteworthy, it could not be expected that the originally planned number of patients (71 evaluable patients) could be reached in a reasonable time. | ||
Interruptions (globally) | |||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats | |||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||