Clinical Trial Results:
Metabolic Response Evaluation for an Individualization of Neoadjuvant Chemo- and Radiotherapy in Esophageal Adenocarcinoma
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Summary
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EudraCT number |
2005-004123-19 |
Trial protocol |
DE |
Global end of trial date |
17 Apr 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
17 Jul 2020
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First version publication date |
17 Jul 2020
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Other versions |
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Summary report(s) |
MUNICON II Trial |
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
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Sponsor protocol code |
MUNICON-2
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Technische Universität München, Fakultät für Medizin
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Sponsor organisation address |
Ismaninger Str. 22, München, Germany, 81675
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Public contact |
Klinik und Poliklinik für Innere Medizin II
Studiensekretariat
Jens-Peter Zimmermann , Technische Universität München, Fakultät für Medizin, 49 89 4140 6706,
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Scientific contact |
Klinikum rechts der Isar
Klinik und Poliklinik für Innere Medizin II, Technische Universität München, Fakultät für Medizin, 49 89 4140 2250,
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
25 Mar 2015
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
17 Apr 2014
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Global end of trial reached? |
Yes
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Global end of trial date |
17 Apr 2014
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
The aim of this prospective trial is to optimize current treatment for patient with chemoresistant locally advanced adenocarcinomas of the esophagogastric junction (AEG Typ I und II).
Compared to the previous protocol MUNICON-1, introduction of a new treatment regimen with using a salvage neoadjuvant radiochemotherapy.
The intention is to investigate in case of metabolic non-Response under neoadjuvant chemotherapie the effectiveness of a radiochemotherapy based on the metabolic Response (primary endpoint) and histological regression (secondary endpoint). In addition, the tolerability of preoperative radiochemotherapy, the rate of residual tumour-free resections as well as overall survival and event-free survival will also be assessed.
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Protection of trial subjects |
Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision.
The study was regularly monitored by the Sponsor and all investigators connected to the study were GCP trained.
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Background therapy |
Concomitant medication and supportive therapy were carried out according to standard clinical guidelines and at the judgement of the investigators. | ||
Evidence for comparator |
Previous studies demonstrated that chemotherapy-induced changes in tumor glucose metabolism measured with 18F-FDG PET identify patients who benefit from preoperative chemotherapy and those who do not. The prognosis for chemotherapy metabolic nonresponders is poorer than for metabolic responders. (MUNICON I). Group B = 1:1 Group A, Control Group (18FDG-PET (PET)-Responder: neoadjuvante Chemotherapie Group B, Treatmeant Group (PET-Non-Responder: neoadjuvante Radiochemotherapie) | ||
Actual start date of recruitment |
28 Sep 2005
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety, Efficacy, Scientific research | ||
Long term follow-up duration |
60 Months | ||
Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Germany: 56
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Worldwide total number of subjects |
56
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EEA total number of subjects |
56
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
46
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From 65 to 84 years |
10
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85 years and over |
0
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Recruitment
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Recruitment details |
The study was conducted single-centre in Germany between 28.09.2005 (first patient recruited) and 17.04.2014 (last patient completed). | |||||||||
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Pre-assignment
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Screening details |
Patients were enrolled to the study, if eligibility was confirmed. A total of 66 patients were screened, 56 were included in the study. According to Gehan’s two-stage design, the number of planned cases for this study was 25 patients in test arm B (PET non-responder; neoadjuvant radiochemotherapy). | |||||||||
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Period 1
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Period 1 title |
Overall Trial (overall period)
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | |||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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A: Control Group - PET Responder | |||||||||
Arm description |
18F-FDG PET assessement before chemotherapy and 14 d after initiation of chemotherapy. PET responder (metabolic response) receive neoadjuvant chemotherapy for 3 mo before surgery Group A: Control Group (PET-Responder; neoadjuvante Chemotherapie) | |||||||||
Arm type |
Active comparator | |||||||||
Investigational medicinal product name |
PACLITAXEL
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Investigational medicinal product code |
SUB09583MIG
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Total: 85 mg/m2 milligram(s)/square meter
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Investigational medicinal product name |
Cisplatin
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Investigational medicinal product code |
L01XA01
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Total: 50 mg/m2 milligram(s)/square meter
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Investigational medicinal product name |
Calciumfolinat
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Investigational medicinal product code |
L01BA01
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Total: 500 mg/m2 milligram(s)/square meter
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Investigational medicinal product name |
5-Fluorouracil
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Investigational medicinal product code |
L01BC02
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Total: 2000 mg/m2 milligram(s)/square meter
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Investigational medicinal product name |
Oxaliplatin
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Investigational medicinal product code |
L01XA03
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Total: 85 mg/m2 milligram(s)/square meter
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Arm title
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B. Treatment Group - Non-Responder | |||||||||
Arm description |
18F-FDG PET assessement before chemotherapy and 14 d after initiation of chemotherapy. PET non-responder receive salvage neoadjuvant radiochemotherapy (2 x 1,6 Gy/d, total dose 32 Gy) before surgery Group B: Treatment Group (PET-Non-Responder; neoadjuvante Radiochemotherapie) | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
CISPLATIN
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Investigational medicinal product code |
L01XA01
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Total: 50 mg/m2 milligram(s)/square meter
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Investigational medicinal product name |
5-Fluorouracil
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Investigational medicinal product code |
L01BC02
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Total: 2000 mg/m2 milligram(s)/square meter
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Baseline characteristics reporting groups
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Reporting group title |
A: Control Group - PET Responder
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Reporting group description |
18F-FDG PET assessement before chemotherapy and 14 d after initiation of chemotherapy. PET responder (metabolic response) receive neoadjuvant chemotherapy for 3 mo before surgery Group A: Control Group (PET-Responder; neoadjuvante Chemotherapie) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
B. Treatment Group - Non-Responder
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Reporting group description |
18F-FDG PET assessement before chemotherapy and 14 d after initiation of chemotherapy. PET non-responder receive salvage neoadjuvant radiochemotherapy (2 x 1,6 Gy/d, total dose 32 Gy) before surgery Group B: Treatment Group (PET-Non-Responder; neoadjuvante Radiochemotherapie) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
A: Control Group - PET Responder
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Reporting group description |
18F-FDG PET assessement before chemotherapy and 14 d after initiation of chemotherapy. PET responder (metabolic response) receive neoadjuvant chemotherapy for 3 mo before surgery Group A: Control Group (PET-Responder; neoadjuvante Chemotherapie) | ||
Reporting group title |
B. Treatment Group - Non-Responder
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Reporting group description |
18F-FDG PET assessement before chemotherapy and 14 d after initiation of chemotherapy. PET non-responder receive salvage neoadjuvant radiochemotherapy (2 x 1,6 Gy/d, total dose 32 Gy) before surgery Group B: Treatment Group (PET-Non-Responder; neoadjuvante Radiochemotherapie) | ||
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End point title |
R0 resection | ||||||||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Assessed after surgery
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Statistical analysis title |
R0 resection rate of non-responders | ||||||||||||||||||
Statistical analysis description |
This is the primary endpoint of the study. The R0 resection rate was assessed according to protocol in the group of non-responders and was compared to 30%. The primary endpoint of this study was not achieved.
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Comparison groups |
A: Control Group - PET Responder v B. Treatment Group - Non-Responder
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Number of subjects included in analysis |
56
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||
Method |
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Parameter type |
frequency | ||||||||||||||||||
Point estimate |
0.7
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Confidence interval |
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level |
95% | ||||||||||||||||||
sides |
2-sided
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lower limit |
0.49 | ||||||||||||||||||
upper limit |
0.84 | ||||||||||||||||||
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End point title |
Metabolic Response | |||||||||
End point description |
Metabolic response is defined as reduction of at least 30% in maxSUV-value as compared to start of radiotherapy.
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End point type |
Secondary
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End point timeframe |
Assessed 14 days after start of the neoadjuvant Radiochemotherapy.
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| No statistical analyses for this end point | ||||||||||
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End point title |
Histological Remission | ||||||||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
At end of therapy
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Statistical analysis title |
Histopathological remission rate | ||||||||||||||||||||||||
Statistical analysis description |
According to the study protocol, only the group of PER-responders was used for this analysis.
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Comparison groups |
B. Treatment Group - Non-Responder v A: Control Group - PET Responder
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Number of subjects included in analysis |
56
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||||||||||
Method |
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Parameter type |
frequency | ||||||||||||||||||||||||
Point estimate |
0.12
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Confidence interval |
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level |
95% | ||||||||||||||||||||||||
sides |
2-sided
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lower limit |
0.03 | ||||||||||||||||||||||||
upper limit |
0.28 | ||||||||||||||||||||||||
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End point title |
Overall survival | |||||||||
End point description |
Patients who died during the trial
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End point type |
Secondary
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End point timeframe |
Starting at first dose of chemotherapy.
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Statistical analysis title |
Overall Survival | |||||||||
Statistical analysis description |
Hazard ratio
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Comparison groups |
A: Control Group - PET Responder v B. Treatment Group - Non-Responder
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Number of subjects included in analysis |
56
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
= 0.1 | |||||||||
Method |
Logrank | |||||||||
Parameter type |
Hazard ratio (HR) | |||||||||
Point estimate |
1.9
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.87 | |||||||||
upper limit |
4.24 | |||||||||
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End point title |
Progression-free survival | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Starting with first dose of Chemotherapy
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Statistical analysis title |
Progression-free survival | |||||||||
Statistical analysis description |
Time to relapse
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Comparison groups |
A: Control Group - PET Responder v B. Treatment Group - Non-Responder
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Number of subjects included in analysis |
56
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
= 0.035 | |||||||||
Method |
Logrank | |||||||||
Parameter type |
Hazard ratio (HR) | |||||||||
Point estimate |
2.22
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
1.04 | |||||||||
upper limit |
4.77 | |||||||||
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End point title |
Postoperative morbidity | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Starting with surgery and ending with end of study
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Statistical analysis title |
Difference in post-OP morbidity | ||||||||||||
Comparison groups |
A: Control Group - PET Responder v B. Treatment Group - Non-Responder
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Number of subjects included in analysis |
56
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.68 | ||||||||||||
Method |
Chi-squared | ||||||||||||
Confidence interval |
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Adverse events information
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Timeframe for reporting adverse events |
AE (SAE) reporting covers the time frame from January 24th, 2006 to January 23th, 2011.
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Adverse event reporting additional description |
A total of 407 AEs were reported during the study, whereby all patients reported AEs at one or more points in time during chemo- or radiochemotherapy.
In total, 234 AEs occurred after the first cycle (167 CTCAE G1, 46 CTCAE G2 and 20 CTCAE G3 and 1 CTCAE G4).
Each adverse event is to be classified by the investigator as SERIOUS or NON-SERIOUS.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
14
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Reporting groups
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Reporting group title |
All patients
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Reporting group description |
As expected, the PET responders, who received an extended cycle 1 and a cycle 2 of chemotherapy, reported significantly more AEs than the PET non-responders, who discontinued chemotherapy after a 2-week cycle 1 and continued treatment with chemoradiation. A total of 407 AEs occurred in 56 patients. The PET responders had 170 AEs (111 CTCAE G1, 41 CTCAE G2 and 17 CTCAE G3 and 1 CTCAE G4) after cycle 1 and 114 AEs (79 CTCAE G1, 32 CTCAE G2 and 1 CTCAE G3 and 2 CTCAE G4) after cycle 2 Chemotherapy. The PET non-responders had 64 AEs (56 CTCAE G1, 5 CTCAE G2 and 3 CTCAE G3) after cycle 1 and 59 AEs (41 CTCAE G1, 11 CTCAE G2 and 7 CTCAE G3) after chemoradiation. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| Despite two recruitment extensions, the number of cases could not be reached. | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/24817185 http://www.ncbi.nlm.nih.gov/pubmed/21764790 http://www.ncbi.nlm.nih.gov/pubmed/17693134 |
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