Back to resultsDe-escalation Study for Stage IIa/IIb < 3 cm Seminoma (EDEN)
Primary Purpose
Seminoma, Stage II
Status
Recruiting
Phase
Phase 2
Locations
France
Study Type
Interventional
Intervention
Radiotherapy boost
Carboplatin AUC7
3 cycles of EP
Sponsored by
About this trial
This is an interventional treatment trial for Seminoma focused on measuring De-escalation, Chemotherapy, Radiotherapy, Carboplatin, Etoposide, Cisplatine, Micro-RNA-M371, PET scan, Overall survival, Biomarker, Efficacy, Progression free rate, Safety, Quality of life
Eligibility Criteria
Inclusion criteria :
- Age ≥ 18 years on the day of signing informed consent.
- Primary testicular seminomatous germ cell tumor.
- Stage IIa/IIb < 3 cm in largest diameter seminoma, histologically proved after orchiectomy.
- Confirmation of a progressive disease (positive PET scan or increase of lymph nodes size by two successive CT scan).
- Good prognosis according to IGCCCG and LDH < 2.5 x Upper Limit of Normal (ULN).
- Normal alpha-fetoprotein (AFP) before and after orchiectomy.
- No prior treatment with radiotherapy or chemotherapy.
- Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 2.
Adequate bone-marrow, hepatic, and renal functions with:
- Neutrophils ≥ 1.5 x Giga/l, platelets ≥ 100 x Giga/l,
- Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 1,5 x ULN,
- Serum creatinine < 140 µmol/l OR calculated clearance > 60 ml/min (using either Cockcroft-Gault formula or Modification of Diet in Renal Disease (MDRD) for > 65 years old),
- Direct and total bilirubin ≤ ULN.
- Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
- Accepting to use effective contraceptive measures or abstain from heterosexual activity, for the course of the study and through 12 months after the last dose of chemotherapy or being surgically sterile. All patients should seek advice regarding cryoconservation of sperm prior treatment initiation because of the possibility of infertility
- Affiliation to a health insurance.
- Signed and dated informed consent.
Non-exclusion criteria :
- Extra-retroperitoneal metastasis on Computed tomography scan (CT scan).
- Infection by Human Immunodeficiency Virus (HIV), or active infection with the Hepatitis B or C virus.
- History, within 2 years, of cancer other than seminoma, except for treated skin cancer (basal cell).
- Uncontrolled or severe cardiovascular pathology.
- Uncontrolled or severe hepatic pathology.
- Patient deprived of liberty or requiring tutorship or curatorship.
- Psychological, physical, sociological, or geographical conditions that would limit compliance with study protocol requirements (at the investigator's discretion).
- Participation to another clinical trial, except for supportive care trials.
Sites / Locations
- CHU Besançon
- CHU Bordeaux
- Centre François Baclesse
- Centre Jean Perrin
- Centre Oscar Lambret
- CHU de Limoges
- Centre Leon BérardRecruiting
- Institut Paoli Calmettes
- Centre Antoine Lacassagne
- Hôpital Saint Louis
- ICO René Gauducheau
- Hôpital Foch
- Institut Universitaire de Cancer de Toulouse (IUCT-O)
- Institut de Cancérologie de Lorraine
- Institut Gustave Roussy
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Experimental
Experimental
Other
No Intervention
Arm Label
ARM A
ARM B
ARM C
OBSERVATIONAL COHORT
Arm Description
RADIOTHERAPY boost 20 to 30 Gy on lymph nodes
One cycle of CARBOPLATIN AUC7
3 cycles of ETOPOSIDE and CISPLATIN
STANDARD RADIOTHERAPY on lymph nodes
Outcomes
Primary Outcome Measures
PFR-36M
Progression-free rate at 36 months
The PFR-36M is assumed to be a random variable following a binomial distribution Bin (n, p) where n is the sample size and p is the true underlying PFR-36M. Conclusions and inferences will be conducted on p. The prior distribution of p (representing the knowledge of the progression-free rate probability prior to observing the data) will be pre-specified. In the absence of a strong idea about the PFR-36M to be observed, a non-informative prior distribution Beta (1,1) will be considered.
Pr[PFR-36M ≥ 80%] will be expressed in each arm, associated with its 95% credibility interval. A treatment arm will be considered a positive sign for efficacy of de-escalation if there is a high probability that PFR-36M will be higher or equal to 80%: Pr[PFR-36M ≥ 80%] ≥ 90%. It means that if most of the distribution (90% of it) falls to the right hand side of 80%, it indicates that it is very likely that the effect is at least 80%
Secondary Outcome Measures
miRNA-M371
Serum level of miRNA-M371 as a potential biomarker of response. Association between serum level of miRNA M371 and response to treatments (according to RECIST v1.1) will be evaluated using a non-parametric Wilcoxon Mann and Whitney test and describe with boxplots.
Association of PET scan results and miRNA-M371 rate
Correlation between serum level of miRNA M371 and FDG-PET results (metabolic response) will be evaluated using the Kendall rank correlation and describe graphically.
Overall survival (OS)
The Overall Survival will be defined as the time from date of inclusion to the date of death, from any cause. Patient whose death is not known at the time of analysis will be censored based on the last recorded date on which the patient was known to be alive.
The Kaplan-Meier (KM) approach will be used to estimate median OS. Median OS as well as Survival rates at specific timepoints will be presented together with their 95% confidence interval (CI).
Quality of life (QoL)
The QoL will be assessed using the EORTC QLQ-C30 questionnaire.
Tolerance to treatment
The tolerance to each treatment will be described mainly on the frequency of adverse events (AEs) and their intensity and severity determined using the National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) grading scale version 5. Descriptive statistics will be provided for characterizing and assessing patient tolerance to treatment.
AEs will be described and coded, in total and per System Organ Class and Preferred Term with Medical Dictionary for Regulatory Activities (MedDRA) coding
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT05529251
Brief Title
De-escalation Study for Stage IIa/IIb < 3 cm Seminoma
Acronym
EDEN
Official Title
Prospective Therapeutic De-escalation and miRNA-M371 Biomarker Evaluation Phase II Study for Stage IIa/IIb < 3 cm Seminomas
Study Type
Interventional
2. Study Status
Record Verification Date
December 2022
Overall Recruitment Status
Recruiting
Study Start Date
September 6, 2022 (Actual)
Primary Completion Date
September 6, 2025 (Anticipated)
Study Completion Date
September 6, 2030 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Centre Leon Berard
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
Phase II, multicenter, prospective, randomized, non-comparative, de-escalation study.
Patients with stage IIa/IIb < 3 cm seminoma histologically proved after orchiectomy will be included in the study and will receive 1 cycle of Etoposide Cisplatine (EP) chemotherapy.
Patients with negative week-3 PET-scan after the EP cycle, will be randomized (1:1 ratio, stratification according to the disease stage (stage IIa versus IIb seminoma)) to receive either radiotherapy (RT) boost on lymph nodes or 1 cycle of carboplatin AUC7 chemotherapy.
Patients with positive week-3 PET-scan will received 3 additional cycles of EP chemotherapy.
In parallel, eligible patients scheduled to receive standard lombo-aortic RT will be registered in an observational cohort.
Detailed Description
Stage II seminoma is defined by the presence of retroperitoneal lymph node metastases. It concerns approximately 15% of patients with seminoma. The standard treatment for patients with stage IIa/b seminoma, after orchiectomy, is extended lumbo-aortic/ipsilateral iliac radiotherapy (RT). Performing chemotherapy (CT) with 3 courses of Bleomycin-Etoposide-Cisplatin (BEP) or 4 courses of Etoposide-Cisplatin (EP) is an alternative.
The optimal treatment choice remains controversial. Both treatment modalities are associated with excellent efficacy but also acute and late toxicities. European Society of Medical Oncology (ESMO) guidelines recommended in equal measure CT and RT for stage IIa. A recent systematic review concluded that RT and cisplatin-based combination CT are equally effective in clinical stage IIa/IIb seminoma, with a trend in favor of chemotherapy in stage IIb because of lower relapse rate. However, due to the rarity of stage II seminoma, a sufficiently powered randomized trial comparing radiotherapy with chemotherapy is unlikely to be completed.
De-escalation strategies are required to minimize acute and long-term toxicities while maintaining efficacy. De-escalated treatment for seminoma patients with stage IIb/IIC/III and good prognosis according to International Germ Cell Cancer Collaborative Group (IGCCCG), based on negative PET after 2 cycles of EP chemotherapy, is feasible and safe according to SEMITEP results (cohort 2). In case of negative PET, 1 additional cycle of CT with carboplatin AUC7 was administered.
Furthermore, serum levels of microRNA (miR)-371a-3p (miRNA-M371) have been significantly associated with clinical stage, primary tumor size and response to treatment in testicular germ cell tumors, with sensitivity and specificity higher than those of classic markers (hCGt, LDH). However, further evaluations are needed before modifying clinical practices.
We propose to conduct a multicenter, prospective, randomized, non-comparative, de-escalation phase II study in patients with stage IIa/IIb seminoma < 3 cm, evaluating:
a more de-escalated CT treatment: 1 cycle of EP followed, in case of negative PET, by either a boost of RT on lymph node or 1 cycle of carboplatin AUC7
the biomarker miRNA-M371 in therapeutic decision and correlation with PET.
In parallel, eligible patients scheduled to receive standard lombo-aortic RT will be registered in an observational cohort.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Seminoma, Stage II
Keywords
De-escalation, Chemotherapy, Radiotherapy, Carboplatin, Etoposide, Cisplatine, Micro-RNA-M371, PET scan, Overall survival, Biomarker, Efficacy, Progression free rate, Safety, Quality of life
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
In case of negative week-3 (after 1 EP cyle) PET-scan: Randomization according to 2 arms
Boost of radiotherapy 20 to 30 Gray (Gy) (ARM A)
Carboplatin AUC7 chemotherapy (ARM B)
In case of positive week-3 PET-scan: 3 courses of EP chemotherapy (ARM C)
Parallel observational cohort for patients scheduled to receive standard lumbo-aortic radiotherapy after orchiectomy
Masking
None (Open Label)
Allocation
Randomized
Enrollment
90 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
ARM A
Arm Type
Experimental
Arm Description
RADIOTHERAPY boost 20 to 30 Gy on lymph nodes
Arm Title
ARM B
Arm Type
Experimental
Arm Description
One cycle of CARBOPLATIN AUC7
Arm Title
ARM C
Arm Type
Other
Arm Description
3 cycles of ETOPOSIDE and CISPLATIN
Arm Title
OBSERVATIONAL COHORT
Arm Type
No Intervention
Arm Description
STANDARD RADIOTHERAPY on lymph nodes
Intervention Type
Radiation
Intervention Name(s)
Radiotherapy boost
Intervention Description
Radiotherapy boost 20 to 30 Gy, in daily 2 Gy fractions and 5 fractions per week :
20 Gy if no more disease is visible (node < 1 cm in large diameter)
24 Gy for nodes <= 2 cm
30 Gy for nodes > 2 cm
Intervention Type
Drug
Intervention Name(s)
Carboplatin AUC7
Intervention Description
Carboplatin at dose (mg) = AUC7 (mg/ml x min) x (DFG ml/min + 25)
Intervention Type
Drug
Intervention Name(s)
3 cycles of EP
Intervention Description
3 Cycles of EP chemotherapy, administred every 3 weeks following standard practice
Primary Outcome Measure Information:
Title
PFR-36M
Description
Progression-free rate at 36 months
The PFR-36M is assumed to be a random variable following a binomial distribution Bin (n, p) where n is the sample size and p is the true underlying PFR-36M. Conclusions and inferences will be conducted on p. The prior distribution of p (representing the knowledge of the progression-free rate probability prior to observing the data) will be pre-specified. In the absence of a strong idea about the PFR-36M to be observed, a non-informative prior distribution Beta (1,1) will be considered.
Pr[PFR-36M ≥ 80%] will be expressed in each arm, associated with its 95% credibility interval. A treatment arm will be considered a positive sign for efficacy of de-escalation if there is a high probability that PFR-36M will be higher or equal to 80%: Pr[PFR-36M ≥ 80%] ≥ 90%. It means that if most of the distribution (90% of it) falls to the right hand side of 80%, it indicates that it is very likely that the effect is at least 80%
Time Frame
Up to 36 months after inclusion
Secondary Outcome Measure Information:
Title
miRNA-M371
Description
Serum level of miRNA-M371 as a potential biomarker of response. Association between serum level of miRNA M371 and response to treatments (according to RECIST v1.1) will be evaluated using a non-parametric Wilcoxon Mann and Whitney test and describe with boxplots.
Time Frame
Up to 5 years
Title
Association of PET scan results and miRNA-M371 rate
Description
Correlation between serum level of miRNA M371 and FDG-PET results (metabolic response) will be evaluated using the Kendall rank correlation and describe graphically.
Time Frame
Up to 5 years
Title
Overall survival (OS)
Description
The Overall Survival will be defined as the time from date of inclusion to the date of death, from any cause. Patient whose death is not known at the time of analysis will be censored based on the last recorded date on which the patient was known to be alive.
The Kaplan-Meier (KM) approach will be used to estimate median OS. Median OS as well as Survival rates at specific timepoints will be presented together with their 95% confidence interval (CI).
Time Frame
Up to 3 years
Title
Quality of life (QoL)
Description
The QoL will be assessed using the EORTC QLQ-C30 questionnaire.
Time Frame
Up to 20 months
Title
Tolerance to treatment
Description
The tolerance to each treatment will be described mainly on the frequency of adverse events (AEs) and their intensity and severity determined using the National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) grading scale version 5. Descriptive statistics will be provided for characterizing and assessing patient tolerance to treatment.
AEs will be described and coded, in total and per System Organ Class and Preferred Term with Medical Dictionary for Regulatory Activities (MedDRA) coding
Time Frame
Up 5 years
10. Eligibility
Sex
Male
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion criteria :
Age ≥ 18 years on the day of signing informed consent.
Primary testicular seminomatous germ cell tumor.
Stage IIa/IIb < 3 cm in largest diameter seminoma, histologically proved after orchiectomy.
Confirmation of a progressive disease (positive PET scan or increase of lymph nodes size by two successive CT scan).
Good prognosis according to IGCCCG and LDH < 2.5 x Upper Limit of Normal (ULN).
Normal alpha-fetoprotein (AFP) before and after orchiectomy.
No prior treatment with radiotherapy or chemotherapy.
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 2.
Adequate bone-marrow, hepatic, and renal functions with:
Neutrophils ≥ 1.5 x Giga/l, platelets ≥ 100 x Giga/l,
Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 1,5 x ULN,
Serum creatinine < 140 µmol/l OR calculated clearance > 60 ml/min (using either Cockcroft-Gault formula or Modification of Diet in Renal Disease (MDRD) for > 65 years old),
Direct and total bilirubin ≤ ULN.
Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
Accepting to use effective contraceptive measures or abstain from heterosexual activity, for the course of the study and through 12 months after the last dose of chemotherapy or being surgically sterile. All patients should seek advice regarding cryoconservation of sperm prior treatment initiation because of the possibility of infertility
Affiliation to a health insurance.
Signed and dated informed consent.
Non-exclusion criteria :
Extra-retroperitoneal metastasis on Computed tomography scan (CT scan).
Infection by Human Immunodeficiency Virus (HIV), or active infection with the Hepatitis B or C virus.
History, within 2 years, of cancer other than seminoma, except for treated skin cancer (basal cell).
Uncontrolled or severe cardiovascular pathology.
Uncontrolled or severe hepatic pathology.
Patient deprived of liberty or requiring tutorship or curatorship.
Psychological, physical, sociological, or geographical conditions that would limit compliance with study protocol requirements (at the investigator's discretion).
Participation to another clinical trial, except for supportive care trials.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Ellen BLANC
Phone
+33 4 78 78 29 67
Email
ellen.blanc@lyon.unicancer.fr
First Name & Middle Initial & Last Name or Official Title & Degree
Aude FLECHON, Dr
Phone
+ 33 4 78 78 26 43
Email
aude.flechon@lyon.unicancer.fr
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Aude FLECHON, Dr
Organizational Affiliation
Centre Leon Berard (Lyon, France)
Official's Role
Principal Investigator
Facility Information:
Facility Name
CHU Besançon
City
Besançon
Country
France
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Elodie KLAJER
Email
elodie.klajer@gmail.com
Facility Name
CHU Bordeaux
City
Bordeaux
Country
France
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Marine GROSS-GOUPIL
Email
marine.gross-goupil@chu-bordeaux.fr
Facility Name
Centre François Baclesse
City
Caen
Country
France
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Florence JOLY
Email
f.joly@baclesse.unicancer.fr
Facility Name
Centre Jean Perrin
City
Clermont-Ferrand
Country
France
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Hakim MAHAMMEDI
Email
hakim.mahammedi@clermont.unicancer.fr
Facility Name
Centre Oscar Lambret
City
Lille
Country
France
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Thomas RYCKEWAERT
Email
t-ryckewaert@o-lambret.fr
First Name & Middle Initial & Last Name & Degree
Aurélien CARNOT
Facility Name
CHU de Limoges
City
Limoges
Country
France
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Julia PESTRE MUNIER
Email
julia.munier-pestre@chu-limoges.fr
First Name & Middle Initial & Last Name & Degree
Valérie LE BRUN-LY
Facility Name
Centre Leon Bérard
City
Lyon
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Aude FLECHON
Email
aude.flechon@lyon.unicancer.fr
First Name & Middle Initial & Last Name & Degree
Armelle VINCENEUX
Facility Name
Institut Paoli Calmettes
City
Marseille
Country
France
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gwenaëlle GRAVIS
Email
gravisg@ipc.unicancer.fr
First Name & Middle Initial & Last Name & Degree
Slimane DERMECHE
First Name & Middle Initial & Last Name & Degree
Mathilde GUERIN
First Name & Middle Initial & Last Name & Degree
Cécile VICIER
Facility Name
Centre Antoine Lacassagne
City
Nice
Country
France
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Agnès DUCOULOMBIER
Email
agnes.ducoulombier@nice.unicancer.fr
First Name & Middle Initial & Last Name & Degree
Delphine BORCHIELLINI
Facility Name
Hôpital Saint Louis
City
Paris
Country
France
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Stéphane CULINE
Email
stephane.culine@sls.aphp.fr
First Name & Middle Initial & Last Name & Degree
Clément DUMONT
First Name & Middle Initial & Last Name & Degree
Tiphaine LAMBERT
Facility Name
ICO René Gauducheau
City
Saint-Herblain
Country
France
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Emmanuelle BOMPAS
Email
emmanuelle.bompas@ico.unicancer.fr
First Name & Middle Initial & Last Name & Degree
Frédéric ROLLAND
Facility Name
Hôpital Foch
City
Suresnes
Country
France
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Christine ABRAHAM
Email
c.abraham@hopital-foch.com
Facility Name
Institut Universitaire de Cancer de Toulouse (IUCT-O)
City
Toulouse
Country
France
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Christine CHEVREAU
Email
chevreau.christine@iuct-oncopole.fr
First Name & Middle Initial & Last Name & Degree
Thibaud VALENTIN
First Name & Middle Initial & Last Name & Degree
Loïc MOUREY
First Name & Middle Initial & Last Name & Degree
Damien POUESSEL
Facility Name
Institut de Cancérologie de Lorraine
City
Vandœuvre-lès-Nancy
Country
France
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Lionel GEOFFROIS
Email
l.geoffrois@nancy.unicancer.fr
First Name & Middle Initial & Last Name & Degree
Camille SIMON
First Name & Middle Initial & Last Name & Degree
Vincent MASSART
Facility Name
Institut Gustave Roussy
City
Villejuif
Country
France
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Pierre BLANCHARD
Email
pierre.blanchard@gustaveroussy.fr
12. IPD Sharing Statement
Learn more about this trial
De-escalation Study for Stage IIa/IIb < 3 cm Seminoma
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