Clinical trial NCT05529251: De-escalation Study for Stage IIa/IIb < 3 cm Seminoma
Official title: Prospective Therapeutic De-escalation and miRNA-M371 Biomarker Evaluation Phase II Study for Stage IIa/IIb < 3 cm Seminomas
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: 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
Lead sponsor: Centre Leon Berard
Sponsor class: OTHER
First posted: 2022-09-07
Enrollment: 90
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: * In case of negative week-3 (after 1 EP cyle) PET-scan: Randomization according to 2 arms

  1. Boost of radiotherapy 20 to 30 Gray (Gy) (ARM A)
  2. 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
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion criteria :

1. Age ≥ 18 years on the day of signing informed consent.
2. Primary testicular seminomatous germ cell tumor.
3. Stage IIa/IIb \< 3 cm in largest diameter seminoma, histologically proved after orchiectomy.
4. Confirmation of a progressive disease (positive PET scan or increase of lymph nodes size by two successive CT scan).
5. Good prognosis according to IGCCCG and LDH \< 2.5 x Upper Limit of Normal (ULN).
6. Normal alpha-fetoprotein (AFP) before and after orchiectomy.
7. No prior treatment with radiotherapy or chemotherapy.
8. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 2.
9. 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.
10. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
11. 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
12. Affiliation to a health insurance.
13. Signed and dated informed consent.

Non-exclusion criteria :

1. Extra-retroperitoneal metastasis on Computed tomography scan (CT scan).
2. Infection by Human Immunodeficiency Virus (HIV), or active infection with the Hepatitis B or C virus.
3. History, within 2 years, of cancer other than seminoma, except for treated skin cancer (basal cell).
4. Uncontrolled or severe cardiovascular pathology.
5. Uncontrolled or severe hepatic pathology.
6. Patient deprived of liberty or requiring tutorship or curatorship.
7. Psychological, physical, sociological, or geographical conditions that would limit compliance with study protocol requirements (at the investigator's discretion).
8. Participation to another clinical trial, except for supportive care trials.

Primary outcomes:
measure: PFR-36M
timeFrame: Up to 36 months after inclusion
Secondary outcomes:
measure: miRNA-M371
timeFrame: Up to 5 years
measure: Association of PET scan results and miRNA-M371 rate
timeFrame: Up to 5 years
measure: Overall survival (OS)
timeFrame: Up to 3 years
measure: Quality of life (QoL)
timeFrame: Up to 20 months
measure: Tolerance to treatment
timeFrame: Up 5 years
Other outcomes:
Locations:
city: Besançon
country: France
facility: CHU Besançon
city: Bordeaux
country: France
facility: CHU Bordeaux
city: Caen
country: France
facility: Centre François Baclesse
city: Clermont-Ferrand
country: France
facility: Centre Jean Perrin
city: Lille
country: France
facility: Centre Oscar Lambret
city: Limoges
country: France
facility: CHU de Limoges
city: Lyon
country: France
facility: Centre Leon Bérard
city: Marseille
country: France
facility: Institut Paoli Calmettes
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Paris
country: France
facility: Hôpital Saint Louis
city: Saint-Herblain
country: France
facility: ICO René Gauducheau
city: Suresnes
country: France
facility: Hôpital Foch
city: Toulouse
country: France
facility: Institut Universitaire de Cancer de Toulouse (IUCT-O)
city: Vandœuvre-lès-Nancy
country: France
facility: Institut de Cancérologie de Lorraine
city: Villejuif
country: France
facility: Institut Gustave Roussy
Study officials:
affiliation: Centre Leon Berard (Lyon, France)
name: Aude FLECHON, Dr
role: PRINCIPAL_INVESTIGATOR
References: