De-escalation Study for Stage IIa/IIb < 3 cm Seminoma (EDEN)

Léon Bérard Center

Status and phase: Enrolling; Phase 2

Conditions: Stage II; Seminoma

Treatments: Radiation: Radiotherapy boost; Drug: 3 cycles of EP; Drug: Carboplatin AUC7

Study type: Interventional

Funder types: Other

Identifiers

NCT05529251

EDEN (ET21-344)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 90 estimated patients

Sex: Male

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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90 participants in 4 patient groups

ARM A

Experimental group

Description:

RADIOTHERAPY boost 20 to 30 Gy on lymph nodes

Treatment:

Radiation: Radiotherapy boost

ARM B

Experimental group

Description:

One cycle of CARBOPLATIN AUC7

Treatment:

Drug: Carboplatin AUC7

ARM C

Other group

Description:

3 cycles of ETOPOSIDE and CISPLATIN

Treatment:

Drug: 3 cycles of EP

OBSERVATIONAL COHORT

No Intervention group

Description:

STANDARD RADIOTHERAPY on lymph nodes