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Avelumab administration at 800 mg every 2 weeks and methotrexate administration at 1mg/kg/day during 4 months ½ (median)

Avelumab administration at 800mg a 1 hour IV infusion once every 14 days during 4 months ½ (median)

Avelumab Injection

methotrexate administration at 1mg/kg/day during 4 months ½ (median)

Methotrexate 1 GM Injection

Benoit YOU, MD

Laurent VILLENEUVE

Coriolan LEBRETON, MD

Florence JOLY, MD

Cyril ABDEDDAIM

Magali PROVANSAL, MD

Philippe FOLLANA, MD

Jean-Pierre LOTZ, MD

Thibault DE LA MOTTE ROUGE

Laurence Gladieff, Dr

Gestational trophoblastic neoplasias (GTN) are characterized by the persistence of elevated hCG titers after complete uterine evacuation of a partial hydatidiform mole (PHM) or a complete hydatidiform mole.

Low-risk GTN patients (FIGO score ≤ 6) are commonly treated with single agent treatment (methotrexate or actinomycin-D) The cure rate, assessed by hCG normalization, is obtained in 65 to 75% of patients with these agents GTN patients with resistance to these treatments are treated with another single agent drug or polychemotherapy regimens, such as EMA-CO or BEP regimen.

Chemotherapy standard regimens are old and toxic for these young lady patients, with potential long term effects detrimental for further maternity and quality of life

There is a strong rational for investigating the anti-PDL1 monoclonal antibody avelumab in chemoresistant GTN patients. Several elements suggest that the normal pregnancy immune tolerance is "hijacked" by GTN cell for proliferating :

* Spontaneous regressions of metastastic GTN are regularly observed, thereby the role of immune system for rejecting GTN cells.
* Strong and constant overexpression of PDL1 and NK cells has been found in all subtypes and settings of GTN tumors from French reference gestational trophoblastic center.
* Complete and durable responses to pembrolizumab were reported in 3 patients with multi-chemoresistant GTN in United Kingdom.
* Three cases of hCG normalization with avelumab in 6 patients with chemo-resistant GTN enrolled in TROPHIMMUN cohort A (resistant to a mono-chemotherapy).
* Cytotoxicity of avelumab is mediated through antibody dependent cell cytotoxicity (ADCC) by NK cells.

Avelumab and Methotrexate in in Low-risk Gestational Trophoblastic Neoplasias as First Line Treatment

TROPHAMET, a Phase I/II Trial of Avelumab and METhotrexate in Low-risk Gestational TROPHoblastic Neoplasias as First Line Treatment

Safety run-in: dose-limiting toxicities (DLT) will be determined during the first 3 months after the start of treatment

The main endpoint of this study is the rate of patients with successful normalization of hCG allowing for treatment discontinuation (hCG normalization). Patients will continue on treatment until the weekly hCG assays reach the institutional normal threshold, and then for 3 additional cycles, or otherwise will be stopped in the case of resistance, defined as a rise (a \> 20% rise between two assays, observed twice on three consecutive weekly assays) or a plateau (a \< 10% decrease between two assays observed three times on four consecutive weekly assays) in the hCG level, or unacceptable toxicity and/or death.

To assess the rate of treatment-emergent adverse events (TEAEs) and treatment-related adverse events (AEs), treatment-related Grade ≥ 3 AEs, and immune-related AEs, according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE v5.0)

Resistance rate will be evaluated according to hCG level.

Resistance-free survival will be evaluated according to hCG level.

Relapse-free survival will be evaluated in the case of relapse requiring treatment resumption after a hCG normalization that enabled study treatment discontinuation

Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

Hospices Civils de Lyon

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