TROPHAMET, a Phase I/II Trial of Avelumab and METhotrexate in Low-risk Gestational TROPHoblastic Neoplasias as First Line Treatment
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.
• \- Woman older than 18 years
• Low-risk gestational trophoblastic neoplasia according to FIGO score (FIGO score ≤ 6) with indication of methotrexate as first line treatment
• Patients with Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
• Patients with adequate bone marrow function measured within 28 days prior to administration of study treatment as defined below
‣ Absolute granulocyte count ≥ 1.5 x 10 9 /L
⁃ Platelet count ≥ 100 x 10 9 /L
⁃ Haemoglobin ≥ 9.0 g/dL (may have been blood transfused)
• Patients with adequate renal function:
• \* Calculated creatinine clearance ≥ 30 ml/min according to the Cockcroft-Gault formula (or local institutional standard method)
• Patients with adequate hepatic function
• \*Serum bilirubin ≤ 1.5 x UNL and AST/ALT ≤ 2.5 X UNL (≤ 5 X UNL for patients with liver metastases)
• Patients must have a life expectancy ≥ 16 weeks
• Confirmation of non-childbearing status for women of childbearing potential.
∙ An evolutive pregnancy can be ruled out in the following cases:
• in case of a previous hysterectomy
• if serum hCG level ≥ 2 000 IU/L and no intra or extra-uterine gestational sac is detected on pelvic ultrasound
• if serum hCG level \< 2 000 IU/L on a first measurement and serum hCG increases \<100% on a second measurement performed 3 days later.
‣ Highly effective contraception if the risk of conception exists. (Note: The effects of the trial drug on the developing human fetus are unknown; thus, women of childbearing potential must agree to use 2 highly effective contraceptions, defined as methods with a failure rate of less than 1 % per year. Highly effective contraception is required at least 28 days prior, throughout and for at least 12 months after avelumab treatment.
⁃ Patients who gave its written informed consent to participate to the study
⁃ Patients affiliated to a social insurance regime
⁃ Patient is willing and able to comply with the protocol for the duration of the treatment