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

Fecha de inicio: 12 de febrero de 2020

Inclusion Criteria: * \- 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 Exclusion Criteria: * Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti- CTLA 4 antibody (including ipilimumab, tremelimumab or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways). * Illness, incompatible with avelumab, such as congestive heart failure; respiratory distress; liver failure; uncontrolled epilepsy; allergy. * Patients with a known allergic hypersensitivity to methotrexate or any of the other ingredients (sodium chloride, sodium hydroxide, and hydrochloric acid if excipient) * Patients with second primary cancer, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumours curatively treated with no evidence of disease for ≥ 5 years. * All subjects with brain metastases, except those meeting the following criteria: * Brain metastases that have been treated locally and are clinically stable for at least 2 weeks prior to enrolment, No ongoing neurological symptoms that are related to the brain localization of the disease (sequelae that are a consequence of the treatment of the brain metastases are acceptable). * Subjects with brain metastases must be either off steroids except a stable or decreasing dose of \<10mg daily prednisone (or equivalent). * Patients receiving any systemic chemotherapy, radiotherapy (except for palliative reasons), within 2 weeks from the last dose prior to study treatment (or a longer period depending on the defined characteristics of the agents used). The patient can receive a stable dose of bisphosphonates for bone metastases, before and during the study as long as these were started at least 4 weeks prior to treatment with study drug. * Persistent toxicities (\>=CTCAE grade 2) with the exception of alopecia and sensory neuropathy, caused by previous cancer therapy. * Treatment with other investigational agents. * Bowel occlusive syndrome, inflammatory bowel disease, immune colitis, or other gastro-intestinal disorder that does not allow oral medication such as malabsorption. * Stomatitis, ulcers of the oral cavity and known active gastrointestinal ulcer disease * Clinically significant (i.e., active) and severe cardiovascular disease according to investigator opinion such as myocardial infarction (\< 6 months prior to enrollment) * Patients with immune pneumonitis, pulmonary fibrosis * Known severe hypersensitivity reactions to monoclonal antibodies, any history of anaphylaxis, or uncontrolled asthma (ie, 3 or more features of partially controlled asthma Global Initiative for Asthma 2011). * Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness. * Active infection requiring systemic therapy. * Positive test for HBV surface antigen and / or confirmatory HCV RNA (if anti-HCV antibody tested positive) * Administration of a live vaccine within 30 days prior to study entry. * Current or prior use of immunosuppressive medication within 7 days prior to start of study treatment. The following are exceptions to this exclusion criterion: * Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular injection); * Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent; * Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication). * Active autoimmune disease that might deteriorate when receiving an immunostimulatory agents. Patients with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible. * Female patients who are pregnant or lactating, or are of childbearing potential and not practicing a medically acceptable method of birth control. * Treatment with oral anticoagulant such Coumadin. * Alcoholism (patient interview, investigator judgment) * Resting ECG with QTc \> 470msec on 2 or more time points within a 24 hour period or family history of long QT syndrome. Torsades de Pointes, arrhythmias (including sustained ventricular tachyarrhythmia and ventricular fibrillation, bradycardia defined as \<50 bpm), right bundle branch block and left anterior hemiblock (bifascicular block), unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (CHF New York Heart Association Class III or IV), cerebrovascular accident, transient ischemic attack or symptomatic pulmonary embolism. * Prior organ transplantation, including allogeneic stem cell transplantation (excluding autologous bone marrow transplant) * Patients under guardianship.