avelumab and methotrexate in in low-risk gestational trophoblastic neoplasias as first line treatment

Conditions: Gestational Trophoblastic Neoplasias (GTN)

Summary: 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.


Eligibility criteria:
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.

Keywords: avelumab methotrexate pdl1 gestational trophoblastic neoplasias, gtn hydatiform mole hcg,