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

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.