Clinical trial: Avelumab and Methotrexate in in Low-risk Gestational Trophoblastic Neoplasias as First Line Treatment (NCT04396223)

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.
Female
No healthy subjects accepted to join the trial.
Subject must be at least 18 Years old.


Patient description (medical language): A 32-year-old woman comes to the hospital with vaginal spotting.  Her last menstrual period was 10 weeks ago. She has regular menses lasting for 6 days and repeating every 29 days. Medical history is significant for appendectomy and several complicated UTIs. She has multiple male partners, and she is inconsistent with using barrier contraceptives. Vital signs are normal.  Serum β-hCG level is 1800 mIU/mL, and a repeat level after 2 days shows an abnormal rise to 2100 mIU/mL.  Pelvic ultrasound reveals a thin endometrium with no gestational sac in the uterus.

Patient description (patient's own words): I just turned 32 and last morning I woke up with strange blood stains on my underwear. My last periods were more than 2 months ago, which is unusual for me because I used to have regular periods lasting for 6 days every 29 days, more or less. I had several UTIs in the past. I also had appendicitis. I'm currently seeing several men and, to be honest, some of them do struggle to wear a condom. I went to the hospital to check myself up and they told me that my vitals were normal. I also had a blood test on Monday, and my β-hCG level was 1800 mIU/mL, and then on Wednesday, it went up to 2100 mIU/mL. The gynecologist also did an ultrasound and she told me that, hopefully, there was no ovule.

Does the patient match the trial criteria? Contradiction