Phase : II, Précoce
Type d'essai : Académique / Institutionnel
Thème spécifique : Cancers Rares
Etat de l'essai : Ouvert
Résumé / Schéma de l'étude
Experimental : Avelumab combined with methotrexate and folinic acid Avelumab administration at 800 mg every 2 weeks and methotrexate administration at 1mg/kg/day during 4 months ½ (median).
- 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 109/L.
- Platelet count ≥ 100 x 109/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.
Critères de non-inclusion
- 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 (≥ 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.
Lancement de l'étude : Février 2020
Fin estimée des inclusions : Juin 2023
Nombre de patients à inclure : 26
Dr. Philippe FOLLANA
Dr. Magali PROVENSAL
HOSPICES civils de Lyon
Dernière mise à jour le 05 mars 2021