Overview

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

Status:
Recruiting
Trial end date:
2026-07-12
Target enrollment:
0
Participant gender:
Female
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.
Phase:
Phase 1/Phase 2
Accepts Healthy Volunteers?
No
Details
Lead Sponsor:
Hospices Civils de Lyon
Collaborator:
Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
Treatments:
Avelumab
Methotrexate
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.