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

Официальное название

TROPHAMET, a Phase I/II Trial of Avelumab and METhotrexate in Low-risk Gestational TROPHoblastic Neoplasias as First Line Treatment

Обзор

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.

Вмешательства

• Препарат Avelumab Injection
  Avelumab administration at 800mg a 1 hour IV infusion once every 14 days during 4 months ½ (median)
• Препарат Methotrexate 1 GM Injection
  methotrexate administration at 1mg/kg/day during 4 months ½ (median)

Первичные конечные точки

• Incidence of Dose limiting toxicities of methotrexate and avelumab combination in low-risk GTN patients as first line. [Срок оценки: treatment duration 3 months (median estimation)]
• Rate of patients with successful normalization of hCG [Срок оценки: treatment duration 3 months (median estimation)]

Вторичные конечные точки (5)

• Evaluate the safety of methotrexate and avelumab combination administration [Срок оценки: during treatment duration (3 months), 1 month after end of treatment and 36 months after end of treatment (median : 8 months 1/2).]
• To assess the efficacy of avelumab and methotrexate in terms of resistance-free survival in low-risk GTN patients as first line setting [Срок оценки: during treatment (3 months median), 1 month after the end of treatment and 36 months after the end of treatment]
• To assess the efficacy of avelumab and methotrexate in terms of resistance-free survival in low-risk GTN patients as first line setting [Срок оценки: during treatment (3 months median), 1 month after the end of treatment and 36 months after the end of treatment]
• To assess the efficacy of avelumab and methotrexate in terms of relapse free survival in low-risk GTN patients as first line setting after an initial hCG normalization that enabled study treatment discontinuation [Срок оценки: during treatment (3 months median), 1 month after the end of treatment and 36 months after the end of treatment]
• To assess the efficacy of avelumab and methotrexate in terms of overall survival in low-risk GTN patients as first line setting [Срок оценки: during treatment (3 months median), 1 month after end of treatment and 36 months after end of treatment]

Критерии участия

Критерии включения

• \- 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

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Франция · 9 центров

• Centre Hospitalier Lyon Sud — Pierre-Bénite
• Institut Bergonié — Bordeaux
• Centre François Baclesse — Caen
• Centre Oscar Lambret — Lille
• Institut Paoli-Calmettes — Marseille
• Centre Antoine Lacassagne — Nice
• Assistance Publique Hôpitaux de Paris — Paris
• Centre Eugène Marquis — Rennes
• … и ещё 1 центр

Публикации

• You B, Lotz JP, Descargues P, Joly F, De La Motte Rouge T, Lebreton C, Gladieff L, Follana P, Jamelot M, Massardier J, Hajri T, Msika A, Alves-Ferreira M, Bin S, Langlois-Jacques C, Subtil F, Roux A, Desauw C, Provansal M, Schwiertz V, Golfier F, Bolze PA. Avelumab Plus Methotrexate for Gestational Trophoblastic Tumors: The TROPHAMET Phase 1/2 Nonrandomized Clinical Trial. JAMA Oncol. 2026 Jun 11: PMID 42275082

Идентификаторы

NCT: NCT04396223 · 69HCL18 0857

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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