Informations générales (source: ClinicalTrials.gov)
TROPHAMET, a Phase I/II Trial of Avelumab and METhotrexate in Low-risk Gestational TROPHoblastic Neoplasias as First Line Treatment (TROPHAMET)
Interventional
Phase 1/Phase 2
Hospices Civils de Lyon (Voir sur ClinicalTrials)
février 2020
octobre 2028
29 juin 2024
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.
Etablissements
| Les établissements hors Île-de-France dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
|---|---|---|---|---|---|
| Centre Antoine Lacassagne - 06000 - Nice - France | Philippe FOLLANA, MD | Contact (sur clinicalTrials) | |||
| Centre Eugène Marquis - 35000 - Rennes - France | Thibault DE LA MOTTE ROUGE | Contact (sur clinicalTrials) | |||
| Centre François Baclesse - 14000 - Caen - France | Florence JOLY, MD | Contact (sur clinicalTrials) | |||
| Centre Hospitalier Lyon Sud - 69495 - Pierre-Bénite - Pierre Bénite - France | Benoit YOU, MD | Contact (sur clinicalTrials) | |||
| Centre Oscar Lambret - 59000 - Lille - France | Cyril ABDEDDAIM | Contact (sur clinicalTrials) | |||
| Institut Bergonié - 33000 - Bordeaux - France | Coriolan LEBRETON, MD | Contact (sur clinicalTrials) | |||
| Les établissements sans correspondance certaine dans le répertoire FINESS dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
| Assistance Publique Hôpitaux de Paris - Paris - France | Jean-Pierre LOTZ, MD | Contact (sur clinicalTrials) | |||
| Institut Paoli-Calmettes - 13000 - Marseille - France | Magali PROVANSAL, MD | Contact (sur clinicalTrials) | |||
| Institut Universitaire du Cancer de Toulouse - Oncopole - 31000 - Toulouse - France | Laurence Gladieff, Dr | Contact (sur clinicalTrials) | |||
Critères
Femme
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
-
- 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
- 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.