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Gestational Trophoblastic Neoplasias (GTN)Phase 1/2TROPHAMETNCT04396223

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

A Phase 1/2 study testing Avelumab Injection and Methotrexate 1 GM Injection in people with Gestational Trophoblastic Neoplasias (GTN), run by Hospices Civils de Lyon at 9 sites in France.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older, women only
What is being tested?
Avelumab Injection and Methotrexate 1 GM Injection
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
26 participants
Where
9 sitesFrance
Study dates
12 Feb 2020to 12 Oct 2028
Phase
Phase 1/2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • Women only
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • - 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
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  • 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

Who cannot join

  • 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).
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  • 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.

Trial locations and contacts

9 sites in 1 country. Contact the study team or a site near you to ask about taking part.

Benoit YOU, MD contact

33 4 78 864 318

benoit.you@chu-lyon.fr

Laurent VILLENEUVE contact

33 4 78 864 536

laurent.villeneuve@chu-lyon.fr

9 sites in 1 country

France9 sites, 9 recruiting

  • Institut Bergonié

    Bordeaux, 33000

    Coriolan LEBRETON, MD

    Recruiting

  • Centre François Baclesse

    Caen, 14000

    Florence JOLY, MD

    Not yet recruiting

  • Centre Oscar Lambret

    Lille, 59000

    Cyril ABDEDDAIM

    Not yet recruiting

  • Institut Paoli-Calmettes

    Marseille, 13000

    Magali PROVANSAL, MD

    Not yet recruiting

  • Centre Antoine Lacassagne

    Nice, 06000

    Philippe FOLLANA, MD

    Recruiting

  • Assistance Publique Hôpitaux de Paris

    Paris

    Jean-Pierre LOTZ, MD

    Recruiting

  • Centre Hospitalier Lyon Sud

    Pierre-Bénite, Pierre Bénite, 69495

    Benoit YOU, MD, benoit.you@chu-lyon.fr

    Recruiting

  • Centre Eugène Marquis

    Rennes, 35000

    Thibault DE LA MOTTE ROUGE

    Recruiting

  • Institut Universitaire du Cancer de Toulouse - Oncopole

    Toulouse, 31000

    Laurence Gladieff, Dr

    Laurence Gladieff, Dr

    Recruiting

Other trials in France

About this study

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

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.

Read more

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.
Being tested
Avelumab Injection, Methotrexate 1 GM Injection
Keywords
avelumab, methotrexate, PDL1, gestational trophoblastic neoplasias, GTN, hydatiform mole, hCG,

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Avelumab InjectionDrug

    Avelumab administration at 800mg a 1 hour IV infusion once every 14 days during 4 months ½ (median)

  • Methotrexate 1 GM InjectionDrug

    methotrexate administration at 1mg/kg/day during 4 months ½ (median)

Study groups in NCT04396223
Study groupRoleWhat they receive
Avelumab combined with methotrexate and folinic acidExperimentalAvelumab administration at 800 mg every 2 weeks and methotrexate administration at 1mg/kg/day during 4 months ½ (median)
Receives: Drug: Avelumab Injection; Drug: Methotrexate 1 GM Injection

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Incidence of Dose limiting toxicities of methotrexate and avelumab combination in low-risk GTN patients as first line.

    Safety run-in: dose-limiting toxicities (DLT) will be determined during the first 3 months after the start of treatment

    Measured: treatment duration 3 months (median estimation)

  2. Rate of patients with successful normalization of hCG

    The main endpoint of this study is the rate of patients with successful normalization of hCG allowing for treatment discontinuation (hCG normalization). Patients will continue on treatment until the weekly hCG assays reach the institutional normal threshold, and then for 3 additional cycles, or otherwise will be stopped in the case of resistance, defined as a rise (a > 20% rise between two assays, observed twice on three consecutive weekly assays) or a plateau (a < 10% decrease between two assays observed three times on four consecutive weekly assays) in the hCG level, or unacceptable toxicity and/or death.

    Measured: treatment duration 3 months (median estimation)

Secondary outcomes (5)

  1. Evaluate the safety of methotrexate and avelumab combination administration

    To assess the rate of treatment-emergent adverse events (TEAEs) and treatment-related adverse events (AEs), treatment-related Grade ≥ 3 AEs, and immune-related AEs, according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE v5.0)

    Measured: during treatment duration (3 months), 1 month after end of treatment and 36 months after end of treatment (median : 8 months 1/2).

  2. To assess the efficacy of avelumab and methotrexate in terms of resistance-free survival in low-risk GTN patients as first line setting

    Resistance rate will be evaluated according to hCG level.

    Measured: during treatment (3 months median), 1 month after the end of treatment and 36 months after the end of treatment

  3. To assess the efficacy of avelumab and methotrexate in terms of resistance-free survival in low-risk GTN patients as first line setting

    Resistance-free survival will be evaluated according to hCG level.

    Measured: during treatment (3 months median), 1 month after the end of treatment and 36 months after the end of treatment

  4. 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

    Relapse-free survival will be evaluated in the case of relapse requiring treatment resumption after a hCG normalization that enabled study treatment discontinuation

    Measured: during treatment (3 months median), 1 month after the end of treatment and 36 months after the end of treatment

  5. To assess the efficacy of avelumab and methotrexate in terms of overall survival in low-risk GTN patients as first line setting

    Overall survival

    Measured: during treatment (3 months median), 1 month after end of treatment and 36 months after end of treatment

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted20 May 2020
  2. Study start12 Feb 2020
  3. Primary completion12 Apr 2025 (estimated)
  4. Study completion12 Oct 2028 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
26 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04396223
Sponsor's protocol ID
69HCL18 0857
Acronym
TROPHAMET
Status last verified
Feb 2024
First submitted
12 May 2020
Last updated
29 Feb 2024
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No

Publications

  • 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:e261697. doi: 10.1001/jamaoncol.2026.1697. Online ahead of print.

    PubMed 42275082

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Avelumab Injection and Methotrexate 1 GM Injection in people with Gestational Trophoblastic Neoplasias (GTN), run by Hospices Civils de Lyon at 9 sites in France.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 21 inclusion and 32 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 29 Feb 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 9 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Benoit YOU, MD (33 4 78 864 318, benoit.you@chu-lyon.fr), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Incidence of Dose limiting toxicities of methotrexate and avelumab combination in low-risk GTN patients as first line. (time frame: treatment duration 3 months (median estimation)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04396223, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Feb 2024.

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