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

NCT04396223 | Recruiting Phase 1 DMC

• 1 other identifier: 69HCL18 0857
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 9

Brief 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.

Conditions

Gestational Trophoblastic Neoplasias (GTN)

Keywords

avelumab; methotrexate; PDL1; gestational trophoblastic neoplasias, GTN; hydatiform mole; hCG,

Outcome Measures

Primary Outcomes (2)

• 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

  treatment duration 3 months (median estimation)

• 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.

  treatment duration 3 months (median estimation)

Secondary Outcomes (5)

• Evaluate the safety of methotrexate and avelumab combination administration

  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

  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

  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

  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

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

Study Arms (1)

Avelumab combined with methotrexate and folinic acid

EXPERIMENTAL

Avelumab administration at 800 mg every 2 weeks and methotrexate administration at 1mg/kg/day during 4 months ½ (median)

Drug: Avelumab Injection; Drug: Methotrexate 1 GM Injection

Interventions

Avelumab Injection DRUG

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

Avelumab combined with methotrexate and folinic acid

Methotrexate 1 GM Injection DRUG

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

Avelumab combined with methotrexate and folinic acid

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \- 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

You may not qualify if:

• 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).

Sponsors & Collaborators

• Hospices Civils de Lyon: lead
• Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany: collaborator

Study Sites (9)

Centre Hospitalier Lyon Sud

Pierre-Bénite, Pierre Bénite, 69495, France

RECRUITING

Institut Bergonié

Bordeaux, 33000, France

RECRUITING

Centre François Baclesse

Caen, 14000, France

NOT YET RECRUITING

Centre Oscar Lambret

Lille, 59000, France

NOT YET RECRUITING

Institut Paoli-Calmettes

Marseille, 13000, France

NOT YET RECRUITING

Centre Antoine Lacassagne

Nice, 06000, France

RECRUITING

Assistance Publique Hôpitaux de Paris

Paris, France

RECRUITING

Centre Eugène Marquis

Rennes, 35000, France

RECRUITING

Institut Universitaire du Cancer de Toulouse - Oncopole

Toulouse, 31000, France

RECRUITING

MeSH Terms

Interventions

avelumab

Central Study Contacts

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

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 12, 2020
• First Posted: May 20, 2020
• Study Start: February 12, 2020
• Primary Completion: April 12, 2025
• Study Completion (Estimated): October 12, 2028
• Last Updated: February 29, 2024

Record last verified: 2024-02

Locations

FR (9)