Avelumab in Chemo-resistant Gestational Trophoblastic Neoplasias
- Conditions
- Gestational Trophoblastic Neoplasias (GTN)
- Interventions
- Registration Number
- NCT03135769
- Lead Sponsor
- Hospices Civils de Lyon
- 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. GTN patients are commonly treated with single agent treatment (methotrexate or actinomycine-D) or polychemotherapy (first line treatment EMA-CO) according to the predicted risk of resistance to single agent treatment by FIGO score. GTN patients with resistance to these treatments are treated with another single agent drug or polychemotherapy regimens.
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 need for modern targeted agents with better benefit/toxicity profiles.
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 metastasic 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.
* The case of complete and durable response to pembrolizumab was reported in a patient with multi chemo-resistant GTN.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Female
- Target Recruitment
- 24
Not provided
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Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti- CTLA 4 (including ipilimumab, tremelimumab or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways).
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Illness, incompatible with avelumab, such as congestive heart failure; respiratory distress; liver failure; allergy.
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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.
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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 enrollment
- No on-going 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)
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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.
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Persistent toxicities (>CTCAE grade 1) with the exception of alopecia and sensory neuropathy ≤ grade 2, caused by previous cancer therapy.
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Treatment with other investigational agents
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Bowel occlusive syndrome, inflammatory bowel disease, immune colitis or other gastro-intestinal disorder that does not allow oral medication such as malabsorption.
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Clinically significant (i.e active) cardiovascular disease : cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication
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Patients with severe acute or chronic medical conditions including immune pneumonitis, inflammatory bowel disease, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
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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).
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Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness.
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Active infection requiring systemic therapy.
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Positive test for HBV surface antigen and / or confirmatory HCV RNA (if anti-HCV antibody tested positive)
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Administration of a live vaccine within 4 weeks prior the first dose of avelumab.
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Treatment with oral anticoagulant such Coumadin.
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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).
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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.
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Female patients who are pregnant or lactating, or are of childbearing potential and not practicing a medically acceptable method of birth control
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Resting ECG with QTc > 470msec on 2 or more time points within a 24 hour period or family history of long QT syndrome.
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Prior organ transplantation, including allogeneic stem cell transplantation (excluding autologous bone marrow transplant)
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Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE Grade ≥ 3)
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Patients under guardianship.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Avelumab Avelumab administration at 10mg/kg Avelumab administration at 10 mg/kg every 14 days during 6 months maximum
- Primary Outcome Measures
Name Time Method The rate of patients with successful normalization of hCG assays up to 6 months Clinical efficacy of avelumab administration will be evaluated by the rate of patients with successful normalization of hCG assays allowing for treatment discontinuation (hCG normalization). Patients will continue on treatment until the hCG assays, measured weekly, reach the institutional normal threshold and then for 3 additional cycles.
- Secondary Outcome Measures
Name Time Method Overall survival up to 6 months Number of patients alive 1 months after the end of treatment.
Resistance free survival up to 6 months Number of patients alive free resistance (defined as a rise ≥ 20% rise over between two assays in three consecutive weekly hCG assays or plateau ≤ 10% decrease between two assays in four consecutive weekly hCG)
Progression free survival up to 6 months Number of patients alive progression free survival (defined as a rise ≥ 20% rise over between two assays in three consecutive weekly hCG assays or plateau ≤ 10% decrease between two assays in four consecutive weekly hCG)
Kinetics of hCG up to 7 months Modeled hCGres parameter calculated with weekly values of hCG measured during treatment days after start of Avelumab treatment.
Phenotype of the intratumoral immune cell infiltrate up to 7 months Immunohistochemistry with anti PD-L1, anti CD3, anti CD8, anti CD4, anti CD56 (uterine NK cells), anti FoxP3 primary antibodies will be performed on serial cuts of formalin fixed and paraffin embedded specimens from patients treated with avelumab.
PD-L1 expression in tumor samples up to 7 months To predict the efficacy of anti-PD-L1 immunotherapy, we will quantify and characterize the intra and peritumoral immune infiltrate of GTN
Overall response rate according to RECIST up to 6 months Radiological response to avelumab assessed by the overall response rate according to RECIST version 1.1 criteria and immune-related RECIST criteria assessed by imaging (TAP CT scanner and / or MRI if contraindication) after cycle 4, 8 and 12
NCI CTCAE version 4.0 up to 7 months The safety of avelumab administration will be evaluated throughout the duration of treatment (6 months max) and until the end of patient follow up (1 month after treatment discontinuation) according to NCI CTCAE version 4.0
Phenotype of the peritumoral immune cell infiltrate up to 7 months Immunohistochemistry with anti PD-L1, anti CD3, anti CD8, anti CD4, anti CD56 (uterine NK cells), anti FoxP3 primary antibodies will be performed on serial cuts of formalin fixed and paraffin embedded specimens from patients treated with avelumab.
Trial Locations
- Locations (6)
Hospices Civils de Lyon - CHLS
🇫🇷Pierre Bénite, France
Centre Francois Baclesse
🇫🇷Caen, France
Institut Paoli-Calmettes
🇫🇷Marseille, France
Institut Bergonie
🇫🇷Bordeaux, France
Aphp Hopital Tenon
🇫🇷Paris, France
Institut Universitaire Du Cancer de Toulouse - Oncopole
🇫🇷Toulouse, France