Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Avelumab in Chemo-resistant Gestational Trophoblastic Neoplasias (TROPHIMMUN)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03135769
Recruitment Status : Recruiting
First Posted : May 1, 2017
Last Update Posted : September 14, 2018
Sponsor:
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Gestational Trophoblastic Neoplasias (GTN) Drug: Avelumab administration at 10mg/kg Phase 2

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 29 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Trial of Avelumab in Chemo-resistant Gestational Trophoblastic Neoplasias (GTN)
Actual Study Start Date : February 21, 2017
Estimated Primary Completion Date : May 2019
Estimated Study Completion Date : February 2023


Arm Intervention/treatment
Experimental: Avelumab
Avelumab administration at 10 mg/kg every 14 days during 6 months maximum
Drug: Avelumab administration at 10mg/kg
Avelumab administration at 10 mg/kg as a 1 hour IV infusion once every 14 days during 6 months (maximum).




Primary Outcome Measures :
  1. The rate of patients with successful normalization of hCG assays [ Time Frame: 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 :
  1. Resistance free survival [ Time Frame: 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)

  2. Progression free survival [ Time Frame: 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)

  3. Overall survival [ Time Frame: up to 6 months ]
    Number of patients alive 1 months after the end of treatment.

  4. Overall response rate according to RECIST [ Time Frame: 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

  5. NCI CTCAE version 4.0 [ Time Frame: 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

  6. Kinetics of hCG [ Time Frame: up to 7 months ]
    Modeled hCGres parameter calculated with weekly values of hCG measured during treatment days after start of Avelumab treatment.

  7. PD-L1 expression in tumor samples [ Time Frame: 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

  8. Phenotype of the intratumoral immune cell infiltrate [ Time Frame: 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.

  9. Phenotype of the peritumoral immune cell infiltrate [ Time Frame: 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Woman older than 18 years
  • Patients with gestational trophoblastic disease resistant to mono-chemotherapy (methotrexate and/or actinomycine-D) or polychemotherapy (such as EMA-CO; EMA-EP; BEP; … regimens) without . limitation in the number of previous chemotherapy lines without limitation in the number of previous chemotherapy lines
  • 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 by a gynecologist of non-childbearing status for women of childbearing potential.

An evolutive pregnancy can be ruled out in the following cases: 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 60 days 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 study including undergoing treatment and scheduled visits and examinations including follow up.

Exclusion Criteria:

  • Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxicT lymphocyte-associated antigen 4 (CTLA 4) antibody (including ipilimumab, tremelimumab or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways).
  • Illness, incompatible with avelumab, such as congestive heart failure; respiratory distress; liver failure; allergy.
  • 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 enrollment ; 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 or other gastro-intestinal disorder that does not allow oral medication such as malabsorption.
  • Known severe hypersensitivity reactions to monoclonal antibodies, any history of anaphylaxis, or uncontrolled asthma
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03135769


Contacts
Layout table for location contacts
Contact: Benoit YOU, MD +33 4 78 864 318 benoit.you@chu-lyon.fr
Contact: Laurent VILLENEUVE +33 4 78 864 536 laurent.villeneuve@chu-lyon.fr

Locations
Layout table for location information
France
Institut Bergonie Not yet recruiting
Bordeaux, France, 33000
Contact: Anne Floquet         
Centre Francois Baclesse Recruiting
Caen, France, 14000
Contact: Florence Joly    (0)2 31 45 50 50 ext +33    f.joly@baclesse.unicancer.fr   
Centre Oscar Lambret Not yet recruiting
Lille, France, 59000
Contact: Anne LESOIN         
Institut Paoli-Calmettes Recruiting
Marseille, France, 13000
Contact: Magali PROVANSAL    (0)4 91 22 33 33 ext +33    provansalm@ipc.unicancer.fr   
Centre Antoine Lacassagne Not yet recruiting
Nice, France, 06000
Contact: Philippe FOLLANA         
Aphp Hopital Tenon Recruiting
Paris, France, 75020
Contact: Jean-Pierre LOTZ    (0)1 56 01 60 58 ext +33    jean-pierre.lotz@tnn.aphp.fr   
Hospices Civils de Lyon - CHLS Recruiting
Pierre Bénite, France, 69495
Contact: Benoit YOU, MD         
Institut Universitaire Du Cancer de Toulouse - Oncopole Recruiting
Toulouse, France, 31000
Contact: Laurence GLADIEFF    (0)5 31 15 51 01 ext +33    gladieff.laurence@iuct-oncopole.fr   
Sponsors and Collaborators
Hospices Civils de Lyon
Investigators
Layout table for investigator information
Principal Investigator: Benoit YOU, MD Hospices Civils de Lyon - Centre Hospitalier Lyon Sud - Service d'Oncologie Médicale

Layout table for additonal information
Responsible Party: Hospices Civils de Lyon
ClinicalTrials.gov Identifier: NCT03135769     History of Changes
Other Study ID Numbers: 69HCL16_0123
First Posted: May 1, 2017    Key Record Dates
Last Update Posted: September 14, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Hospices Civils de Lyon:
avelumab
PDL1
Gestational Trophoblastic Neoplasias
GTN
Hydatiform mole
hCG
Additional relevant MeSH terms:
Layout table for MeSH terms
Gestational Trophoblastic Disease
Neoplasms
Trophoblastic Neoplasms
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Pregnancy Complications, Neoplastic
Pregnancy Complications
Dihydrotachysterol
Antibodies, Monoclonal
Vitamins
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs
Bone Density Conservation Agents
Immunologic Factors