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About
In the present TACTIC clinical trial, the investigators propose to determine the clinical interest and immunological efficacy of a treatment combining MP0317 the FAP (Fibroblast Activation Protein)-dependent CD40 agonist, with anti-PD-L1(Programmed Death-Ligand 1) therapy (durvalumab) and gemcitabine-cisplatin-based chemotherapy in unresectable cholangiocarcinoma.
The main objective is to assess the 12-month progression free survival (PFS) rate in the experimental arm. The trial proposed is a non-comparative proof of concept randomized two-stage phase II. The control arm will serve to verify the good calibration of the null hypothesis made in the experimental arm and to provide "true" controls for translational investigations. A semi-continuous monitoring of toxicity is planned in the experimental arm during the first stage of the study to warrant the tolerability of the experimental treatment and then to guarantee the security of the patients.
75 patients (50 in the experimental arm) will be included. The investigators will also decipher, as a translational objective, the molecular and immunological parameters determining the clinical outcomes.
Enrollment
Sex
Ages
Volunteers
Inclusion criteria
Signed and dated informed consent
Histologically confirmed biliary tract carcinoma: intra/extrahepatic cholangiocarcinoma (note that gallbladder carcinoma are not eligible)
Locally advanced unresectable or metastatic
Patient who had not previously received systemic anti-cancer treatment (adjuvant treatment with Capecitabine is allowed if the end of the chemotherapy was at least 6 months ago)
Age ≥ 18 years
Measurable disease defined according to RECIST v1.1 (Response Evaluation Criteria In Solid Tumours) guidelines Note: Previously irradiated lesions can be considered as measurable disease only if disease progression has been unequivocally documented at that site since radiation.
Patients who have received previous chemoembolization, radioembolization and/or radiotherapy should have recovered from any treatment related toxicity, to a level of ≤ grade 1 according to National Cancer Institute [NCI] common terminology criteria for adverse events, version 5 (CTCAE v5); with the exception of Grade 2 alopecia
Performance status ECOG-PS < 2 (Eastern Cooperative Oncology Group)
Females must be using highly effective contraceptive measures, and have a negative pregnancy test prior to the start of dosing if of childbearing potential, and during treatment and at least 7 months after the end of the treatment with cisplatin, 6 months after the end of the treatment with gemcitabine, 3 months after the end of the treatment with durvalumab, or must have evidence of non-childbearing potential by fulfilling one of the following criteria at screening:
Documented virology status of hepatitis, as confirmed by screening HBV and HCV tests:
Patient affiliated to or beneficiary of French social security system
Ability to comply with the study protocol, in the Investigator's judgment.
Exclusion criteria
For patients whose tumors present a genetic alteration of IDH1, FGFR2 or BRAF as well as an amplification of HER2, the investigators of the TACTIC study recommend, if possible, the orientation for preferential inclusion in the SAFIR ABC10 study".
Patients previously exposed to anti-tumor immunotherapy such as anti-PD-1, anti-PD-L1, or anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) agent or any immune therapy
Diagnosis of additional malignancy within 3 years prior to the inclusion with the exception of curatively treated basal cell carcinoma of the skin and/or curatively resected in situ cervical or breast cancer
Patient with any medical or psychiatric condition or disease, which would make the patient inappropriate for entry into this study
Current participation in a study of an investigational agent or in the period of exclusion
Patient under guardianship, curatorship or under the protection of justice
Other liver malignancy: hepatocellular carcinoma and hepato-cholangiocarcinoma
Uncontrolled pleural effusion, pericardial effusion, ascites or symptomatic fistula
Uncontrolled tumor-related pain: exposing patients to risk of exposure to corticoids or iterative hospitalizations. Symptomatic lesions amenable to palliative radiotherapy should be treated prior to inclusion. Patients should be recovered from the effects of radiation. There is no required minimum recovery period
Known active central nervous system metastases and/or carcinomatous meningitis.
History of angiocholitis, liver abscess, or acute pancreatitis within 4 weeks prior to initiation of study treatment
Inadequate organ functions: known cardiac failure of unstable coronaropathy, respiratory failure, or uncontrolled infection or another life-risk condition. Patients requiring oxygen therapy or with LEVF<40% (Left ventricular ejection fraction).
HIV (human immunodeficiency virus) positive (HIV 1/2 antibodies patients), or a known history of active Tuberculosis bacillus
Any immunosuppressive therapy (i.e. corticosteroids >10 mg of hydrocortisone or equivalent dose) within 14 days before the planned start of study therapy
Active autoimmune disease that has required a systemic treatment in the past 2 years (i.e. corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin) is allowed. Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions:
Patients with a history of autoimmune-related hypothyroidism who are on thyroid replacement hormone are eligible for the study
Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met:
Prior allogeneic bone marrow transplantation or prior solid organ transplantation
History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
Known hypersensitivity or allergy to Chinese hamster ovary cell products or any component of durvalumab
Receipt of a live, attenuated vaccine within 30 days prior to inclusion or anticipation that such a live, attenuated vaccine will be required during the study Note: Patients must agree not to receive live, attenuated influenza vaccine within 28 days prior to randomization, during treatment or within 5 months following the last dose of durvalumab
Inadequate hematology function: Lymphocyte count at baseline < 700/mm3; neutrophil count < 1 500/mm3, platelets < 10 0000/mm3 (without transfusion), Hemoglobin < 9g/dL (patients may be transfused to meet this criterion).
Inadequate hepatic function: bilirubin >2 fold ULN (upper limit of normal), AST/ALT >3 fold ULN, International normalized thromboplastin time ratio >2
Creatinine clearance (CrCl) < 60 ml/min (by the Modification of Diet in Renal Disease [MDRD], Cockroft formula, or chronic kidney disease [CKD] formula])
Serum albumin < 28 g/L
Surgery within 4 weeks previously the initiation of the study treatment
Radiotherapy within 2 weeks previously the initiation of the study treatment
Patient with weight < 36 kg.
Pregnant or breastfeeding woman
Known hypersensitivity to components of MP0317, for exemple, histidine buffer or the Tween diluent, according to section 7.2 " Contraindications " of the Investigator's brochure of MP0317
Hypersensitivity to gemcitabine or to cisplatin, or to any of their excipients, according to the SmPCs of these products
According to the SmPC of cisplatin: hearing problem, in case of combination with phenytoin with prophylactic aim, patients with neuropathy caused by cisplatin, in case of cardiorespiratory pathology in particular, which forbids a hyperhydration
Primary purpose
Allocation
Interventional model
Masking
75 participants in 2 patient groups
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Central trial contact
Christophe BORG, Pr
Data sourced from clinicaltrials.gov
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