Etude : MS200647_0055 /

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Type d'étude
Présentation de l'étude
Acronyme : MS200647_0055

Nom :

Traitement : Métastatique ou localement avancé

Type d'étude : Ciblage moléculaire / Innovation thérapeutique

Dernière MÀJ : 25/06/2020
CIM10 - Localisation(s)
Informations principales
Titre : A Phase II/III, Multicenter, Randomized, Placebo-controlled Study of Gemcitabine Plus Cisplatin With or Without Bintrafusp Alfa (M7824) as First-line Treatment of Biliary Tract Cancer

Spécialité : Organes digestifs
Localisation : C22 - Tumeur maligne du foie et des voies biliaires intrahépatiques

Spécialité : Organes digestifs
Localisation : C23 - Tumeur maligne de la vésicule biliaire

Spécialité : Organes digestifs
Localisation : C24 - Tumeurs malignes des voies biliaires, autres et non précisées
Informations complémentaires
Schéma : Study consists of an open-label, safety run-in part and a randomized, double-blind, placebo-controlled Phase 2/3 part. In the Phase 2/3 part, the study will evaluate whether bintrafusp alfa in combination with the current standard of care (SoC) (gemcitabine plus cisplatin) improves overall survival (OS) or progression-free survival (PFS) in chemotherapy and immunotherapy-naïve participants with locally advanced or metastatic BTC compared to placebo, gemcitabine and cisplatin.

Study arms:
- Experimental: Safety Run-In Part: Bintrafusp alfa + Gemcitabine + Cisplatin
• Bintrafusp alfa (M7824): Participants after the first onset of Complete Response (CR) will receive Bintrafusp alfa intravenously at a dose of 2400 milligram (mg) once every 3 weeks (Q3W) until confirmed disease progression, death, unacceptable toxicity, study withdrawal.
• Gemcitabine: Gemcitabine will be received intravenously at a dose of 1000 milligram per meter square (mg/m^2) on Day 1 and Day 8 of 21- day cycle, for 8 cycles every 3 weeks (Q3W).
• Cisplatin: Cisplatin will be received intravenously at a dose of 25 mg/m^2 on Day 1 and Day 8 of 21-day cycle, for 8 cycles every 3 weeks (Q3W)

- Experimental: Double-blinded Part: Bintrafusp alfa + Gemcitabine + Cisplatin
- Placebo Comparator: Double-blinded Part: Placebo + Gemcitabine + Cisplatin

Main objectives of the trial:
• Open-label Safety Run-in: To assess if M7824 2400 mg Q3W is safe and tolerable and to confirm this dose as the recommended Phase II dose for the randomized, double-blind part of the study.
• Randomized, Double-blind Part: To assess Progression Free Survival (PFS) and Overall Survival (OS) with M7824 in combination with gemcitabine plus cisplatin versus placebo with gemcitabine plus cisplatin in participants with advanced or metastatic BTC who have not received chemotherapy/immunotherapy in the advanced/metastatic setting

Secondary objectives of the trial:
• To evaluate clinical efficacy of M7824 based on objective response (ORR)
• To evaluate clinical efficacy of M7824 based on duration of response (DOR)
• To evaluate clinical efficacy of M7824 based on durable response rate (DRR)
• To evaluate ORR, DOR, DRR and PFS by Investigator read
• To evaluate safety profile of M7824 or placebo in combination with gemcitabine plus cisplatin
• To characterize the pharmacokinetic (PK) profile of M7824
• To characterize the immunogenicity of M7824 and to correlate it to exposure

Phase : II/III

Stade : Localement avancé à Métastasique

Informations libres de droit
Critères d'inclusion
Critères de non-inclusion
Informations libres de droit
Critères d'inclusion et de non-inclusion
Critères d'inclusion : 1. Patients aged ≥ 18 years of age at the time of signing the informed consent.
2. Participants with histologically or cytologically confirmed locally advanced or metastatic BTC, including intrahepatic CCA and extrahepatic CCA, gallbladder cancer and ampulla of Vater’s cancer.
3. Naïve to chemotherapy, immunotherapy, and interventional radiological treatment (transaortic chemo-embolization, transaortic embolization, transaortic infusion) for locally advanced or metastatic BTC. Participants whose disease has recurred ≥ 6 months after completion of neoadjuvant or adjuvant treatments will be considered eligible.
4. Availability of tumor tissue (primary or metastatic) (fresh or archival biopsies) before the first administration of study intervention. Availability of tumor tissue is mandatory except for the safety run-in part. Transductal aspirates, brush cytology, and cell blocks are not acceptable. Tumor tissue (fresh or archival) must be suitable for biomarker assessment as described in the Laboratory Manual.
5. At least 1 measurable lesion according to RECIST 1.1 verified independently by 2 separate IRC readers. Participants in the safety run-in part do not require a measurable lesion at baseline and IRC verification is not required.
6. ECOG PS of 0 or 1 at study entry and at Week 1, Day 1 prior to dosing.
7. Life expectancy of ≥ 12 weeks, as judged by the Investigator.
8. Adequate hematological function defined by white blood cell count ≥ 2.0 × 10^9/Lwith absolute neutrophil count ≥ 1.0 × 10^9/L, lymphocyte count ≥ 0.5 × 10^9/L, platelet count ≥ 100 × 10^9/L, and hemoglobin (Hgb) ≥ 9 g/dL (participants may have been transfused) at study entry and at Week 1 Day 1 prior to dosing. Previously transfused participants are allowed in the study with a stable Hgb of ≥ 9 g/dL at the time of study entry.
9. Adequate hepatic function defined by a total bilirubin level ≤ 1.5 × upper limit of normal (ULN), an aspartate aminotransferase level ≤ 3.0 × ULN, and an alanine aminotransferase level ≤ 3.0 × ULN. For participants with liver involvement, aspartate aminotransferase ≤ 5.0 × ULN and alanine aminotransferase ≤ 5.0 × ULN are acceptable.
10. Adequate renal function defined by an estimated creatinine clearance (CrCl) > 50 mL/min according to the Cockcroft-Gault formula or by measure of CrCl from 24-hour urine collection.
CrCl (mL/min) = (140-age) × weight (kg) / (72 × serum creatinine [Crjaffe])
If female, × 0.85
If creatinine is measured by the enzymatic method, add 0.2 and use as Crjaffe = 0.2 + Crenzyme.
11. Albumin ≥ 2.8 g/dL.
12. Adequate coagulation function defined as prothrombin time or international normalized ratio ≤ 1.5 × ULN unless the participant is receiving anticoagulant therapy.
13. Hepatitis B virus (HBV) deoxyribonucleic acid (DNA) positive participants must be treated and on a stable dose of antivirals (eg, entecavir, tenofovir, or lamivudine; adefovir or interferon is not allowed) at study entry and with planned monitoring and management including baseline HBV DNA quantity according to appropriate labeling guidance. Participants receiving active hepatitis C virus (HCV) therapy must be on a stable dose at study entry and with planned monitoring and management according to appropriate labeling guidance of approved antiviral.

Critères de non-inclusion : 1. Previous and/or intercurrent cancers. With the exception of: curatively-treated cancers with no recurrence in > 3 years or early cancers treated with curative intent, including but not limited to cervical carcinoma in situ, superficial, noninvasive bladder cancer, basal cell carcinoma, squamous cell carcinoma in situ, or endoscopically resected gastrointestinal cancers limited in mucosal layer.
2. Rapid clinical deterioration not related to malignancy which, in the opinion of the Investigator, may predispose to inability to tolerate treatment or study procedures.
3. Participants with symptomatic central nervous system (CNS) metastases are excluded. Participants with a history of treated CNS metastases (by surgery or radiation therapy) are not eligible unless they are judged to have fully recovered from treatment.
4. Receipt of any organ transplantation, including allogeneic stem-cell transplantation, but with the exception of transplants that do not require immunosuppression (eg, corneal transplant, hair transplant).
5. Significant acute or chronic infections including:
- Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome
- Active tuberculosis (presence of clinical symptoms, physical or radiographic findings of active tuberculosis).
- Uncontrolled biliary infection. Biliary tract obstruction should be released by stenting or percutaneous transhepatic biliary drainage.
- Active bacterial or fungal infection requiring systemic therapy.

6. Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent:
- Participants with type 1 diabetes, vitiligo, alopecia, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible.
- Participants requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses ≤ 10 mg of prednisone or equivalent per day.
- Administration of steroids for other conditions through a route known to result in a minimal systemic exposure (topical, intranasal, intra-ocular, or inhalation) is acceptable.

7. History of, or concurrent, interstitial lung disease.
8. Known history of hypersensitivity reactions to M7824 or its products or known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3 National Cancer Institute [NCI]-Common Terminology Criteria for Adverse Events [CTCAE] Version 5.0), any history of anaphylaxis, or recent (within 5 months) history of uncontrolled asthma.
9. Clinically significant cardiovascular/cerebrovascular disease as follows: 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.
10. Other severe, acute, or chronic medical conditions, including immune colitis, inflammatory bowel disease, immune pneumonitis, or psychiatric conditions, including recent (within the past year) or active suicidal ideation or behavior.
11. Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days before randomization.
12. Concurrent treatment with nonpermitted drugs. Participants who have completed prior adjuvant therapy > 6 months prior to randomization are eligible.
13. Prior therapy with any antibody/drug targeting T-cell coregulatory proteins (immune checkpoints), including but not limited to anti-PD-1, anti-PD-L1, anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody, or anti-4-1BB antibody is not allowed, inclusive of localized administration of such agents.
14. Prior therapy with any antibody/drug targeting TGFβ/TGFβ receptor.
15. Radiation within 14 days other than focal palliative bone-directed radiotherapy.
16. Systemic therapy with immunosuppressive agents within 7 days before the start of study intervention; or use of any investigational drug within 28 days before the start of study intervention.
17. Live vaccine administration within 4 weeks of study intervention administration.
18. Participation in any concurrent interventional clinical study for BTC.
19. Unable to tolerate CT or magnetic resonance imaging (MRI) in the opinion of the Investigator and/or allergy to contrast material.
20. Major surgery within 28 days before the start of study intervention (excluding prior diagnostic biopsy and stenting/percutaneous transhepatic biliary drainage for the purpose of releasing biliary tract obstruction).
21. Pregnancy or breastfeeding.
22. Known alcohol or drug abuse.
23. Legal incapacity or limited legal capacity
Informations relatives au promoteur
Promoteur :
EMD Serono Research & Development Institute, Inc.
Type de sponsor : Industriel

Coordonnateur :
Centre investigateur
Informations relatives aux investigateurs