Etude : MK-3475-937 / KEYNOTE-937

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Type d'étude
Présentation de l'étude
Acronyme : MK-3475-937

Nom : KEYNOTE-937

Traitement : Adjuvant

Type d'étude : Hors ciblage moléculaire

Dernière MÀJ : 11/07/2019
CIM10 - Localisation(s)
Informations principales
Titre : A Phase 3 Double-blinded, Two-arm Study to Evaluate the Safety and Efficacy of Pembrolizumab (MK-3475) Versus Placebo as Adjuvant Therapy in Participants With Hepatocellular Carcinoma and Complete Radiological Response After Surgical Resection or Local Ablation

Spécialité : Organes digestifs
Localisation : C22 - Tumeur maligne du foie et des voies biliaires intrahépatiques
Informations complémentaires
Schéma : This study will evaluate the safety and efficacy of pembrolizumab (MK-3475) versus placebo as adjuvant therapy in participants with hepatocellular carcinoma (HCC) and complete radiological response after surgical resection or local ablation. The primary hypotheses of this study are that adjuvant pembrolizumab is superior to placebo with respect to: 1) recurrence-free survival (RFS) as assessed by blinded independent central review (BICR); and 2) overall survival (OS).

Phase : III

Stade : Localisé à Localement avancé

Critères d'inclusion
Critères de non-inclusion
Critères d'inclusion et de non-inclusion
Critères d'inclusion : 1. Has a diagnosis of HCC documented radiologically by AASLD criteria (participants undergoing ablation without a prior biopsy) and/or pathologically (participants undergoing ablation and not meeting AASLD criteria, and participants undergoing surgical resection); fibrolamellar, sarcomatoid and mixed hepatocellular/cholangiocarcinoma subtypes are not eligible and:
A. Has an intermediate risk (Stage IB), high risk (Stage II, IIIA) or very high risk of recurrence (subtypes of Stage IIIB as described below) as per American Joint Committee on Cancer (AJCC) 8th edition with adaptations based on tumor characteristics as established by the pathology report
- Intermediate risk of recurrence: solitary tumor ≥2 cm and ≤3 cm without microvascular invasion and not histologic grade 3 or 4
- High risk of recurrence: solitary tumor ≥2 and <10 cm with microvascular invasion or same size and histologic grade 3 or 4, or multiple tumors, none >10 cm, regardless of microvascular invasion or histologic grade
- Very high risk of recurrence: single tumor or multiple tumors of any size involving a major branch of the portal or hepatic vein, regardless of microvascular invasion or histologic grade. Stage IIIB tumor(s) with direct invasion of adjacent organs or with perforation of visceral peritoneum will not be eligible
B. Has a complete radiological response after local ablation (only radiofrequency or microwave ablation are allowed) and intermediate or high risk of recurrence
- Intermediate risk of recurrence: Solitary tumor ≥2 cm and ≤3 cm
- High risk of recurrence: 2-4 tumors, all ≥2 cm and ≤3 cm or one solitary tumor >3 cm and ≤5 cm
2. No more than 6 weeks must have elapsed between the date of the staging and the date of surgical resection or local ablation. Staging is based on the initial computed tomography (CT) scan or magnetic resonance imaging (MRI)
3. Has an eligibility scan (CT of the chest, triphasic CT scan or MRI of the abdomen, and CT or MRI of the pelvis) confirming complete radiological response ≥4 weeks after complete surgical resection or local ablation. Randomization needs to occur within 12 weeks of the date of surgical resection or local ablation
4. Has no radiologic evidence of disease prior to enrollment as per investigator assessment
5. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 within 7 days prior to C1D1
6. Has a Child-Pugh class A liver score (5 to 6 points) within 7 days prior to C1D1
7. Has AFP concentration lower than 400 ng/mL within 28 days prior to C1D1 (if there are several AFP values available within 28 days prior to C1D1, all values should be below 400 ng/mL)
8. Has AFP concentration at initial diagnosis prior to resection or ablation available
9. Has a past or ongoing HCV infection. Participants must have completed their treatment at least 1 month prior to C1D1
10. Has controlled hepatitis B, as long as they meet the following criteria:
- Antiviral therapy for HBV must be given for at least 4 weeks and HBV viral load must be less than 100 IU/mL prior to first dose of study intervention. Participants on active HBV therapy with viral loads under 100 IU/mL should stay on the same therapy throughout study intervention
- However, participants who are anti-HBc (+), negative for HbsAg, and negative or positive for anti-HBs, and who have an HBV viral load under 100 IU/mL, do not require HBV anti-viral prophylaxis
11. Has recovered adequately from toxicity and/or complications from the local intervention (surgical resection or local ablation) prior to starting study intervention
12. Is male or female, at least 18 years of age at the time of signing the informed consent
13. Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
14. Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
15. Participant (or legally acceptable representative if applicable) provides written informed consent for the study and agrees to RFS, DMFS, TTR and OS data collection until the study endpoints are reached. The participant may also provide consent for future biomedical research; however, the participant may participate in the main study without participating in future biomedical research
16. All participants who undergo surgical resection will be required to submit a tumor tissue sample during Screening. Confirmation of the tumor tissue sample adequacy at a central pathology laboratory is not required prior to enrollment. Participants who undergo local ablation are encouraged to submit a tumor tissue sample (and surrounding non-tumor tissue if available) during Screening if available
17. Has adequate organ function

Critères de non-inclusion : 1. Has a known additional malignancy that is progressing or has required active antineoplastic treatment (including hormonal) or surgery within the past 3 years
2. Has had esophageal or gastric variceal bleeding within the last 6 months. All cirrhotic participants will be screened for esophageal varices with an upper endoscopy, unless such assessment has been performed in the past 12 months before C1D1. If varices are present,they should be treated according to institutional standards before starting study intervention
3. Has clinically apparent ascites on physical examination
4. Has had clinically diagnosed hepatic encephalopathy in the last 6 months. Participants on rifaximin or lactulose to control their hepatic encephalopathy regardless of when the diagnosis of hepatic encephalopathy occurred are not eligible
5. Has received local therapy to liver ablation other than with radiofrequency or microwave ablation (ie alcohol ablation, transcatheter chemoembolization [TACE], transcatheter embolization [TAE], hepatic arterial infusion [HAI], local radiation/Stereotactic Body Radiation Therapy [SBRT] or radioembolization)
6. Has a history of (noninfectious) pneumonitis that required steroids or has current pneumonitis
7. Has an active infection requiring systemic therapy
8. Has dual active HBV infection (HbsAg (+) and /or detectable HBV DNA) and HCV infection (anti-HCV Ab (+) and detectable HCV RNA) at study entry
9. Has dual active HBV infection and HDV at the study entry
10. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority
11. Has a known active tuberculosis (TB; Bacillus tuberculosis)
12. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137)
13. Has received prior systemic anti-cancer therapy for HCC including investigational agents
14. Is receiving any of the following prohibited concomitant therapies:
- Antineoplastic systemic chemotherapy or biological therapy
- Immunotherapy not specified in this protocol
- Investigational agents other than pembrolizumab
- Radiation therapy
- Oncological surgical therapy
- Systemic glucocorticoids for any purpose other than to modulate symptoms from an AE that is suspected to have an immunologic etiology. Inhaled or topical steroids are allowed, and systemic steroids at doses ≤10 mg/day prednisone or equivalent are allowed. Exception: steroids may be used for premedication prior to imaging
15. Has received a live vaccine within 30 days prior to the first dose of study intervention. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®, [Influenza Vaccine Live, AstraZeneca]) are live attenuated vaccines and are not allowed
16. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to C1D1
17. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to C1D1
18. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients
19. Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs)
20. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant’s participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
21. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study
22. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study intervention
23. Has had an allogenic tissue/solid organ transplant
Informations relatives au promoteur
Promoteur :
MSD (Merck Sharp & Dohme Corp.)
Type de sponsor : Industriel

Coordonnateur :
Centre investigateur
Informations relatives aux investigateurs
Centre investigateur :
Centre Hospitalier Universitaire de Lille - 2 Avenue Oscar Lambret - 59000 LILLE

Investigateur :
Docteur Stéphane CATTAN

Madame Daphnée SORET
03 20 44 59 62 - Poste 30671

Ouverture de l'essai : OUVERT

MAJ : 11/07/2019