PETAL protocol: a phase Ib study of pembrolizumab after transarterial chemoembolization in hepatocellular carcinoma

Figures & data

Figure 1. Study flowchart.

DLT: Dose-limiting toxicity; LRT: Locoregional therapy; Q3W: Every 3 weeks; Q6W: Every 6 weeks; TACE: Transarterial chemoembolization.

Table 1. Inclusion and exclusion criteria.

Key inclusion criteria

Key exclusion criteria

1. Voluntary written informed consent/assent for the trial 2. ≥18 years of age on day of signing informed consent 3. Histological or radiological diagnosis of HCC according to AASLD criteria 4. Barcelona Clinic Liver Cancer Stage B HCC diagnosis 5. ≥1 unidimensional lesion measurable by CT scan or MRI based on mRECIST criteria 6. Patients who received prior TACE treatment (conventional or DEB-TACE) are eligible, provided they have at least one previously untreated lesion that is measurable based on mRECIST criteria 7. Ineligible for surgical resection or liver transplantation 8. ECOG performance status of 0 or 1 9. Demonstrate adequate organ function 10. Child-Pugh score ≤7 11. Females of childbearing potential should have a negative urine or serum pregnancy 12. Females of childbearing potential and sexually active males must be willing to use contraception for the course of the study through 120 days after last dose of the IMP

1. Extrahepatic metastases 2. Systemic anticancer treatment for HCC^† 3. Contraindications to TACE, including portosystemic shunt, hepatofugal blood flow, known severe atheromatosis 4. Bleeding within 4 weeks preceding screening 5. Hepatic encephalopathy 6. Diuretic-refractory ascites 7. Hepatic artery or main portal vein occlusion 8. Has received another IMP or used an investigational device within 4 weeks of the first dose of PETAL IMP 9. Immunodeficiency or immunosuppressive therapy, including systemic steroids 10. Active TB 11. Hypersensitivity to pembrolizumab 12. Additional malignancy that is progressing or requires active treatment 13. Active autoimmune disease that has required disease-modifying agents in past 2 years 14. Noninfectious pneumonitis 15. Active infection requiring systemic therapy, excluding hepatitis B and C viruses 16. History or current evidence of any condition, therapy or laboratory abnormality that might confound results of the trial, interfere with subject’s participation for the full duration of the trial, or is not in the best interest of the participant to participate, in the opinion of the PI 17. Known psychiatric or substance abuse disorders that would interfere with cooperation with requirements of the trial 18. Pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial, starting from screening through to 120 days after the last dose of IMP 19. Prior therapy with an anti-PD-1, anti-PD-L1 or anti-PD-L2 agent 20. Known history of HIV 21. Live vaccine within 30 days of first dose of IMP

† Systemic anticancer treatment is considered for patients who do not achieve complete tumor devascularization after two TACE sessions, who will be excluded from the study.

AASLD: American Association for the Study of Liver Diseases; DEB-TACE: Doxorubicin-eluting beads-transarterial chemoembolization; ECOG: Eastern Cooperative Oncology Group; HCC: Hepatocellular carcinoma; IMP: Investigative medicinal product; mRECIST: Modified Response Evaluation Criteria in Solid Tumours; PD-1: Programmed cell death-1; PD-L1/2: Programmed cell death ligand-1/2; PI: Principal investigator; TACE: Transarterial chemoembolization; TB: Tuberculosis.

Table 2. General recommendations for managing immunotherapy-related adverse events.

Immunotherapy-related adverse events	Withhold/discontinue pembrolizumab?	Supportive care
Grade 1	No action	Provide symptomatic treatment
Grade 2	May withhold pembrolizumab	Consider systemic corticosteroids in addition to appropriate symptomatic treatment. Steroid taper should be considered once symptoms improve to grade 1 or less and tapered over at least 4 weeks
Grade 3 and Grade 4	Withhold pembrolizumab Discontinue if unable to reduce corticosteroid dose to <10 mg per day prednisone equivalent within 12 weeks of toxicity	Systemic corticosteroids are indicated in addition to appropriate symptomatic treatment. May utilize 1–2 mg/kg prednisone or equivalent per day Steroid taper should be considered once symptoms improve to grade 1 or less and tapered over at least 4 weeks Consider adding a second immunosuppressive drug in patients without rapid response to systemic corticosteroids