P1101 and Anti-PD1 for After Curative Surgery of Hepatitis B-related Hepatocellular Carcinoma

Phase 1

Brief Summary: The main purpose of this trial is to evaluate the safety of the new adjuvant treatment of curative HCC, or the treatment of long-acting interferon P1101 alone, or the use of long-acting interferon P1101 and subsequent treatment of anti-PD1, and any efficacy in reducing the recurrence rate of patients after surgery.

Detailed Description: secondary end-point: P1101 and anti-PD1 sequential therapy on hepatitis B (especially on HbsAg).

Recruitment & Eligibility

Inclusion Criteria

Subject with HCC who meet the following criteria
1. Subjects diagnosed as having typical HCC on dynamic CT, or dynamic MRI performed within 8 weeks before surgery, or subjects who diagnosed HCC by pathology after surgery resection;
2. Subjects with the primary occurrence HCC ;
3. Subjects with the HCC related to hepatitis B virus (HBV) ;
Subject who have undergone surgical liver reaction within 8 weeks prior to study entry.
Subjects showing a complete cure shows no findings suggestive of recurrence or remnant. ;
Subject who are able to begin treatment with the study drug within 12 weeks after liver surgery resection. ;
Subjects confirmed of satisfying the following conditions based on the screening performed at enrollment: Positive for HBsAg/ Undetectable HBV DNA, with or without current anti HBV treatment/ Grade A on Child-Pugh classification;
Normal fundoscopic examination by ophthalmologist at screening;
ECOG 0 to 1 ;

Exclusion Criteria

Subjects positive for anti-HCV ;
Subjects showing vascular invasion of HCC on imaging diagnosis ;
Subjects who have uncontrolled hypertension;
Subjects with a history of pneumonitis or interstitial lung disease . cardiac arrest . an active infection requiring therapy .;
Diabetes mellitus with HbA1c ≥ 7.4% with insulin treatment;

Arm && Interventions

Group	Intervention	Description
P1101 monotherapy	P1101 (Ropeginterferon alfa-2b)	Phase II Study Group II: P1101 arm 450mcg 12 doses
Sequential administration of P1101 and anti-PD1	P1101 (Ropeginterferon alfa-2b)	Phase I of Study : To determine the safety, tolerability, DLT, and potential phase 2 dose of sequential administration of P1101 and anti-PD1 :Sequential administration 6 doses (450mcg) of P1101 and 3 doses of anti-PD1 (Escalating from 0.3, 0.75, 1.5, 3 mg/kg) for Phase I Study
sequential administration of P1101 and anti-PD1	P1101 (Ropeginterferon alfa-2b)	Phase II Study GroupIII:Sequential administration of 6 doses of 450mcg P1101 and followed by 3 doses of anti-PD1 dosage (base on Phase I study result)
Sequential administration of P1101 and anti-PD1	Nivolumab	Phase I of Study : To determine the safety, tolerability, DLT, and potential phase 2 dose of sequential administration of P1101 and anti-PD1 :Sequential administration 6 doses (450mcg) of P1101 and 3 doses of anti-PD1 (Escalating from 0.3, 0.75, 1.5, 3 mg/kg) for Phase I Study
anti-PD1	Nivolumab	Phase II Study Group I: anti-PD1 arm 3mg/kg 3 doses
sequential administration of P1101 and anti-PD1	Nivolumab	Phase II Study GroupIII:Sequential administration of 6 doses of 450mcg P1101 and followed by 3 doses of anti-PD1 dosage (base on Phase I study result)

Primary Outcome Measures

Name	Time	Method
Phase I portion - Dose-limiting Toxicity	18 weeks	To determine the potential phase 2 dose of sequestial administration of P1101 and anti-PD1. The MTD is determine by the prior dose level below the dose level at which ≥2/3 or ≥2/6 subjects suffer dose-limiting toxicity (DLT).
Phase II portion - Recurrence-free survival (defined as the time from randomization to HCC recurrence or death from any cause, whichever occured first)	48 weeks	To evaluate safety(assessment of AE, SAE and unanticipated problem) and the recurrence-free survival (defined as the time from randomization to HCC recurrence or death from any cause, whichever occured first) at 48 weeks after randomization of anti-PD 1 monotherapy, P1101 monotherapy, and sequential administration of P1101 and anti-PD 1 therapy arms

Secondary Outcome Measures

Name	Time	Method
Disease-free survival	48 weeks	To assess the effect of anti-PD1 monotherapy, P1101 monotherapy, and sequential administration of P1101 and anti-PD1 in inhibiting the recurrence, using disease-free survival (defined as the time from randomization to HCC recurrence, death from any cause, or onset of secondary tumor, whichever occurred first) at 48 weeks after randomization as the endpoint
Recurrence-free survival	96 weeks	To assess the treatment effect of anti-PD1 monotherapy, P1101 monotherapy, or sequential administration of P1101 and anti-PD1 in inhibiting the recurrence, using recurrence-free survival (defined as the time from randomization to HCC recurrence or death from any cause, whichever occurred first) at 96 weeks after randomization as the endpoint
HBsAg level	End of treatment of Anti-PD1 arm is up to 6 weeks; End of treatment of P1101 arm is up to 24 weeks; End of treatment of sequential administration of P1101 and anti-PD1 is up to 18 weeks, 24 weeks and 48 weeks	To assess the change in mean HBsAg level from baseline at the end of treatment (EOT), 24 weeks and 48 weeks after randomization