Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial

TPS595 Background: CYT001 (CYTLIMIC Inc.) is a novel cancer vaccine involving artificial intelligence (AI)-designed shared-antigen peptides and optimal combined adjuvants that boost the cancer-immunity cycle. The two multi-HLA reactive peptides heat shock protein 70 (HSP70) and glypican 3 (GPC3) were screened by an AI-based prediction system according to the proteome, mRNA, and histopathology data fromhuman samples. These immunogenic peptides were confirmed to show cross-reactivity to HLA-A 24:02, 02:01, and 02:06. Poly-ICLC (Oncovir Inc.) binds to Toll-like receptor 3 (TLR3) and melanoma differentiation antigen 5 (MDA5) on antigen-presenting cells (APCs)and activates APCs. LAG-3Ig (Immutep Inc.) binds to the major histocompatibility complex (MHC) class II molecules of APCs and activates APCs. Both poly-ICLC and LAG-3Ig synergistically activate antigen-specific CTL reactions as effective combination adjuvants. The present study aims to evaluate the safety and tolerability of CYT001 (mixture of HSP70 peptide [2.0 mg], GPC3 peptide [2.0 mg], poly-ICLC [1.0 mg], and LAG-3Ig [1.4 mg]) in patients with advanced hepatocellular carcinoma (HCC). Methods: This is a single-center, phase 1, open-label, single-arm, investigator-initiated clinical trial of CYT001 for advanced HCC patients with no eligible standard systemic therapy, Child–Pugh A liver disease, and HLA-A 24:02, 02:01, or 02:06. Enrolled patients will receive CYT001 as a subcutaneous injection on days 1, 8, 15, and 21 in the 1st and 2nd cycles, days 1 and 15 in the 3rd and 4th cycles, and day 1 in the 5th cycle or later of 28-day cycles. The primary endpoint is dose-limiting toxicity, and the secondary endpoints are safety and the response rate. The transition of the CTL reactions of both the HSP70 and GPC3 peptides will be evaluated using blood samples of the subjects. Exploratory analyses include investigation of candidate biomarkers for treatment efficacy using liver tumor biopsy samples (baseline and after the 1st cycle) and blood samples (baseline and every days of administration). Clinical trial information: jRCT2031190072.

Download Full-text

Phase 1, First in Human, Open-Label, Dose-Escalation Study of 609A in China

Case Medical Research ◽

10.31525/ct1-nct03998345 ◽

2019 ◽

Author(s):

Keyword(s):

Dose Escalation ◽

Phase 1 ◽

Open Label ◽

Dose Escalation Study ◽

Label Dose

Download Full-text

Sorafenib-Regorafenib Sequential Therapy in Advanced Hepatocellular Carcinoma: A Single-Institute Experience

Digestive Diseases ◽

10.1159/000480257 ◽

2017 ◽

Vol 35 (6) ◽

pp. 611-617 ◽

Cited By ~ 9

Author(s):

Kazuomi Ueshima ◽

Naoshi Nishida ◽

Masatoshi Kudo

Keyword(s):

Hepatocellular Carcinoma ◽

Objective Response ◽

Progression Free Survival ◽

Sequential Therapy ◽

Advanced Hepatocellular Carcinoma ◽

Open Label ◽

Effective Treatment Option ◽

Sorafenib Treatment ◽

Advanced Hcc ◽

Grade 3

Objectives: Previously, no therapeutic agent has been known to improve the overall survival compared with placebo in patients with hepatocellular carcinoma (HCC), who have progressed after sorafenib. In this patient population, regorafenib was first demonstrated to confer a survival benefit in the RESORCE trial, and subsequently it was approved as a second-line treatment for patients with advanced HCC. An open-label expanded access program (EAP) of regorafenib was implemented for compassionate use. We investigated the efficacy and safety of regorafenib based on our experience of the RESORCE trial and the EAP. Methods: Data from 5 patients from the RESORCE trial and 6 from the EAP were analyzed retrospectively. All patients had tolerated prior sorafenib and were progressing during sorafenib treatment. Results: The median progression-free survival was 9.2 months (95% CI 2.3-16.1). One patient achieved a partial response and 7 achieved stable disease. The objective response rate was 9.1%, and the disease control rate was 72.7%. No treatment-associated mortalities were observed. Grade 3 hypophosphatemia was observed in 2 patients, grade 2 anorexia was observed in 5 patients, and grade 3 neutropenia was observed in 2 patients. Grade 2 and grade 3 thrombocytopenia were observed in 2 and 3 patients, respectively. All treatment-related adverse events were improved by reduction or interruption of regorafenib. Five patients showed decreased serum albumin levels. Conclusion: Sorafenib and regorafenib sequential therapy presents a safe and effective treatment option for patients with advanced HCC.

Download Full-text

A first-in-human, phase 1 study of the NEDD8 activating enzyme E1 inhibitor TAS4464 in patients with advanced solid tumors

Investigational New Drugs ◽

10.1007/s10637-020-01055-5 ◽

2021 ◽

Author(s):

Noboru Yamamoto ◽

Toshio Shimizu ◽

Kan Yonemori ◽

Shigehisa Kitano ◽

Shunsuke Kondo ◽

...

Keyword(s):

Liver Function ◽

Solid Tumors ◽

Dose Escalation ◽

Enzyme Inhibitor ◽

Phase 1 ◽

Maximum Tolerated Dose ◽

Primary Objective ◽

Open Label ◽

Phase 1 Study ◽

Open Label Phase

SummaryBackground This open-label, phase 1 study investigated TAS4464, a potent NEDD8-activating enzyme inhibitor, in patients with advanced/metastatic solid tumors (JapicCTI-173,488; registered 13/01/2017). The primary objective was dose-limiting toxicities (DLTs). Maximum-tolerated dose (MTD) was investigated using an accelerated titration design. Methods The starting 10-mg/m2 dose was followed by an initial accelerated stage (weekly dosing; n = 11). Based on liver function test (LFT) results, a 14-day, 20-mg/m2 dose lead-in period was implemented (weekly dosing with lead-in; n = 6). Results Abnormal LFT changes and gastrointestinal effects were the most common treatment-related adverse events (AEs). DLTs with 56-mg/m2 weekly dosing occurred in 1/5 patients; five patients had grade ≥ 2 abnormal LFT changes at 40- and 56-mg/m2 weekly doses. Further dose escalation ceased because of the possibility of severe abnormal LFT changes occurring. DLTs with weekly dosing with lead-in occurred in 1/5 patients at a 56-mg/m2 dose; MTD could not be determined because discontinuation criteria for additional enrollment at that particular dose level were met. As no further enrollment at lower doses occurred, dose escalation assessment was discontinued. Serious treatment-related AEs, AEs leading to treatment discontinuation, and DLTs were all related to abnormal LFT changes, suggesting that TAS4464 administration could affect liver function. This effect was dose-dependent but considered reversible. Complete or partial responses to TAS4464 were not observed; one patient achieved prolonged stable disease. Conclusions MTD could not be determined due to TAS4464 effects on liver function. Further evaluation of the mechanism of NEDD8-activating enzyme inhibitor-induced abnormal liver function is required. Trial registration number JapicCTI-173,488 (registered with Japan Pharmaceutical Information Center). Registration date 13 January 2017

Download Full-text