Investigational New Drugs (2019) 37:118–126 https://doi.org/10.1007/s10637-018-0636-3 PHASE I STUDIES A phase 1b study of transforming growth factor-beta receptor I inhibitor galunisertib in combination with sorafenib in Japanese patients with unresectable hepatocellular carcinoma Masafumi Ikeda1 & Manabu Morimoto2 & Masaomi Tajimi3 & Koichi Inoue3 & Karim A. Benhadji4 & Michael M. F. Lahn5 & Daisuke Sakai6 Received: 7 May 2018 /Accepted: 4 July 2018 /Published online: 11 July 2018 # The Author(s) 2018 Summary Background Galunisertib inhibits type I transforming growth factor-beta receptor serine/threonine kinase. The primary objective of this study was to evaluate the safety and tolerability of galunisertib in combination with sorafenib in Japanese patients with unresectable hepatocellular carcinoma. Patients and methods This open-label, dose-escalation, multicenter, nonrandomized phase 1b study consisted of two dose levels of galunisertib, 160 or 300 mg/day, in combination with sorafenib 800 mg/day. Galunisertib 80 mg or 150 mg was administered orally twice daily for 14 days followed by 14 days of rest plus sorafenib 400 mg administered orally twice daily for 28 days. The dose-limiting toxicity evaluation was 28 days after the first dose. Safety measures, pharmacokinetics, and antitumor activity were assessed. Results Fourteen patients, 7 at each galunisertib dose, were enrolled and treated. Three dose-limiting toxicities were reported for 2 patients. The most common treatment-emergent adverse events (TEAEs) were hypophosphatemia (14 patients [100%]), palmar-plantar erythrodysesthesia syndrome (12 patients [85.7%]), and decreased platelet count (10 patients [71.4%]). The most common grade ≥ 3 TEAEs were hypophosphatemia (10 patients [71.4%]) and palmar-plantar erythrodysesthesia syndrome (7 patients [50.0%]). No grade 5 TEAEs were reported. The pharmacokinetic profile of galunisertib in combination with sorafenib was similar to that previously reported for galunisertib. Eleven patients had a best overall response of stable disease, and 1 patient achieved a partial response by hepatocellular carcinoma-specific modified RECIST. Conclusions These data are consistent with the known safety profile for galunisertib and sorafenib and confirm tolerability of the recommended dose of galunisertib (150 mg twice daily for 14 days) in combination with sorafenib in Japanese patients with unresectable hepatocellular carcinoma. Keywords Galunisertib . Hepatocellular carcinoma . Japan . Phase I clinical trial . Sorafenib Introduction Liver cancer is the fifth most common cancer in men, the ninth * Masafumi Ikeda [email protected] most common cancer in women, and the second-leading cause of cancer deaths for both genders worldwide [1]. The inci- dence of liver cancer varies by geographical region, with the 1 National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa-shi, Chiba-ken 277-8577, Japan highest reported incidence in East Asia, including Japan [1]. Prognosis for liver cancer also varies between regions. For 2 Kanagawa Cancer Center, Yokohama, Japan instance, an Asia-Pacific study of sorafenib versus placebo 3 Eli Lilly Japan K.K, Kobe, Japan in East Asian patients with hepatocellular carcinoma (HCC), 4 Eli Lilly and Company, New York, NY, USA which is the most common form of liver cancer [2], showed 5 Formerly Eli Lilly and Company, Indianapolis, IN, USA that median overall survival (OS) in both treatment groups 6 Osaka University Hospital, Osaka, Japan was shorter than the median OS in either group of the global Invest New Drugs (2019) 37:118–126 119 SHARP study of sorafenib versus placebo in patients with 0 or 1 and adequate organ function were enrolled. Patients HCC [3, 4]. In addition, the GIDEON observational study of must have had the presence of a measurable or evaluable sorafenib treatment in patients with HCC found that median lesion per Response Evaluation Criteria in Solid Tumors time from initial diagnosis to death was 79.6 months in Japan (RECIST) v1.1 and had resolution of all toxic effects of prior compared to 20.9 months in the Asia-Pacific region, therapies before enrollment. Exclusion criteria included major 25.0 months in Europe, 19.5 months in Latin America, and surgery, hepatic locoregional therapy, or systemic chemother- 14.8 months in the United States [5]. Regardless of regional apy within 28 days before enrollment, serious pre-existing differences, prognosis for liver cancer remains dismal, with medical condition(s), active infection(s), or a previous or con- the global SHARP study showing a median OS of only current malignancy. 10.7 months for sorafenib and 7.9 months for placebo [4]. Improved therapies for HCC are therefore needed. Study design and treatment Preclinical studies indicate that inhibition of transforming growth factor-beta (TGF-β) may inhibit tumor cell invasion All eligible patients in this phase 1b, open-label, dose-escala- and metastasis, reduce tumor neoangiogenesis, and enhance tion, multicenter, nonrandomized study received oral admin- antitumor immunity [6–8]. Galunisertib is a small molecule istration of galunisertib (160 mg or 300 mg/day) in combina- designed to selectively inhibit the serine/threonine kinase of tion with oral administration of sorafenib 800 mg/day. A cycle the TGF-β receptor type I. Clinical studies have shown favor- was defined as 28 days. Galunisertib was administered at ei- able short- and long-term toxicity profiles and efficacy with a ther 80 mg twice daily or 150 mg twice daily for 14 days, galunisertib dose range of 40 mg to 300 mg/day in patients followed by 14 days of galunisertib treatment rest, and soraf- with gliomas or advanced cancer [9, 10]. In Japanese patients enib 400 mg twice daily for 28 days. Patients continued treat- with advanced solid tumors, galunisertib monotherapy has ment until a discontinuation criterion was met. been shown to have an acceptable tolerability and safety pro- The DLTevaluation period was 28 days after the first dose. file with no dose-limiting toxicities (DLTs) [11]. Furthermore, Tolerability was defined as a dose where 2 or fewer of 6 galunisertib in combination with gemcitabine has been shown patients experience DLTs. A minimum of 3 patients were to have an acceptable tolerability and safety profile with evi- planned to be enrolled in the galunisertib 160 mg/day plus dence of antitumor activity in Japanese patients with metasta- sorafenib group, and a minimum of 6 patients were planned tic or locally advanced pancreatic cancer [12]. In a phase 2 to be enrolled in the galunisertib 300 mg/day plus sorafenib study in non-Asian countries, in patients with advanced HCC group. Dose escalation to galunisertib 300 mg/day could oc- who had progressed on sorafenib or were ineligible to receive cur after confirmation by the sponsor of DLT assessments sorafenib, galunisertib monotherapy was shown to have an provided by investigators. acceptable safety profile without cardiotoxicity [13]. The me- The primary objective of this study was to evaluate the dian OS was 7.2 months (90% confidence interval [CI], 5.3– safety and tolerability of galunisertib when combined with 9.3) in patients with baseline alpha-fetoprotein (AFP) ≥1.5 sorafenib. The secondary objectives were to characterize the ULN (part A) and 16.8 months (90% CI, 10.4–24.1) in pa- pharmacokinetic (PK) profile of galunisertib and sorafenib tients with AFP <1.5 ULN (part B), with a median time-to- and evaluate TTP, progression-free survival (PFS), and anti- progression (TTP) of 2.7 months (90% CI, 1.4−2.9) in part A tumor response per RECIST version 1.1 as well as the HCC- and 4.1 months (90% CI, 2.3–5.5) in part B [13]. Collectively, specific modified RECIST (mRECIST) [14]. Clinicaltrials. these studies support the evaluation of a combination regimen gov identifier: NCT02240433. of a well-tolerated agent such as galunisertib with an existing therapy such as sorafenib in patients with HCC. Safety evaluations The purpose of this phase 1b study was to evaluate the safety and tolerability of galunisertib in combination with so- Safety analyses included the extent of exposure, adverse rafenib in Japanese patients with HCC. events, DLTs, clinical laboratory tests, cardiac monitoring, and other safety evaluations, such as vital signs and ECOG performance status. Adverse events were listed and summa- Patients and methods rized using the Common Terminology Criteria for Adverse Events (CTCAE version 4.03) and the Medical Dictionary Eligibility for Regulatory Activities version 20.0. A DLT was defined as an adverse event during cycle 1 in Japanese patients at least 20 years of age with HCC not ame- each treatment group that was possibly related to galunisertib, nable to curative therapy, who were Child-Pugh Class A, who or the combination of galunisertib plus sorafenib, and fulfilled had not received sorafenib previously, and who had an Eastern any of the following criteria using the CTCAE version 4.03: Cooperative Oncology Group (ECOG) performance status of 1) ≥ grade 3 nonhematologic toxicity, except alopecia, fatigue, 120 Invest New Drugs (2019) 37:118–126 skin rash, nausea, vomiting, constipation, diarrhea, or electro- Statistical analyses lyte disturbance, that can be controlled with treatment or op- timal supportive care; transient (≤7 days) elevations of alanine The sample size was determined based on the study design to aminotransferase, aspartate aminotransferase, alkaline phos- evaluate the DLTs, safety, and tolerability of galunisertib in phatase, and/or gamma glutamyltransferase; hand-foot syn- two sequential study treatment groups. Patients who had at drome attributed to sorafenib only; or hypertension attributed least one DLT were evaluable for DLTs. Patients without a to sorafenib that cannot be adequately controlled, 2) hemato- DLT who received <80% of the galunisertib dose in cycle 1 logical toxicity, 3) any other toxicity deemed to be dose lim- for reasons other than drug-related toxicity were considered iting, or 4) failure to recover sufficiently from toxicities to nonevaluable for DLTs and replaced by a new patient.