Cancer Chemother Pharmacol DOI 10.1007/s00280-015-2741-8
ORIGINAL ARTICLE
A phase I study of resminostat in Japanese patients with advanced solid tumors Satoru Kitazono1 · Yutaka Fujiwara1 · Shinji Nakamichi1 · Hidenori Mizugaki1 · Hiroshi Nokihara1 · Noboru Yamamoto1 · Yasuhide Yamada2 · Eri Inukai3 · Osamu Nakamura3 · Tomohide Tamura1
Received: 26 October 2014 / Accepted: 26 March 2015 © Springer-Verlag Berlin Heidelberg 2015
Abstract Purpose This study was performed to evaluate the safety and determine the recommended dose (RD) of resminostat monotherapy, an oral histone deacetylase (HDAC) inhibitor, in Japanese patients with advanced solid tumors. Methods Resminostat was administered to patients with advanced solid tumors on a 14-day cycle consisting of once-daily administration on days 1–5. The dose was initiated at 400 mg and increased to 600 mg and then 800 mg. Treatment with resminostat was continued until disease progression or discontinuation for any other reason. Doselimiting toxicities (DLTs) were assessed according to the adverse drug reactions occurring in the first cycle. Secondary objectives included the pharmacokinetics, pharmacodynamics, and efficacy. Results A total of 12 patients were enrolled in the study and received resminostat. No DLTs were reported in any patient. The maximum tolerated dose was not reached. Frequently reported grade 3/4 adverse drug reactions were as follows: lymphocytopenia (33.3 %), thrombocytopenia (25.0 %), neutropenia (16.7 %), and leukocytopenia The oral presentation was presented at the Japanese Society of Medical Oncology 2014 Annual Scientific Meeting. * Yutaka Fujiwara [email protected] 1
Department of Thoracic Oncology, National Cancer Center Hospital, 5‑1‑1, Tsukiji, Chuo‑ku, Tokyo 104‑0045, Japan
2
Department of Gastrointestinal Oncology, National Cancer Center Hospital, 5‑1‑1, Tsukiji, Chuo‑ku, Tokyo 104‑0045, Japan
3
Pharmaceutical Research and Development Department, Yakult Honsha Co., Ltd., 16‑21, Giza 7‑chome, Chuo‑ku, Tokyo 104‑0061, Japan
(16.7 %). Pharmacokinetic analysis revealed that there was no accumulation of the drug over the 5-day administration period and no significant difference in pharmacokinetic parameters between the single dose and multiple doses. Measurement of acetylated H4 histone protein levels in peripheral blood mononuclear cells demonstrated that resminostat inhibited HDAC activity at all the doses assessed. No patients had a complete or partial response, whereas three patients had stable disease. Conclusions Resminostat was safely administered to Japanese patients with advanced solid tumors. The RD of resminostat monotherapy in Japanese patients was estimated to be 800 mg. Keywords Resminostat · Histone deacetylase · Phase I · Solid tumor
Introduction Histone deacetylases (HDACs) are a family of currently 18 isoenzymes belonging to four subclasses based on their sequence homology [1]. It has been reported that various HDACs are overexpressed in cancer patients. The action of HDACs on nucleosomal histones leads to tight coiling of chromatin and silencing of gene expression, including genes implicated in the regulation of cell survival, proliferation, differentiation, and apoptosis [2–6]. Inhibition of HDAC activity accelerates posttranslational acetylation of core nucleosomal histones, which affects chromatin structure, thereby regulating gene expression. DNA wrapped around condensed, non-acetylated histones is transcriptionally inactive, whereas acetylation of the N-terminal histone lysine residue exposes DNA to important transcription factors that promote transcriptional activity [2].
13
In addition, HDAC can also regulate gene expression in an indirect fashion by mediating the acetylation of more than 50 known nonhistone protein substrates such as DNAbinding proteins, transcription factors signal transducers, DNA repair, and chaperon proteins [7]. HDAC inhibitors can induce cell cycle arrest or apoptosis in numerous solid cell lines [3, 8]. At present, epigenetic regulation of gene expression with HDAC inhibitors has been proposed as a novel anticancer treatment. A variety of HDAC inhibitors are under clinical development. Vorinostat is approved for the treatment of cutaneous T cell lymphoma (CTCL) in more than 20 countries including Japan and the USA [9, 10]. In the USA, romidepsin and belinostat are also approved, respectively, for the treatment of CTCL and/or peripheral T cell lymphoma (PTCL) [11–13]. Resminostat is an oral hydroxamate-type pan-inhibitor of class I and II HDAC enzymes [14] that inhibits HDAC by binding to a zinc ion in the catalytic domain of the enzyme [6, 9, 14, 15]. In vitro and in vivo studies, the antitumor activities were equal to or higher than those of currently approved HDAC inhibitors. A first-in-human, exploratory, open-label, interpatient dose escalation, single-center phase I study of resminostat was performed in UK [16], in which the drug was administered to patients with advanced solid tumors on a 14-day cycle consisting of once-daily administration on days 1–5 followed by a 9-day drug-free interval. Resminostat, when orally administered once daily at doses of 100–800 mg, was demonstrated to be safe and well tolerated. Since only one of seven patients received 800 mg, the highest dose level assessed, experienced combined dose-limiting toxicities (DLT), and the maximum tolerated dose (MTD) was not formally determined in this first-in-man study with resminostat. In the pharmacokinetic profile, resminostat showed dose-dependent increase in Cmax and AUC. It is more favorable than vorinostat. Subsequently, clinical studies were performed in EU, in which resminostat was administered as monotherapy to treat patients with relapsed or refractory Hodgkin’s lymphoma, in combination with sorafenib (Nexavar®) to treat patients with advanced hepatocellular carcinoma in second line after sorafenib failure and in combination with folinic acid, fluorouracil, and irinotecan (FOLFIRI regimen) to treat patients with colorectal cancer (CRC). The present study was designed to evaluate the safety and determine the recommended dose of resminostat administered alone in Japanese patients with advanced solid tumors, and to assess DLTs based on adverse drug reactions occurring in the first treatment cycle. Secondary objectives included evaluation of the pharmacokinetics, pharmacodynamics, and efficacy of resminostat monotherapy.
13
Cancer Chemother Pharmacol
Materials and methods Patient selection Inclusion criteria included adults aged 20–74 years with histologically or cytologically proven advanced solid tumors, for which standard treatments had failed or no standard treatment options were available, an Eastern Cooperative Oncology Group performance status of 0 or 1, adequate organ and bone marrow function, ability to swallow resminostat, and a life expectancy of ≥12 weeks. Despite no limitation on the number of prior chemotherapies, patients were required to have completed all the prior chemotherapy, radiation, endocrine, and immune therapies at least 4 weeks before study enrollment. Exclusion criteria included previous HDAC inhibitor treatment, persistence of acute toxicities from any prior therapy, active infection, a history of clinically significant allergy, brain tumors or brain metastases requiring treatment, significant cardiovascular diseases, QT prolongation syndrome, coexisting multiple carcinomas, and body cavity fluid requiring treatment. Patients who were considered by the investigators to be inappropriate for participating in the study were also excluded. This study was conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice guidelines. Approval from the independent institutional review board of the National Cancer Center (Tokyo, Japan) was acquired. All patients provided written informed consent. Study design This study was a single-center, open-label, phase I study that employed a standard 3 + 3 dose-escalation scheme. Since the previous first-in-man phase I study in Western populations [16] demonstrated that resminostat was well tolerated at a daily dose of up to 800 mg, the daily dose assessed in this study was initiated at 400 mg, escalating to 600 mg, and finally to 800 mg. Intrapatient dose escalation was not permitted. Resminostat was orally administered on a 14-day cycle consisting of once-daily administration on days 1–5 followed by a 9-day drug-free interval. Patients fasted for 2 h before and 1 h after administration. Treatment with resminostat was continued until disease progression or until discontinuation for any other reason. When any DLT was found in ≥2 of 3 patients or ≥3 of 6 patients within a dose level group, that dose level was defined as the MTD and the preceding dose level was determined as the recommended dose. If none of the three patients receiving 800 mg experienced any DLT, three patients were added and DLTs were assessed among six patients.
Cancer Chemother Pharmacol
Definition of DLT Dose-limiting toxicities (DLT) was defined as any of the following adverse drug reactions occurring in the first cycle: grade 4 thrombocytopenia, grade 4 neutropenia lasting >7 days, febrile neutropenia, grade 3 electrocardiogram prolonged QT-corrected interval, grade 4 aspartate aminotransferase (AST) increased or grade 3 AST increased lasting >7 days, grade 4 alanine aminotransferase (ALT) increased or grade 3 ALT increased lasting >7 days, and any other clinically significant grade ≥3 non-hematologic toxicity. Assessments Safety assessments included hematology testing, blood biochemistry testing, a blood coagulation test, troponin level assessment, urinalysis, physical examinations, vital signs, performance status, 12-lead electrocardiogram (ECG), and echocardiography. Adverse events were graded and reported according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Radiographic assessment was performed at 6 weeks after study enrollment, followed by every two treatment cycles. Tumor response was assessed by the investigators using Response Evaluation Criteria in
Table 1 Baseline patient characteristics
Solid Tumors (RECIST) version 1.1. Blood samples for pharmacokinetic assessment were collected on day 1 of the first cycle at pre-dose, and 1, 1.5, 2, 3, 4, 5, 6, and 24 h postdose, and on day 5 of the first and second cycles at pre-dose, and 1, 1.5, 2, 3, 4, 5, and 6 h post-dose. Plasma resminostat concentrations were determined using a validated high-performance liquid chromatography/tandem mass spectrometry method [16]. Blood samples for pharmacodynamic assessment were collected on day 1 of the first cycle at pre-dose, and 2, 5, and 24 h post-dose, and on day 5 of the first and second cycles at pre-dose, and 2 and 5 h post-dose, to isolate peripheral blood mononuclear cells (PBMCs). Acetylated histone H4 protein levels were determined by luminescence intensity using a Western blotting method as previously described [16].
Results Patients characteristics A total of 12 patients were enrolled in the study between May 2012 and March 2013. A median of two cycles (range 1–8) per patient was delivered. Patient characteristics at the study enrollment are summarized in Table 1.
Dose level
400 mg
600 mg
800 mg
Total (%)
N
3
3
6
12
0 3 61.0 (47–70)
4 2 65.5 (58–69)
5 (41.7) 7 (58.3) 62.5 (33–70)
Sex Male 1 Female 2 Median age (years) 54.0 (33–70) (range) ECOG PS 0 0 1 3 Diagnosis CRC 2 Pancreatic carcinoma 0 NSCLC 1 Others 0 Prior treatment (chemotherapy)
ORIGINAL ARTICLE
A phase I study of resminostat in Japanese patients with advanced solid tumors Satoru Kitazono1 · Yutaka Fujiwara1 · Shinji Nakamichi1 · Hidenori Mizugaki1 · Hiroshi Nokihara1 · Noboru Yamamoto1 · Yasuhide Yamada2 · Eri Inukai3 · Osamu Nakamura3 · Tomohide Tamura1
Received: 26 October 2014 / Accepted: 26 March 2015 © Springer-Verlag Berlin Heidelberg 2015
Abstract Purpose This study was performed to evaluate the safety and determine the recommended dose (RD) of resminostat monotherapy, an oral histone deacetylase (HDAC) inhibitor, in Japanese patients with advanced solid tumors. Methods Resminostat was administered to patients with advanced solid tumors on a 14-day cycle consisting of once-daily administration on days 1–5. The dose was initiated at 400 mg and increased to 600 mg and then 800 mg. Treatment with resminostat was continued until disease progression or discontinuation for any other reason. Doselimiting toxicities (DLTs) were assessed according to the adverse drug reactions occurring in the first cycle. Secondary objectives included the pharmacokinetics, pharmacodynamics, and efficacy. Results A total of 12 patients were enrolled in the study and received resminostat. No DLTs were reported in any patient. The maximum tolerated dose was not reached. Frequently reported grade 3/4 adverse drug reactions were as follows: lymphocytopenia (33.3 %), thrombocytopenia (25.0 %), neutropenia (16.7 %), and leukocytopenia The oral presentation was presented at the Japanese Society of Medical Oncology 2014 Annual Scientific Meeting. * Yutaka Fujiwara [email protected] 1
Department of Thoracic Oncology, National Cancer Center Hospital, 5‑1‑1, Tsukiji, Chuo‑ku, Tokyo 104‑0045, Japan
2
Department of Gastrointestinal Oncology, National Cancer Center Hospital, 5‑1‑1, Tsukiji, Chuo‑ku, Tokyo 104‑0045, Japan
3
Pharmaceutical Research and Development Department, Yakult Honsha Co., Ltd., 16‑21, Giza 7‑chome, Chuo‑ku, Tokyo 104‑0061, Japan
(16.7 %). Pharmacokinetic analysis revealed that there was no accumulation of the drug over the 5-day administration period and no significant difference in pharmacokinetic parameters between the single dose and multiple doses. Measurement of acetylated H4 histone protein levels in peripheral blood mononuclear cells demonstrated that resminostat inhibited HDAC activity at all the doses assessed. No patients had a complete or partial response, whereas three patients had stable disease. Conclusions Resminostat was safely administered to Japanese patients with advanced solid tumors. The RD of resminostat monotherapy in Japanese patients was estimated to be 800 mg. Keywords Resminostat · Histone deacetylase · Phase I · Solid tumor
Introduction Histone deacetylases (HDACs) are a family of currently 18 isoenzymes belonging to four subclasses based on their sequence homology [1]. It has been reported that various HDACs are overexpressed in cancer patients. The action of HDACs on nucleosomal histones leads to tight coiling of chromatin and silencing of gene expression, including genes implicated in the regulation of cell survival, proliferation, differentiation, and apoptosis [2–6]. Inhibition of HDAC activity accelerates posttranslational acetylation of core nucleosomal histones, which affects chromatin structure, thereby regulating gene expression. DNA wrapped around condensed, non-acetylated histones is transcriptionally inactive, whereas acetylation of the N-terminal histone lysine residue exposes DNA to important transcription factors that promote transcriptional activity [2].
13
In addition, HDAC can also regulate gene expression in an indirect fashion by mediating the acetylation of more than 50 known nonhistone protein substrates such as DNAbinding proteins, transcription factors signal transducers, DNA repair, and chaperon proteins [7]. HDAC inhibitors can induce cell cycle arrest or apoptosis in numerous solid cell lines [3, 8]. At present, epigenetic regulation of gene expression with HDAC inhibitors has been proposed as a novel anticancer treatment. A variety of HDAC inhibitors are under clinical development. Vorinostat is approved for the treatment of cutaneous T cell lymphoma (CTCL) in more than 20 countries including Japan and the USA [9, 10]. In the USA, romidepsin and belinostat are also approved, respectively, for the treatment of CTCL and/or peripheral T cell lymphoma (PTCL) [11–13]. Resminostat is an oral hydroxamate-type pan-inhibitor of class I and II HDAC enzymes [14] that inhibits HDAC by binding to a zinc ion in the catalytic domain of the enzyme [6, 9, 14, 15]. In vitro and in vivo studies, the antitumor activities were equal to or higher than those of currently approved HDAC inhibitors. A first-in-human, exploratory, open-label, interpatient dose escalation, single-center phase I study of resminostat was performed in UK [16], in which the drug was administered to patients with advanced solid tumors on a 14-day cycle consisting of once-daily administration on days 1–5 followed by a 9-day drug-free interval. Resminostat, when orally administered once daily at doses of 100–800 mg, was demonstrated to be safe and well tolerated. Since only one of seven patients received 800 mg, the highest dose level assessed, experienced combined dose-limiting toxicities (DLT), and the maximum tolerated dose (MTD) was not formally determined in this first-in-man study with resminostat. In the pharmacokinetic profile, resminostat showed dose-dependent increase in Cmax and AUC. It is more favorable than vorinostat. Subsequently, clinical studies were performed in EU, in which resminostat was administered as monotherapy to treat patients with relapsed or refractory Hodgkin’s lymphoma, in combination with sorafenib (Nexavar®) to treat patients with advanced hepatocellular carcinoma in second line after sorafenib failure and in combination with folinic acid, fluorouracil, and irinotecan (FOLFIRI regimen) to treat patients with colorectal cancer (CRC). The present study was designed to evaluate the safety and determine the recommended dose of resminostat administered alone in Japanese patients with advanced solid tumors, and to assess DLTs based on adverse drug reactions occurring in the first treatment cycle. Secondary objectives included evaluation of the pharmacokinetics, pharmacodynamics, and efficacy of resminostat monotherapy.
13
Cancer Chemother Pharmacol
Materials and methods Patient selection Inclusion criteria included adults aged 20–74 years with histologically or cytologically proven advanced solid tumors, for which standard treatments had failed or no standard treatment options were available, an Eastern Cooperative Oncology Group performance status of 0 or 1, adequate organ and bone marrow function, ability to swallow resminostat, and a life expectancy of ≥12 weeks. Despite no limitation on the number of prior chemotherapies, patients were required to have completed all the prior chemotherapy, radiation, endocrine, and immune therapies at least 4 weeks before study enrollment. Exclusion criteria included previous HDAC inhibitor treatment, persistence of acute toxicities from any prior therapy, active infection, a history of clinically significant allergy, brain tumors or brain metastases requiring treatment, significant cardiovascular diseases, QT prolongation syndrome, coexisting multiple carcinomas, and body cavity fluid requiring treatment. Patients who were considered by the investigators to be inappropriate for participating in the study were also excluded. This study was conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice guidelines. Approval from the independent institutional review board of the National Cancer Center (Tokyo, Japan) was acquired. All patients provided written informed consent. Study design This study was a single-center, open-label, phase I study that employed a standard 3 + 3 dose-escalation scheme. Since the previous first-in-man phase I study in Western populations [16] demonstrated that resminostat was well tolerated at a daily dose of up to 800 mg, the daily dose assessed in this study was initiated at 400 mg, escalating to 600 mg, and finally to 800 mg. Intrapatient dose escalation was not permitted. Resminostat was orally administered on a 14-day cycle consisting of once-daily administration on days 1–5 followed by a 9-day drug-free interval. Patients fasted for 2 h before and 1 h after administration. Treatment with resminostat was continued until disease progression or until discontinuation for any other reason. When any DLT was found in ≥2 of 3 patients or ≥3 of 6 patients within a dose level group, that dose level was defined as the MTD and the preceding dose level was determined as the recommended dose. If none of the three patients receiving 800 mg experienced any DLT, three patients were added and DLTs were assessed among six patients.
Cancer Chemother Pharmacol
Definition of DLT Dose-limiting toxicities (DLT) was defined as any of the following adverse drug reactions occurring in the first cycle: grade 4 thrombocytopenia, grade 4 neutropenia lasting >7 days, febrile neutropenia, grade 3 electrocardiogram prolonged QT-corrected interval, grade 4 aspartate aminotransferase (AST) increased or grade 3 AST increased lasting >7 days, grade 4 alanine aminotransferase (ALT) increased or grade 3 ALT increased lasting >7 days, and any other clinically significant grade ≥3 non-hematologic toxicity. Assessments Safety assessments included hematology testing, blood biochemistry testing, a blood coagulation test, troponin level assessment, urinalysis, physical examinations, vital signs, performance status, 12-lead electrocardiogram (ECG), and echocardiography. Adverse events were graded and reported according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Radiographic assessment was performed at 6 weeks after study enrollment, followed by every two treatment cycles. Tumor response was assessed by the investigators using Response Evaluation Criteria in
Table 1 Baseline patient characteristics
Solid Tumors (RECIST) version 1.1. Blood samples for pharmacokinetic assessment were collected on day 1 of the first cycle at pre-dose, and 1, 1.5, 2, 3, 4, 5, 6, and 24 h postdose, and on day 5 of the first and second cycles at pre-dose, and 1, 1.5, 2, 3, 4, 5, and 6 h post-dose. Plasma resminostat concentrations were determined using a validated high-performance liquid chromatography/tandem mass spectrometry method [16]. Blood samples for pharmacodynamic assessment were collected on day 1 of the first cycle at pre-dose, and 2, 5, and 24 h post-dose, and on day 5 of the first and second cycles at pre-dose, and 2 and 5 h post-dose, to isolate peripheral blood mononuclear cells (PBMCs). Acetylated histone H4 protein levels were determined by luminescence intensity using a Western blotting method as previously described [16].
Results Patients characteristics A total of 12 patients were enrolled in the study between May 2012 and March 2013. A median of two cycles (range 1–8) per patient was delivered. Patient characteristics at the study enrollment are summarized in Table 1.
Dose level
400 mg
600 mg
800 mg
Total (%)
N
3
3
6
12
0 3 61.0 (47–70)
4 2 65.5 (58–69)
5 (41.7) 7 (58.3) 62.5 (33–70)
Sex Male 1 Female 2 Median age (years) 54.0 (33–70) (range) ECOG PS 0 0 1 3 Diagnosis CRC 2 Pancreatic carcinoma 0 NSCLC 1 Others 0 Prior treatment (chemotherapy)
