PMID- 36270753 OWN - NLM STAT- MEDLINE DCOM- 20221027 LR - 20221115 IS - 2044-6055 (Electronic) IS - 2044-6055 (Linking) VI - 12 IP - 10 DP - 2022 Oct 21 TI - Safety, tolerability, pharmacokinetics and preliminary antitumour activity of an antisense oligonucleotide targeting STAT3 (danvatirsen) as monotherapy and in combination with durvalumab in Japanese patients with advanced solid malignancies: a phase 1 study. PG - e055718 LID - 10.1136/bmjopen-2021-055718 [doi] LID - e055718 AB - OBJECTIVES: We assessed the safety, tolerability, pharmacokinetics, preliminary antitumour activity and pharmacodynamics of danvatirsen, an antisense oligonucleotide targeting signal transducer and activator of transcription 3 (STAT3), monotherapy and danvatirsen plus durvalumab, an antiprogrammed cell death ligand 1 monoclonal antibody, in patients with advanced solid malignancies. DESIGN: Phase 1, open-label study with two cohorts. SETTING: Two centres in Japan. PARTICIPANTS: Japanese individuals aged >/=20 years, with histologically confirmed solid malignancies, except for hepatocellular carcinoma, refractory to standard therapy. INTERVENTIONS: In cohort 1, patients received danvatirsen monotherapy; in cohort 2, patients received danvatirsen plus durvalumab combination therapy. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary endpoint was safety and tolerability based on adverse events (AEs). Secondary endpoints were pharmacokinetics, immunogenicity, antitumour activity and pharmacodynamics. RESULTS: Eleven patients were assigned to treatment and included in the analysis. Danvatirsen dose reductions were only required in cohort 2 for hepatic function abnormal (alanine aminotransferase (ALT)/ aspartate aminotransferase (AST)/gamma-glutamyl transferase (gammaGT) increased), neutrophil count decreased and platelet count decreased. One patient experienced grade 3 ALT/AST increased and new appearance of eosinophilia as a dose-limiting toxicity. AEs were reported in 90.9% (10/11) patients. Commonly reported AEs causally related to the danvatirsen were platelet count decreased (60% (3/5)) and ALT/AST/gammaGT increased (50% (3/6)) in cohorts 1 and 2, respectively; none was causally related to durvalumab. One serious AE occurred in cohort 1 (pancreatitis; unrelated to study treatment). One case of ALT/AST/gammaGT increased occurred in cohort 2, leading to discontinuation. No AEs led to death. Danvatirsen did not accumulate in plasma after multiple dosing. In cohort 2, three patients had disease control at 12 weeks and one had unconfirmed partial response. STAT3 expression tended to decrease regardless of monotherapy or combination therapy. CONCLUSIONS: Danvatirsen was well tolerated by Japanese patients with advanced solid tumours as monotherapy and combined with durvalumab. No new safety signals arose. TRIAL REGISTRATION NUMBER: NCT03394144; ClinicalTrials.gov. CI - (c) Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. FAU - Nishina, Tomohiro AU - Nishina T AUID- ORCID: 0000-0002-4073-3757 AD - Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan. FAU - Fujita, Tomoko AU - Fujita T AUID- ORCID: 0000-0002-6629-6380 AD - Research & Development, AstraZeneca K.K, Osaka, Japan. FAU - Yoshizuka, Naoto AU - Yoshizuka N AUID- ORCID: 0000-0002-2798-2564 AD - Research & Development, AstraZeneca K.K, Osaka, Japan. FAU - Sugibayashi, Ko AU - Sugibayashi K AUID- ORCID: 0000-0003-0285-8054 AD - Research & Development, AstraZeneca K.K, Tokyo, Japan. FAU - Murayama, Kosho AU - Murayama K AUID- ORCID: 0000-0003-3301-9966 AD - Research & Development, AstraZeneca K.K, Osaka, Japan. FAU - Kuboki, Yasutoshi AU - Kuboki Y AUID- ORCID: 0000-0003-3675-953X AD - Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan ykuboki@east.ncc.go.jp. LA - eng SI - ClinicalTrials.gov/NCT03394144 PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20221021 PL - England TA - BMJ Open JT - BMJ open JID - 101552874 RN - EC 2.6.1.2 (Alanine Transaminase) RN - 0 (Antibodies, Monoclonal) RN - EC 2.6.1.1 (Aspartate Aminotransferases) RN - 31N550RD05 (danvatirsen) RN - 28X28X9OKV (durvalumab) RN - 0 (Oligonucleotides, Antisense) RN - 0 (STAT3 protein, human) RN - 0 (STAT3 Transcription Factor) SB - IM MH - Humans MH - Alanine Transaminase MH - Antibodies, Monoclonal/therapeutic use MH - *Antineoplastic Combined Chemotherapy Protocols/adverse effects MH - Aspartate Aminotransferases MH - Japan MH - *Neoplasms/drug therapy MH - *Oligonucleotides, Antisense/adverse effects/pharmacokinetics MH - STAT3 Transcription Factor PMC - PMC9594513 OTO - NOTNLM OT - clinical pharmacology OT - clinical trials OT - genetics OT - oncology COIS- Competing interests: TN has received grants from AstraZeneca K.K., during the conduct of the study; grants from Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., MSD K.K., Ono Pharmaceutical Co., Ltd., Bristol-Myers Squibb K.K., Eli Lilly Japan K.K., and Sumitomo Dainippon Pharma Co., Ltd., outside the submitted work. TF is an employee of, and reports stock ownership in, AstraZeneca K.K. NY is an employee of AstraZeneca K.K. KS is an employee of, and reports stock ownership in, AstraZeneca K.K. KM is an employee of, and reports stock ownership in, AstraZeneca K.K. YK has received grants and honoraria from Taiho Pharmaceutical Co., Ltd., and Ono Pharmaceutical Co., Ltd.; honoraria from Bayer Yakuhin, Ltd., Sanofi K.K., Eli Lilly Japan K.K., and Bristol-Myers Squibb K.K.; and grants from Takeda Pharmaceutical Co., Ltd., AstraZeneca K.K., Daiichi Sankyo Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Amgen K.K., Chugai Pharmaceutical Co., Ltd., AbbVie GK, and GlaxoSmithKline K.K., outside the submitted work. EDAT- 2022/10/22 06:00 MHDA- 2022/10/26 06:00 PMCR- 2022/10/11 CRDT- 2022/10/21 21:12 PHST- 2022/10/21 21:12 [entrez] PHST- 2022/10/22 06:00 [pubmed] PHST- 2022/10/26 06:00 [medline] PHST- 2022/10/11 00:00 [pmc-release] AID - bmjopen-2021-055718 [pii] AID - 10.1136/bmjopen-2021-055718 [doi] PST - epublish SO - BMJ Open. 2022 Oct 21;12(10):e055718. doi: 10.1136/bmjopen-2021-055718.