PMID- 30105668 OWN - NLM STAT- MEDLINE DCOM- 20200121 LR - 20221207 IS - 1573-0646 (Electronic) IS - 0167-6997 (Print) IS - 0167-6997 (Linking) VI - 37 IP - 1 DP - 2019 Feb TI - Phase 1 dose-escalation study of momelotinib, a Janus kinase 1/2 inhibitor, combined with gemcitabine and nab-paclitaxel in patients with previously untreated metastatic pancreatic ductal adenocarcinoma. PG - 159-165 LID - 10.1007/s10637-018-0650-5 [doi] AB - Purpose Preclinical evidence suggests the importance of Janus activating kinase (JAK) and TANK-binding kinase 1 (TBK1) in pancreatic ductal adenocarcinoma (PDAC). We evaluated the safety and efficacy of momelotinib (MMB), a JAK1/2 inhibitor with additional activity against TBK1, plus albumin-bound paclitaxel + gemcitabine (nab-P + G), in patients with previously untreated metastatic PDAC. Experimental Design Patients were enrolled into five cohorts of increasing doses of MMB between 100 and 200 mg administered once or twice daily in combination with nab-P + G in 28-day cycles to determine maximum tolerated dose (MTD). Safety, efficacy, pharmacokinetics, and pharmacodynamics were assessed for all patients. Results Twenty-five patients were enrolled. Dose-limiting toxicities of Grade 3 diarrhea occurred in 1 patient each in the 100 and 200 mg MMB once-daily dose groups. MTD was not reached. The 200 mg MMB twice-daily was the maximum administered dose. Objective response rate was 28% (all partial responses), and 13 (52%) patients had a best response of stable disease. The most common adverse events (AEs) were fatigue (80%), nausea (76%), and anemia (68%). Grade 3 or 4 AEs, most commonly neutropenia (32%), were reported by 88% of patients, of which 44% were considered related to MMB. Pharmacokinetic analyses showed MMB concentrations were too low for TBK1 inhibition. Conclusions MMB was safe and well tolerated in combination with nab-P + G. As no OS or PFS benefit vs nab-P + G was apparent in context of suboptimal engagement of the target TBK1, this study does not support further development of MMB as a first-line therapy in pancreatic cancer. FAU - Ng, Kimmie AU - Ng K AD - Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. Kimmie_Ng@DFCI.HARVARD.EDU. FAU - Hendifar, Andrew AU - Hendifar A AD - Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA. FAU - Starodub, Alexander AU - Starodub A AD - Parkview Physicians Group Medical Oncology, Fort Wayne, IN, USA. FAU - Chaves, Jorge AU - Chaves J AD - Northwest Medical Specialties, Tacoma, WA, USA. FAU - Yang, Yingsi AU - Yang Y AD - Gilead Sciences, Foster City, CA, USA. FAU - Koh, Brian AU - Koh B AD - Gilead Sciences, Foster City, CA, USA. FAU - Barbie, David AU - Barbie D AD - Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. FAU - Hahn, William C AU - Hahn WC AD - Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. FAU - Fuchs, Charles S AU - Fuchs CS AD - Yale Cancer Center/Smilow Cancer Hospital, New Haven, CT, USA. LA - eng GR - R01 CA118553/CA/NCI NIH HHS/United States GR - R01 CA169141/CA/NCI NIH HHS/United States GR - P50 CA127003/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20180730 PL - United States TA - Invest New Drugs JT - Investigational new drugs JID - 8309330 RN - 0 (130-nm albumin-bound paclitaxel) RN - 0 (Albumins) RN - 0 (Benzamides) RN - 0 (Pyrimidines) RN - 0W860991D6 (Deoxycytidine) RN - 6O01GMS00P (N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide) RN - EC 2.7.10.2 (JAK1 protein, human) RN - EC 2.7.10.2 (JAK2 protein, human) RN - EC 2.7.10.2 (Janus Kinase 1) RN - EC 2.7.10.2 (Janus Kinase 2) RN - P88XT4IS4D (Paclitaxel) RN - 0 (Gemcitabine) SB - IM MH - Albumins/administration & dosage MH - Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics/*therapeutic use MH - Benzamides/administration & dosage MH - Carcinoma, Pancreatic Ductal/*drug therapy/enzymology/secondary MH - Deoxycytidine/administration & dosage/analogs & derivatives MH - Female MH - Follow-Up Studies MH - Humans MH - Janus Kinase 1/*antagonists & inhibitors MH - Janus Kinase 2/*antagonists & inhibitors MH - Male MH - Maximum Tolerated Dose MH - Middle Aged MH - Paclitaxel/administration & dosage MH - Pancreatic Neoplasms/*drug therapy/enzymology/pathology MH - Prognosis MH - Pyrimidines/administration & dosage MH - Tissue Distribution MH - Gemcitabine PMC - PMC6510909 OTO - NOTNLM OT - JAK inhibitor OT - Momelotinib OT - Phase 1 OT - TBK1 inhibitor COIS- CONFLICTS OF INTEREST: KN: research funding from Gilead, Genentech, Tarrex, and Pharmavite, and advisory board for Bayer. AH: consultant/advisory role for Genentech, Ipsen, Novartis, Perthera. JC: None. AS: consulting/advisory role for Sandoz, Bayer, and speakers bureau for BMS. YY: employee of Gilead Sciences, Inc. BK: employee of Gilead Sciences, Inc. DB: consultant for N of One. WCH: None. CSF: consultant for Eli Lilly, Entrinsic Health, Genentech, Merck, Sanofi, Five Prime Therapeutics, Merrimack, Bayer, Agios, Taiho, Kew, Bain Capital, Unum, and board member for CytomX. ETHICAL APPROVAL: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. INFORMED CONSENT: Informed consent was obtained from all individual participants included in the study. EDAT- 2018/08/15 06:00 MHDA- 2020/01/22 06:00 PMCR- 2018/07/30 CRDT- 2018/08/15 06:00 PHST- 2018/07/06 00:00 [received] PHST- 2018/07/20 00:00 [accepted] PHST- 2018/08/15 06:00 [pubmed] PHST- 2020/01/22 06:00 [medline] PHST- 2018/08/15 06:00 [entrez] PHST- 2018/07/30 00:00 [pmc-release] AID - 10.1007/s10637-018-0650-5 [pii] AID - 650 [pii] AID - 10.1007/s10637-018-0650-5 [doi] PST - ppublish SO - Invest New Drugs. 2019 Feb;37(1):159-165. doi: 10.1007/s10637-018-0650-5. Epub 2018 Jul 30.