3620 - Safety, efficacy, PK and PD biomarker results of the first-in-human study of mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor BAY 1436032 in patients (pts) with mIDH1 advanced solid tumours

Background

BAY 1436032 (BAY) inhibits R132X-mIDH1, which aberrantly generates oncometabolite 2-hydroxyglutarate (2-HG). In animal studies, BAY decreased 2-HG levels in mIDH1 tumours and showed brain penetration (brain/plasma ratio ∼0.2). Plasma 2-HG levels are increased in pts with mIDH1 tumours like intrahepatic cholangiocarcinoma (IHCC), but not in mIDH1 gliomas.

Methods

In this ongoing phase I dose-escalation and expansion study, BAY was administered orally (150-1500 mg BID) to pts with advanced mIDH1-R132X solid tumours. 4 expansion cohorts (1500 mg BID) enrolled pts with anaplastic and advanced grade 2 gliomas, glioblastoma (GBM), IHCC and other tumours. Response was assessed by RECIST (solid tumours) and RANO criteria (gliomas). Plasma BAY and 2-HG levels were measured.

Results

29 pts were treated in the escalation part in 5 dose-escalation cohorts and 52 in the expansion part. Pts had glioma (n = 55), IHCC (n = 16), chondrosarcoma (n = 7) and other tumours (n = 3). As of the 8 Nov 2018 preliminary cut-off, the most common all-cause treatment-emergent AEs reported in ≥ 10% of pts were: headache (20%), vomiting, diarrhoea and fatigue (19% each), nausea (16%), ALT increased (12%) and blood bilirubin increased (11%). There was 1 DLT (grade 3 rash maculopapular, 1500 mg BID). MTD was not reached; RP2D was 1500 mg BID. BAY exposure increased broadly dose proportionally from 150-1200 mg, with high variability. Consistent with short half-life, no accumulation was observed. Plasma 2-HG reduction occurred in nearly all non-glioma pts, with up to 98% inhibition. A pt with anaplastic astrocytoma (AA) (1200 mg BID) achieved complete response and is still on treatment (>23 months at cut-off); 2 glioma pts (AA and oligodendroglioma, both 1500 mg BID) had a partial response. 6 additional pts remained on treatment with stable disease at cut-off (3 gliomas, 2 GBM, 1 IHCC; treatment duration 4-11 months). Updated safety, efficacy and PK/PD analyses will be presented.

Conclusions

BAY is well tolerated as anticipated due to specificity for mIDH1. BAY inhibited mIDH1-R132X activity as evidenced by a PD effect in pts with measurable 2-HG, with objective response in 3 pts (all gliomas).

Clinical trial identification

NCT02746081.

Editorial acknowledgement

Medical writing assistance was provided by Laura Valenzo, PhD, of Complete Health Vizion and funded by Bayer AG.

Legal entity responsible for the study

Bayer AG.

Funding

Bayer AG.

Disclosure

W. Wick: Non-remunerated activity/ies, patent: IDH vaccine; Non-remunerated activity/ies, patent: IDH diagnostic; Non-remunerated activity/ies, patent: APG diagnostic. G. Tabatabai: Research grant / Funding (self): Roche Diagnostics; Research grant / Funding (self): Medac; Travel / Accommodation / Expenses: BMS; Travel / Accommodation / Expenses: Novocure; Travel / Accommodation / Expenses: Medac; Speaker Bureau / Expert testimony: Medac; Speaker Bureau / Expert testimony: Novocure; Advisory / Consultancy: AbbVie; Advisory / Consultancy: BMS; Advisory / Consultancy: TIGER NIS (Novocure); Advisory / Consultancy: ON-TRK NIS (Bayer). M. Schuler: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche; Honoraria (self): Abbvie; Honoraria (self): Alexion; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Celgene; Honoraria (self): Lilly; Honoraria (self): MSD; Honoraria (self): Novartis; Honoraria (self): Pierre Fabre; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Bristol Myers-Squibb; Research grant / Funding (institution): Novartis. K. Rorhberg: Research grant / Funding (self), Non-remunerated activity/ies: Bayer; Research grant / Funding (self), Travel / Accommodation / Expenses, Non-remunerated activity/ies: Roche; Research grant / Funding (self), Non-remunerated activity/ies: Loxo Oncology; Research grant / Funding (self), Non-remunerated activity/ies: Orion Pharma; Research grant / Funding (self), Non-remunerated activity/ies: Pfizer; Research grant / Funding (self), Non-remunerated activity/ies: PUMA; Research grant / Funding (self), Non-remunerated activity/ies: Cantargia; Research grant / Funding (self), Non-remunerated activity/ies: Genmab; Research grant / Funding (self), Non-remunerated activity/ies: Novartis; Research grant / Funding (self), Non-remunerated activity/ies: Incyte; Research grant / Funding (self), Non-remunerated activity/ies: Symphogen; Research grant / Funding (self), Non-remunerated activity/ies: AstraZeneca; Research grant / Funding (self), Non-remunerated activity/ies: Alligator; Research grant / Funding (self), Non-remunerated activity/ies: Merck; Travel / Accommodation / Expenses: Sanofi; Research grant / Funding (self), Non-remunerated activity/ies: BMS. S.P. Chawla: Research grant / Funding (self): Amgen; Research grant / Funding (self): Roche; Research grant / Funding (self): Threshold Pharmaceuticals; Research grant / Funding (self): GlaxoSmithKline; Research grant / Funding (self): Immune Design; Research grant / Funding (self): TRACON Pharma; Research grant / Funding (self): SARC; Research grant / Funding (self): Karyopharma Therapeutics; Research grant / Funding (self): Jansen. F. Janku: Research grant / Funding (self): Novartis; Research grant / Funding (self): Genentech; Research grant / Funding (self): Bayer; Research grant / Funding (self): BioMed Valley Discoveries; Research grant / Funding (self): Astellas; Research grant / Funding (self): Agios; Research grant / Funding (self): Plexxikon; Research grant / Funding (self): Deciphera; Research grant / Funding (self): Piqur; Research grant / Funding (self): Symphogen; Research grant / Funding (self): Bristol-Myers Squibb; Research grant / Funding (self): Asana; Research grant / Funding (self): Upsher-Smith Laboratories; Advisory / Consultancy: Guardant Health; Advisory / Consultancy: IFM Therapeutics; Advisory / Consultancy: Synlogic; Advisory / Consultancy: Deciphera; Advisory / Consultancy: Trovagene; Advisory / Consultancy: Immunomet; Shareholder / Stockholder / Stock options: Trovagene. Y. Narita: Speaker Bureau / Expert testimony, Research grant / Funding (self): Chugai Pharmaceutical; Speaker Bureau / Expert testimony, Research grant / Funding (self): Ono Pharmaceutical; Speaker Bureau / Expert testimony, Research grant / Funding (self): Abbvie; Speaker Bureau / Expert testimony, Research grant / Funding (self): Dainippon-Sumitomo; Speaker Bureau / Expert testimony, Research grant / Funding (self): Daiichi-Sankyo; Speaker Bureau / Expert testimony, Research grant / Funding (self): Eisai; Speaker Bureau / Expert testimony, Research grant / Funding (self): Stella-pharma; Speaker Bureau / Expert testimony, Research grant / Funding (self): Ohtuka; Speaker Bureau / Expert testimony, Research grant / Funding (self): Meiji-seika; Speaker Bureau / Expert testimony, Research grant / Funding (self): SBI pharma. Y. Ando: Honoraria (self), Research grant / Funding (self): Chugai Pharmaceutical Co.,Ltd.; Honoraria (self), Research grant / Funding (self): Kyowa Hakko Kirin Co.,Ltd.; Honoraria (self), Research grant / Funding (self): Nippon Kayaku Co., Ltd.; Honoraria (self), Research grant / Funding (self): Yakult Honsha Co.,Ltd.; Honoraria (self), Research grant / Funding (self): Eli Lilly Japan K.K.; Honoraria (self), Research grant / Funding (self): Mochida Pharmaceutical Co.,Ltd.; Honoraria (self), Research grant / Funding (self): Ono Pharmaceutical Co.,Ltd.; Honoraria (self), Research grant / Funding (self): Taiho Pharmaceutical Co.,Ltd.; Honoraria (self): Novartis Pharma K.K.; Honoraria (self): Merck Serono Co.,Ltd.; Honoraria (self): Bayer Holding Ltd.; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Otsuka Holdings Co.,Ltd.; Honoraria (self): Sawai Pharmaceutical Co., Ltd; Honoraria (self), Research grant / Funding (self): Daiichi Sankyo Company, Ltd.; Research grant / Funding (self): Eisai Co.,Ltd.; Research grant / Funding (self): Hisamitsu Pharmaceutical Co., Inc.; Research grant / Funding (self): Takeda Pharmaceutical Co.,Ltd.; Honoraria (self): Tsumura & Co.; Honoraria (self): Shionogi & Co.,Ltd; Honoraria (self): Janssen Pharmaceutical K.K.; Honoraria (self): Pharma International Inc. H.J. Lenz: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck KG. M. Ikeda: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Eisai; Honoraria (self), Advisory / Consultancy: MSD; Research grant / Funding (self): Ono; Advisory / Consultancy, Research grant / Funding (self): ASLAN; Honoraria (self), Research grant / Funding (self): Yakult; Research grant / Funding (self): J-Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Eli Lilly; Honoraria (self), Research grant / Funding (self): Sumitomo Dainippon; Research grant / Funding (self): Kowa; Honoraria (self): Abbott; Honoraria (self): EA Pharma; Advisory / Consultancy, Research grant / Funding (self): Chugai; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Novartis; Honoraria (self), Advisory / Consultancy: Teijin Pharma; Advisory / Consultancy, Research grant / Funding (self): Kyowa Hakko Kirin; Advisory / Consultancy, Research grant / Funding (self): NanoCarrier; Advisory / Consultancy: Shire; Honoraria (self), Research grant / Funding (self): Taiho; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Baxalta; Research grant / Funding (self): Merck Serono; Advisory / Consultancy, Research grant / Funding (self): Takara Bio; Research grant / Funding (self): Zeria; Honoraria (self): Nobelpharma; Honoraria (self), Advisory / Consultancy: Otsuka; Honoraria (self): Kaken Pharmaceutical; Honoraria (self): Gilead; Advisory / Consultancy: Astellas Pharma; Research grant / Funding (self): Takeda Pharmaceutical; Advisory / Consultancy: Micron. I. Genvresse: Full / Part-time employment: Bayer AG. C. Rentzsch: Full / Part-time employment: Bayer AG. S. Reschke: Full / Part-time employment: Bayer AG. C. Cyris: Full / Part-time employment: CHRESTOS Concept GmbH & Co. KG. C. Cai: Full / Part-time employment: Bayer HealthCare Pharmaceuticals, Inc. M. Jeffers: Full / Part-time employment: Bayer HealthCare Pharmaceuticals, Inc. C. Peña: Full / Part-time employment: Bayer HealthCare Pharmaceuticals, Inc. O. Bähr: Honoraria (self): Novocure; Honoraria (self): Medac Pharma; Honoraria (self): BMS. All other authors have declared no conflicts of interest.