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Poster Display session 1

2537 - Evaluation of Pharmacodynamic (PD) Biomarkers in Advanced Cancer Patients Treated with Oxidative Phosphorylation (OXPHOS) Inhibitor, OPC-317 (OPC)

Date

28 Sep 2019

Session

Poster Display session 1

Topics

Clinical Research

Tumour Site

Presenters

Jie Qing Eu

Citation

Annals of Oncology (2019) 30 (suppl_5): v159-v193. 10.1093/annonc/mdz244

Authors

J.Q. Eu1, K. Yadav1, Y. Lim2, J. Hirpara1, L.R. Kong1, Z.C. Ng3, V.K. Lee4, S.C. Lee3, D.S. Tan5, R.A. Soo6, C.E. Chee3, W.P. Yong3, R. Sundar3, J.S. Lim3, L. Wang1, N. Ohi7, T. Tsunoda8, S. Pervaiz2, B. Goh3, A.L. Wong3

Author affiliations

  • 1 Cancer Science Institute, National University of Singapore, 117599 - Singapore/SG
  • 2 Physiology, National University of Singapore, 117593 - Singapore/SG
  • 3 Haematology-oncology, National University of Singapore, 119228 - Singapore/SG
  • 4 Pathology, National University of Singapore, 119077 - Singapore/SG
  • 5 Haematology-oncology, National University Cancer Institute, Singapore (NCIS), 119228 - Singapore/SG
  • 6 Haematology-oncology, National University Cancer Institute Singapore (NCIS), 119074 - Singapore/SG
  • 7 Fujii Memorial Research Institute, Otsuka Pharmaceutical Co. Ltd., 520-0106 - Shiga/JP
  • 8 Otsuka Pharmaceutical Co. Ltd, Otsuka Pharmaceutical Co. Ltd, 1018535 - Tokyo/JP

Resources

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Abstract 2537

Background

We reported that metabolic reprogramming towards OXPHOS-induced drug resistance in oncogene-addicted tumors. OXPHOS is an attractive drug target but clinical PD markers of OXPHOS inhibition are lacking. We present interim PD biomarker data from a dose-finding/phase IIa study of OPC in an advanced cancer population enriched for molecular pathway-driven tumors.

Methods

After the dose-finding phase of OPC monotherapy at 3 levels (600mg, 400mg, 300mg), the study is now enrolling HER2+ breast cancer, EGFR+ NSCLC and c-KIT+ GIST patients to receive OPC 300mg, 3x/week, 21 days, in combination with their respective pathway inhibitors. Baseline (BL) and C1D15 tumor biopsies were analysed for mitochondrial DNA (mtDNA) copy number [qPCR] and immunohistochemistry (IHC) markers of mitochondrial biogenesis/OXPHOS [PGC1α, TFAM, SIRT1] and cancer stem cells [ALDH1A2]. Blood collected on days 1, 4/5 and 11/12 was analysed by flow cytometry of PBMCs for mitochondrial membrane potential (MMP) and serum metabolomics of amino/organic acids by LC-MS/GC-MS.

Results

13 patients (8 with molecular pathway-activated cancers) have been enrolled so far; 5 had evaluable paired biopsies. There were no G3/4 toxicities at the 300mg dose level (n = 8). Tumor mtDNA copy number declined significantly with treatment (-45.0 + 6.0%, C1D15 vs BL, p = 0.006). The expected decrease in IHC expression of ALDH1A2, TFAM, PGC1α (C1D15 vs BL) occurred in 80% (4/5), 60% (3/5) and 40% (2/5), respectively; expected rebound increase in SIRT1 expression was seen in 80% (4/5). Serum metabolomics (C1D4 vs BL) showed significant increase in TCA intermediates, citrate (+18.7 + 14.2%, p = 0.004) and fumarate (+29.7 + 37.1%, p = 0.043), indicative of NADH accumulation following OXPHOS inhibition. There was a non-significant rise in serum lactate (+17.2+ 27.1%, p = 0.094) and reduction in PBMC MMP [0.71 + 0.67 vs 0.29 + 0.23, BL vs C1D11/12, p = 0.068] (n = 11).

Conclusions

We identified novel tumor/blood PD biomarkers with clear evidence of target modulatory effects at clinically tolerable doses of OPC. With validation, they can aid the clinical development of OXPHOS inhibitors as a novel class of cancer therapy.

Clinical trial identification

NCT03158324.

Editorial acknowledgement

Legal entity responsible for the study

Otsuka Pharmaceutical Co. Ltd.

Funding

Otsuka Pharmaceutical Co. Ltd.

Disclosure

D.S. Tan: Honoraria (self): Roche; Honoraria (self), Research grant / Funding (institution): Bayer; Honoraria (self): MSD; Honoraria (self): Genmab; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self): Merck Serono; Honoraria (self): Tessa Therapeutics; Honoraria (self): Novartis; Research grant / Funding (self): Karyopharm. R. Sundar: Honoraria (self): MSD; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self): Lilly; Advisory / Consultancy: Eisai; Research grant / Funding (self): Paxman; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Taiho Pharmaceutical. J.S. Lim: Advisory / Consultancy: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Research grant / Funding (institution): Synthon; Travel / Accommodation / Expenses: AstraZeneca. N. Ohi: Full / Part-time employment: Fujii Memorial Research Institute, Otsuka Pharmaceutical Co. Ltd., Shiga, Japan. T. Tsunoda: Full / Part-time employment: Otsuka Pharmaceutical Co. Ltd., Tokyo, Japan. B. Goh: Research grant / Funding (institution): Otsuka Pharmaceutical Co. Ltd. A.L. Wong: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy: Novartis; Travel / Accommodation / Expenses: Eisai; Research grant / Funding (institution): Otsuka Pharmaceutical Co Ltd. All other authors have declared no conflicts of interest.

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