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References: 1: Slusarczyk; et al. J Med Chem2014; 57:1531-1542. 2: Blagden et al Br J Cancer 2018; 119:815-822. 3: Blagden et al Cancer Res 2016; 76: Suppl abstr 2514. 4: McNamara et al Ann Oncol 2018; 29 :Suppl 8 Abstract ID: TPS544. 5: Valle et al. N Engl J Med 2010; 362:1273-1281. DBD: Distal bile duct IHC: Intrahepatic cholangiocarcinoma Hilar: Hilar cholangiocarcinoma GB: Gallbladder Amp: Ampullary Anti-cancer activity in patients with advanced ovarian and biliary tract cancers treated with NUC-1031 and platinum agents SP Blagden 1 , J Bré 2 , P Mullen 2 , C Gnanaranjan 3 , EA Ghazaly 3 , MG McNamara 4,5 , JW Valle 4,5 1) University of Oxford, Oxford, UK 2) School of Medicine, University of St Andrews, St Andrews, UK 3) Barts Cancer Institute, London, UK 4) Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK 5) University of Manchester, Division of Cancer Sciences, Manchester, UK Copies of this poster obtained through Quick Response (QR) Code are for personal use only and may not be reproduced without permission from ASCO® and the author of this poster. PRO-002 data current as of Sept 1 2017. Data cleaning ongoing. ABC-08 data current as of Aug 30 2018. Data cleaning ongoing. Objective response rates Background • Nucleoside analogs and platinum agents remain cornerstone therapies for many solid malignancies • Resistance to chemotherapy reduces patient survival • Patients with advanced biliary tract cancer (BTC) or recurrent ovarian cancer (OC) have limited treatment options • Effective new agents and rational combinations are required ProTides: NucleoTide Analogs • A new class of anti-cancer agents • Transformative phosphoramidate chemistry • Increased intracellular levels of active anti-cancer metabolites • Potential for broad clinical utility NUC-1031: The First Anti-Cancer ProTide • ProTide transformation of gemcitabine • Overcomes key gemcitabine resistance mechanisms associated with a poor survival prognosis 1 • Cellular uptake independent of nucleoside transporters (hENT1) • Activation independent of deoxycytidine kinase (dCK) • Protected from breakdown by cytidine deaminase (CDA) • Increased intracellular generation of the active anti-cancer metabolite, dFdCTP: 217 greater than gemcitabine 2 Ovarian Cancer: NUC-1031 + Carboplatin (PRO-002 study) 3 Biliary Tract Cancer: NUC-1031 + Cisplatin (ABC-08 study) 4 Phase Ib study of NUC-1031 (500-750 mg/m 2 ) + carboplatin (AUC 4 or 5) in 25 patients with recurrent OC who had exhausted all therapeutic options • Heavily pre-treated population (median 3 prior chemotherapy lines; range: 2-6) • 23 patients evaluable for response (received ≥1 cycle): • 7 platinum-refractory • 10 platinum-resistant • 4 partially platinum-sensitive • 2 platinum-sensitive • High levels of disease control across all platinum status subgroups • Combination is well-tolerated over multiple cycles • Intention-to-treat (ITT) population: 14 patients • Evaluable population: 11 patients (completed ≥1 cycle) • Promising ORR compared to standard of care (gemcitabine + cisplatin) • Responses achieved in all BTC subtypes • Durable tumor shrinkage • Combination is well-tolerated over multiple cycles Phase Ib study of NUC-1031 (625 or 725 mg/m 2 ) + cisplatin (25 mg/m 2 ) as first-line therapy in patients with advanced BTC dCK CDA TRANSPORTER hENT1 DEPROTECTION NUC-1031 overcomes the key cancer resistance mechanisms of gemcitabine Treatment duration and best overall response by BTC anatomic site of origin (Efficacy Evaluable Population, n=11) Best overall response A confirmatory scan was not performed in all responders Platinum status as of last platinum-containing regimen All evaluable patients (n=23) Platinum-refractory patients (n=7) Platinum-resistant patients (n=10) Platinum-partially sensitive patients (n=4) CR PR ORR SD DCR 1 (4%) 8 (35%) 9 (39%) 1 (14%) 13 (57%) 22 (96%) 1 (14%) 5 (71%) 0 6 (86%) 0 4 (40%) 4 (40%) 6 (60%) 10 (100%) 0 2 (50%) 2 (50%) 2 (50%) 4 (100%) Platinum-sensitive patients (n=2) 1 (50%) 1 (50%) 2 (100%) 0 2 (100%) Percentage change in tumor measurement RECIST-defined % change in tumor measurement -100 # Platinum status as of last platinum-containing regimen -80 -60 -40 -20 0 20 40 1 2 2 2 1 1 2 2 3 3 3 1 1 1 1 2 2 2 2 2 3 4 4 Refractory (7) Resistant (10) Partially-sensitive (4) Sensitive (2) 1 2 3 4 Platinum Status # • NUC-1031 and platinum agents induce cancer cell death through a variety of different mechanisms • Platinum forms DNA adducts • Activates DNA damage response • Attempted repair by removal of adducts and synthesis of new DNA strands • Anti-cancer metabolite (dFdCTP) incorporated into DNA leading to cell death • These mechanisms may be complementary in causing irreversible DNA damage • Hypothesis: Platinum treatment primes or sensitizes cancer cells to further damage with NUC-1031 • This synergy is proposed to exist in both platinum-sensitive and platinum-resistant tumors Abstract Number: 3030 Registry Number: NCT02303912 NCT0235176 Email: sarah.blagden@ oncology.ox.ac.uk Summary • High response rates achieved in difficult to treat patient populations • 39% ORR in recurrent OC • 50% ORR in advanced BTC • NUC-1031 + platinum agents are well tolerated over multiple cycles • Clinical observations coupled with known mechanisms of action support hypothesis that NUC-1031 is synergistic with platinum agents • Future clinical studies will explore platinum combinations in: • Recurrent OC (Phase II/III planned) • Advanced BTC (Phase III, NuTide:121, to open in 2019) Complete Response ITT Evaluable Note: Responses unconfirmed in ABC-08 and ABC-02 Partial Response Objective Response Rate ABC-08 NUC-1031 + cisplatin ABC-02 5 gemcitabine + cisplatin 7% (1/14) 43% (6/14) 50% (7/14) 0.6% (1/161) 25.5% (41/161) 26.1% (42/161) 114+ wks 131+ wks 0 12 24 36 48 Weeks Complete Response Partial Response Stable Disease Progressive Disease Off Treatment 2nd Line Treatment Alive at last follow-up 60 72 78 F (IHC) Radiological pneumonitis Small bowel perforation Suitable for resection Reduced performance status Patient request Progressive disease Consent withdrawn Blocked biliary stent Liver cirrhosis 55 M (DBD) 48 M (Hilar) 63 M (Hilar) 71 M (Hilar) 60 M (IHC) 60 M (Amp) 61 M (Amp) 70 F (GB) 48 F (Hilar) 120 132 625 mg/m 2 625 mg/m 2 625 mg/m 2 625 mg/m 2 625 mg/m 2 625 mg/m 2 725 mg/m 2 725 mg/m 2 Progressive disease 59 F (DBD) 725 mg/m 2 725 mg/m 2 725 mg/m 2 Potential Mechanism of NUC-1031 + Platinum Synergy DNA repair in presence of NUC-1031 Adenine Thymine Cytosine Guanine DNA Repair Proteins PLATINUM DNA Platinum Cross-linking DNA Damage Cell Death Incorporation of NUC-1031 into DNA Nucleotide Excision Repair Homologous Recombination Platinum-sensitive Single strand break Double strand break Inter-strand cross-linking Platinum-sensitive Platinum-resistant Platinum-resistant Intra-strand cross-linking Platinum-resistant Platinum-sensitive Platinum Platinum
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