Acelarin (fosgemcitabine palabenamide) / NuCana - LARVOL DELTA

Design, synthesis, and anti-cancer evaluation of the novel conjugate of gemcitabine's ProTide prodrug based on CD13. (PubMed, Bioorg Chem) - "In this study, we designed and synthesized a novel series of bestatin-gemcitabine's ProTide prodrug conjugates aimed at enhancing the antitumor efficacy of NUC1031. 5f demonstrates significant in vivo anti-tumor activity in 22Rv1 xenograft tumor models. Our findings indicate that 5f shows strong potential for further development as a candidate for the treatment of prostate cancer."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • ANPEP

A phase III randomised study of first-line NUC-1031/cisplatin vs. gemcitabine/cisplatin in advanced biliary tract cancer. (PubMed, J Hepatol) - P3 | "NuTide:121 was terminated early due to futility. NUC-1031/cisplatin did not set a new standard in first-line aBTC."

Clinical • Journal • P3 data • Ampulla of Vater Carcinoma • Biliary Cancer • Biliary Tract Cancer • Cholangiocarcinoma • Hematological Disorders • Hepatology • Liver Failure • Oncology • Solid Tumor

Defining the mode of action of cisplatin combined with NUC-1031, a phosphoramidate modification of gemcitabine. (PubMed, Transl Oncol) - "The damage associated with NUC-1031 may be potentiated by a second mechanism, via binding the RRM1 subunit of ribonucleotide reductase and perturbing the nucleotide pools; however, this may be mitigated by increased RRM1 expression. The implication of this was investigated in case studies from a Phase I clinical trial to observe whether baseline RRM1 expression in tumour tissue at time of diagnosis correlates with patient survival."

Journal • Biliary Cancer • Biliary Tract Cancer • Gastrointestinal Cancer • Oncology • Ovarian Cancer • Solid Tumor • RRM1

Characterization of Chemical Interactions between Clinical Drugs and the Oral Bacterium, Corynebacterium matruchotii, via Bioactivity-HiTES. (PubMed, ACS Chem Biol) - "As a result, we identified two cryptic metabolites, methylindole-3-acetate (MIAA) and indole-3-acetic acid (IAA), elicited by imidafenacin, a urinary antispasmodic drug approved by the Japanese Pharmaceuticals and Medical Devices Agency (PMDA)...Unexpectedly, we also found that C. matruchotii metabolized fludarabine phosphate, a USFDA-approved anticancer drug, to 2-fluoroadenine which displayed moderate antibacterial activity against both Bacillus subtilis and Escherichia coli, with IC50 values of 8.9 and 20.1 μM, respectively. Finally, acelarin, a prodrug of the anticancer drug gemcitabine, was found to exhibit unreported antibacterial activity against B. subtilis with an IC50 value of 33.6 μM through the bioactivity-HiTES method as well. These results indicate that bioactivity-HiTES can also be applied to discover biotransformed products in addition to finding cryptic metabolites in microbes."

Journal • Oncology • Pulmonary Disease • Respiratory Diseases

Phase III study of NUC-1031 + cisplatin vs gemcitabine + cisplatin for first-line treatment of patients with advanced biliary tract cancer (NuTide:121) (ESMO-GI 2023) - P3 | "At the dose and schedule utilised for NUC-1031 in this study, the primary endpoint was not met with a longer OS with GemCis, despite a higher ORR with NUC-1031+cis. NUC-1031+cis was associated with more liver-related TEAEs, leading to early discontinuation. While these early liver events were more frequent in NUC-1031+cis, they were observed in both arms and are likely a combination of drug-induced liver toxicity, disease progression, and underlying liver dysfunction in this patient population."

Clinical • Metastases • P3 data • Ampulla of Vater Carcinoma • Biliary Cancer • Biliary Tract Cancer • Cholangiocarcinoma • Gallbladder Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

NUC-1031 + cisplatin clearly reduces survival time compared to gemcitabine + cisplatin in first-line treatment of advanced biliary tract cancer [WCGC 2023] [Google translation] (Nikkei) - P3 | N=773 | NuTide:121 (NCT04163900) | Sponsor: NuCana plc | "As a first-line treatment for locally advanced or metastatic biliary tract cancer, the combination of NUC-1031 (fosgemcitabine palabenamide), a gemcitabine derivative, and cisplatin was associated with better overall survival (OS) and no survival compared to gemcitabine plus cisplatin....The median OS was 9.2 months in the NUC-1031 group and 12.3 months in the gemcitabine group, which was significantly shorter in the NUC-1031 group with a hazard ratio of 1.79 and p<0.001. The Kaplan-Meier curves of both groups diverged early. Median PFS was 4.9 months in the NUC-1031 group and 6.4 months in the gemcitabine group."

P3 data • Biliary Tract Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor

"吉西他滨+顺铂联合化疗是晚期胆道癌的经典治疗。这个研究评估了“改良版”的吉西他滨（NUC-1031）能不能提高疗效。但可惜的是，研究做下来使用NUC-1031替换吉西他滨，疗效还不如经典的化疗方案。 #WCGIC2023" (@whyeszhu)

Gastrointestinal Cancer

PRO-105, a phase II open-label study of NUC-1031 in patients with platinum-resistant ovarian cancer. (ASCO 2018) - P2; "NUC-1031, a phosphoramidate transformation of gemcitabine, is designed to overcome the three key resistance mechanisms associated with gemcitabine: transport, activation and breakdown. Enrollment will continue in Part II until 44 response evaluable patients are recruited at the selected dose. To date, 22 patients with platinum-resistant ovarian cancer have been randomized into Part I of the study, which is currently recruiting across 15 US and 8 UK sites."

BRCA Biomarker • Clinical • P2 data • Ovarian Cancer

ACELARATE: A phase III, open label, multicentre randomised clinical study comparing Acelarin (NUC-1031) with gemcitabine in patients with metastatic pancreatic carcinoma. (ASCO-GI 2018) - "Secondary outcome measures include Progression Free Survival, Response Rate, Disease Control Rate and Toxicity. Translational research will explore the use of biomarkers for predictive benefit of Acelarin over gemcitabine."

Clinical • P3 data • Ovarian Cancer • Pancreatic Cancer

PRO-002, a phase Ib dose-escalation study of NUC-1031 with carboplatin for recurrent ovarian cancer (ESMO 2017) - P1b; "All had received prior platinum regimens (10 had prior carboplatin + gemcitabine). NUC-1031 combined with carboplatin is well tolerated and effective in recurrent platinum resistant and sensitive OC. dFdCTP levels were increased 25% by the addition of carboplatin. The RP2D was 500 mg/m2 NUC-1031 on days 1 & 8 with AUC5 carboplatin day 1, q21d."

Adverse events • Clinical • P1 data • Hepatocellular Cancer • Ovarian Cancer

Design, Synthesis, and Anti-Cancer Evaluation of Novel Cyclic Phosphate Prodrug of Gemcitabine. (PubMed, J Med Chem) - "Cyclic phosphate ester derivative 18c exhibits much higher anti-proliferative activity than positive control NUC-1031 with ICs of 3.6-19.2 nM on multiple cancer cells...18c displays significant in vivo anti-tumor activity in both 22Rv1 and BxPC-3 xenograft tumor models. These results suggest that compound 18c is a promising anti-tumor candidate for treating human castration-resistant prostate and pancreatic cancer."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor

CD44-targeting hydrophobic phosphorylated gemcitabine prodrug nanotherapeutics augment lung cancer therapy. (PubMed, Acta Biomater) - "Here, we report on CD44-targeting GEM nanotherapeutics obtained by encapsulating hydrophobic phosphorylated GEM prodrug (HPG), a single isomer of NUC-1031, into A6 peptide-functionalized disulfide-crosslinked micelles (A6-mHPG). A6-mHPG demonstrates stability against degradation, enhanced internalization and inhibition toward CD44 cells, and increased accumulation in A549 lung tumor xenografts, leading to potent repression of orthotopic tumor growth, depleted toxicity and marked survival benefits. The targeted delivery of GEM prodrug using A6-mHPG is a highly appealing strategy to GEM cancer therapy."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD44

NuTide:121: Comparing NUC-1031 Plus Cisplatin to Gemcitabine Plus Cisplatin in Patients With Advanced Biliary Tract Cancer (clinicaltrials.gov) - P3 | N=775 | Terminated | Sponsor: NuCana plc | Trial completion date: Dec 2023 ➔ Mar 2022 | Recruiting ➔ Terminated | Trial primary completion date: Dec 2023 ➔ Mar 2022; A pre-planned futility analysis concluded that NUC-1031 plus cisplatin was unlikely to achieve its primary objective of improving overall survival. Based on the IDMC's recommendation, NuCana has closed the study.

Trial completion date • Trial primary completion date • Trial termination • Biliary Cancer • Biliary Tract Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

NuCana Reports Third Quarter 2021 Financial Results and Provides Business Update (GlobeNewswire) - "Anticipated Milestones: Q4 2021 & H1 2022: Acelarin (a ProTide transformation of gemcitabine): In the first half of 2022, NuCana expects to: Announce whether the overall response rate objective for the first interim data from the Phase III study of Acelarin combined with cisplatin as a first-line treatment for patients with advanced biliary tract cancer has been met, which may allow for accelerated approval of an NDA submission in the United States; NUC-7738 (a ProTide transformation of 3’-deoxyadenosine): In Q4 2021, NuCana expects to: Initiate the Phase II study of NUC-7738 in patients with solid tumors; In the first half of 2022, NuCana expects to: Report data from the Phase II study of NUC-7738 in patients with solid tumors."

New P2 trial • P2 data • P3 data • Biliary Tract Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor

NuCana Receives Fast Track Designation from the U.S. Food and Drug Administration for Acelarin (NUC-1031) for the Treatment of Biliary Tract Cancer (GlobeNewswire) - "NuCana plc...announced that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to Acelarin (NUC-1031), currently being evaluated in a Phase III study (NuTide:121) for the first-line treatment of patients with advanced biliary tract cancer."

Fast track designation • Biliary Tract Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology

[VIRTUAL] Phase III study of NUC-1031 + cisplatin vs gemcitabine + cisplatin for first-line treatment of patients with advanced biliary tract cancer (NuTide:121) (ESMO 2021) - P3 | "In addition to the final analysis, three interim analyses are planned. NuTide:121 is being conducted at approximately 125 sites across North America, Europe and Asia Pacific."

Clinical • P3 data • Ampulla of Vater Carcinoma • Biliary Cancer • Biliary Tract Cancer • Cholangiocarcinoma • Gallbladder Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

NUC-1031 in combination with cisplatin for first-line treatment of patients with advanced biliary tract cancer (NuTide:121). (ASCO-GI 2020) - P3; "Although gemcitabine + cisplatin (GemCis) is accepted as the global standard of care (SoC) for 1st-line treatment, the reported unconfirmed ORR and OS from randomized studies of this combination are low at 18.5-26.1% and 11.2-11.7 months, respectively. Clinical trial information: NCT04163900. Research Funding: NuCana"

Clinical • Combination therapy

NUC-1031 in combination with cisplatin for first-line treatment of advanced biliary tract cancer. (ASCO 2019) - P1; "Background: Cisplatin and gemcitabine (CisGem) is the global standard of care for 1st-line treatment of patients (pts) with advanced biliary tract cancer (BTC). The study will be conducted at approximately 120 sites across North America, Europe and Asia Pacific countries. Clinical trial information: NCT02351765"

Clinical • Combination therapy

[VIRTUAL] Global phase III study of NUC-1031 plus cisplatin vs gemcitabine plus cisplatin for first-line treatment of patients with advanced biliary tract cancer (NuTide:121) (ESMO 2020) - P3 | "Funding: NuCana plc. Clinical trial identification: NCT04163900."

Clinical • P3 data • Biliary Cancer • Biliary Tract Cancer • Cholangiocarcinoma • Gallbladder Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

ACELARATE – A randomised Phase III, open label, clinical study comparing NUC-1031 with gemcitabine in patients with metastatic pancreatic carcinoma (ESMO 2018) - "Secondary outcome measures include progression free survival, objective response rate, disease control rate, quality of life and safety. Translational research will explore the use of biomarkers for predictive benefit of NUC-1031 over gemcitabine."

Clinical • P3 data • Pancreatic Cancer

A new ProTide, NUC-1031, combined with cisplatin for the first-line treatment of advanced biliary tract cancer (ABC-08) (ESMO 2018) - P1; "NCT02351765.;Background: Cisplatin + gemcitabine (cis/gem) is the global standard of care for 1st-line treatment of patients (pts) with locally advanced/metastatic biliary tract cancer (BTC). NUC-1031 + cisplatin demonstrated a very high ORR, with a favourable safety profile, and may provide an improved treatment option over cis/gem for advanced BTC. Further development of NUC-1031 in BTC is planned."

Clinical • Biliary Cancer

[VIRTUAL] Phase III study of NUC-1031 + cisplatin versus gemcitabine + cisplatin for first-line treatment of patients with advanced biliary tract cancer (NuTide:121). (ASCO 2021) - P3 | "The study has passed an initial safety analysis, with no protocol changes required . NuTide:121 is being conducted at approximately 130 sites across North America, Europe and Asia Pacific."

Clinical • P3 data • Ampulla of Vater Carcinoma • Biliary Cancer • Biliary Tract Cancer • Cholangiocarcinoma • Gallbladder Cancer • Gastrointestinal Cancer • Hepatology • Oncology • Solid Tumor

Anticancer activity in patients with advanced ovarian and biliary tract cancers treated with NUC-1031 and a platinum agent. (ASCO 2019) - "...NUC-1031, a phosphoramidate transformation of gemcitabine is designed to overcome resistance mechanisms that limit the efficacy of this nucleoside analog...NUC-1031 + carboplatin was well-tolerated with no unexpected AEs; DLTs were myelosuppression and fatigue...NUC-1031 + cisplatin was well-tolerated, with no unexpected AEs or DLTs... Increasing evidence suggests that NUC-1031 in combination with a platinum agent may have synergistic properties, leading to enhanced anti-cancer activity. In both OC and BTC, durable tumor shrinkage was observed. This was particularly encouraging in a platinum resistant/refractory OC population."

Clinical

ABC-08: A phase Ib, multi-centre, open-label study of a first-in-class nucleotide analogue NUC-1031 in combination with cisplatin in patients with locally advanced/metastatic biliary tract cancers. (ASCO-GI 2018) - P1; "The UK ABC-02 study established cisplatin and gemcitabine as the reference regimen for first-line treatment of patients (pts) with advanced biliary tract cancers (BTCs) (median overall survival (OS): 11.7 months). Cohort 1 has been completed without dose-limiting toxicities. Enrolment to cohort 2 is on-going."

Clinical • Combination therapy • P1 data • Biliary Cancer • Urothelial Cancer

[VIRTUAL] Phase III study of NUC-1031 + cisplatin vs gemcitabine + cisplatin for first-line treatment of patients with advanced biliary tract cancer (NuTide:121). (ASCO-GI 2021) - "The study has passed an initial safety analysis, with no protocol changes required. NuTide:121 is being conducted at approximately 130 sites across North America, Europe and Asia Pacific countries."

Clinical • P3 data • Ampulla of Vater Carcinoma • Biliary Cancer • Biliary Tract Cancer • Cholangiocarcinoma • Gallbladder Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor