fosifloxuridine nafalbenamide (NUC-3373) / NuCana - LARVOL DELTA

NuCana Announces Encouraging Data for NUC-3373 in Combination with Anti-PD-1 Therapy (GlobeNewswire) - "A 100% reduction in tumor lesion size (classified as a partial response due to the presence of non-target lesions) in a patient with urothelial carcinoma of the bladder who remained on treatment for over 15 months; and an 81% reduction in target lesions in a patient with metastatic melanoma resistant to prior pembrolizumab therapy, who continues to remain progression-free at 23 months....Preclinical data...demonstrate that NUC-3373...in combination with a PD-1 inhibitor, enhances tumor cell death by activating lymphocytes, regardless of the tumor’s genomic stability status."

P1/2 data • Preclinical • Melanoma • Urothelial Cancer

A phosphoramidate modification of FUDR, NUC-3373, causes DNA damage and DAMPs release from colorectal cancer cells, potentiating lymphocyte-induced cell death. (PubMed, PLoS One) - "Lastly, the PD-1 immune checkpoint inhibitor nivolumab showed synergistic activity when HCT116 cells were pre-treated with NUC-3373. To conclude, we show that NUC-3373 can modulate immune signaling and may therefore facilitate immune mediated tumour cell death in vitro."

IO biomarker • Journal • Colorectal Cancer • Oncology • Solid Tumor • IFNG • LAMP1

Anticipated Milestones:…NUC-3373 (GlobeNewswire) - "Announce additional data from the Phase 1b/2 modular study (NuTide:303) of NUC-3373 in combination with pembrolizumab in patients with solid tumors in 2025."

P1/2 data • Solid Tumor

NuTide:303: NUC-3373 in Combination With Other Agents in Patients With Advanced Solid Tumours (clinicaltrials.gov) - P1/2 | N=19 | Terminated | Sponsor: NuCana plc | N=91 ➔ 19 | Trial completion date: Dec 2025 ➔ May 2025 | Recruiting ➔ Terminated | Trial primary completion date: Dec 2025 ➔ May 2025; The NuTide:303 study was terminated at NuCana's discretion due to refinement of the pipeline strategy. The overall risk benefit assessment of NUC-3373 remains positive and future NUC-3373 studies are under consideration.

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Breast Cancer • Classical Hodgkin Lymphoma • Colorectal Cancer • Endometrial Cancer • Esophageal Cancer • Gastric Cancer • Genito-urinary Cancer • Head and Neck Cancer • Hematological Malignancies • Hodgkin Lymphoma • Hormone Receptor Positive Breast Cancer • Lung Cancer • Lymphoma • Malignant Pleural Mesothelioma • Melanoma • Mesothelioma • Microsatellite Instability • Non Small Cell Lung Cancer • Oncology • Pleural Mesothelioma • Renal Cell Carcinoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • Urothelial Cancer • MSI

NuCana Reports Fourth Quarter and Year-End 2024 Financial Results and Provides Business Update (GlobeNewswire) - "2025 Anticipated Milestones - NUC-7738: Initiate an expansion of the Phase 1/2 study (NuTide:701) of NUC-7738 in combination with pembrolizumab in patients with melanoma; Announce data from the Phase 1/2 expansion study (NuTide:701) of NUC-7738 in combination with pembrolizumab; and Obtain regulatory guidance from the U.S. Food and Drug Administration on pivotal study design for NUC-7738 in melanoma. NUC-3373: Announce data from the Phase 1b/2 modular study (NuTide:303) of NUC-3373 in combination with pembrolizumab in patients with solid tumors."

FDA event • P1/2 data • Trial status • Colorectal Cancer • Endometrial Cancer • Gastroesophageal Cancer • Melanoma • Microsatellite Instability • Non Small Cell Lung Cancer • Pleural Mesothelioma • Renal Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Urothelial Cancer

NuTide:303: NUC-3373 in Combination With Other Agents in Patients With Advanced Solid Tumours (clinicaltrials.gov) - P1/2 | N=91 | Recruiting | Sponsor: NuCana plc | Trial completion date: Jan 2025 ➔ Dec 2025 | Trial primary completion date: Jan 2025 ➔ Dec 2025

Trial completion date • Trial primary completion date • Breast Cancer • Classical Hodgkin Lymphoma • Colorectal Cancer • Endometrial Cancer • Esophageal Cancer • Gastric Cancer • Genito-urinary Cancer • Head and Neck Cancer • Hematological Malignancies • Hodgkin Lymphoma • Lung Cancer • Lymphoma • Malignant Pleural Mesothelioma • Melanoma • Mesothelioma • Microsatellite Instability • Non Small Cell Lung Cancer • Oncology • Pleural Mesothelioma • Renal Cell Carcinoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • Urothelial Cancer • MSI

A Phase Ib/II multi-arm, dose finding and expansion study of a novel thymidylate synthase inhibitor with immune modulating properties, NUC-3373, in combination with pembrolizumab or docetaxel in patients with advanced solid tumors (NuTide:303) (medRxiv) - P1/2 | N=91 | NCT05714553 | Sponsor: NuCana plc | "Thirteen patients were enrolled in Module 1, with 9 evaluable for response. No DLTs were observed in these heavily pre-treated PD-(L)1 experienced patients with a variety of different tumor types. Four patients remained on treatment for >3 months and 3 patients were ongoing at the time of data cut-off. An objective response rate of 22% and a disease control rate of 67% were reported. NUC-3373 + LV + pembrolizumab was well tolerated, the most common treatment-related adverse events (AEs) were nausea, vomiting, and diarrhea and the majority of events were Grade 1 (100%) or 2 (85%). Four patients were enrolled in Module 2, with 3 evaluable for response. Two patients treated at the first dose level achieved stable disease and completed >6 months of treatment The most common treatment-related AEs were fatigue (n=4) and diarrhea (n=3) and the majority of events were Grade 1 (100%) or 2 (100%)."

P1/2 data • Preprint • Lung Cancer • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Solid Tumor

NuCana Reports Third Quarter 2024 Financial Results and Provides Business Update (GlobeNewswire) - "2025 Anticipated Milestones - NUC-7738: Initiate an expansion of the Phase 1/2 study (NuTide:701) of NUC-7738 in combination with pembrolizumab in patients with melanoma; Announce data from the Phase 1/2 expansion study (NuTide:701) of NUC-7738 in combination with pembrolizumab; and Obtain regulatory guidance from the U.S. Food and Drug Administration on pivotal study design for NUC-7738 in melanoma. NUC-3373: Initiate an expansion of the Phase 1b/2 modular study (NuTide:303) of NUC-3373 in combination with pembrolizumab in patients with solid tumors; and Announce data from the Phase 1b/2 modular study (NuTide:303) of NUC-3373 in combination with pembrolizumab in patients with solid tumors."

P1/2 data • Trial status • Melanoma • Solid Tumor

[PREPRINT] A phosphoramidate modification of FUDR, NUC-3373, causes DNA damage and DAMPs release from colorectal cancer cells, potentiating lymphocyte-induced cell death (bioRxiv) - "Pre-treatment with NUC-3373 and subsequent coculture with NK-92 MI natural killer cells caused an increase in LAMP1 expression (degranulation), production of gamma-IFN, and NK-mediated cytotoxicity compared to vehicle controls. Cocultures with patient-derived PBMCs with heterologous CRC cells pre-treated with NUC-3373 demonstrated increased cell death compared to both vehicle controls and monocultures of CRC cells exposed to NUC-3373. Lastly, the PD-1 immune checkpoint inhibitor nivolumab showed synergistic activity when HCT116 cells were pre-treated with NUC-3373."

Preclinical • Preprint • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

NUC-3373 in Combination With Other Agents in Patients With Advanced Solid Tumours (clinicaltrials.gov) - P1/2 | N=91 | Recruiting | Sponsor: NuCana plc | Trial primary completion date: Aug 2024 ➔ Jan 2025

Combination therapy • Metastases • Trial primary completion date • Breast Cancer • Colorectal Cancer • Endometrial Cancer • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Head and Neck Cancer • Hematological Malignancies • Hodgkin Lymphoma • Lung Cancer • Lymphoma • Malignant Pleural Mesothelioma • Melanoma • Mesothelioma • Microsatellite Instability • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • Urothelial Cancer • MSI

NuTide:323: A Study of NUC-3373 in Combination With Other Agents in Patients With Colorectal Cancer (clinicaltrials.gov) - P2 | N=182 | Terminated | Sponsor: NuCana plc | Trial completion date: Mar 2025 ➔ Aug 2024 | Active, not recruiting ➔ Terminated; A pre-planned initial analysis concluded that the study was unlikely to achieve its primary objective of demonstrating superior progression-free survival. Based on the Steering Committee's recommendation, the Sponsor has closed the study.

Combination therapy • Metastases • Trial completion date • Trial termination • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF • KRAS • UGT1A1

NuCana Announces Update for Phase 2 Randomized Colorectal Cancer Study (NuCana Press Release) - "NuCana plc...announced that the NuTide:323 study is being discontinued following a pre-planned initial analysis and recommendation from the NuTide:323 Study Steering Committee. While there were prognostic imbalances favoring the control arm, the Steering Committee believed that the combination of NUC-3373 with leucovorin, irinotecan and bevacizumab (NUFIRI+bev) was unlikely to achieve the study’s primary objective of superior Progression Free Survival (PFS) compared to the control arm of 5-FU, leucovorin, irinotecan and bevacizumab (FOLFIRI+bev) in the final analysis....'We look forward to sharing the latest data from the Phase 2 part of the NuTide:701 study of NUC-7738 in combination with pembrolizumab in patients with melanoma at the ESMO annual conference in September 2024'."

P2 data • Trial termination • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

NuCana Reports First Quarter 2024 Financial Results and Provides Business Update (GlobeNewswire) - "Anticipated Cash Runway into Q1 2025: As of March 31, 2024, NuCana had cash and cash equivalents of £12.9 million compared to £17.2 million at December 31, 2023. NuCana continues to advance its numerous clinical programs and reported a net loss of £6.8 million for the quarter ended March 31, 2024, as compared to a net loss of £7.9 million for the quarter ended March 31, 2023....NUC-3373 (a ProTide transformation of 5-FU): In 2024, NuCana expects to: Announce data from the randomized Phase 2 (NuTide:323) study of NUFIRI + bev compared to the standard of care FOLFIRI + bev for the second-line treatment of patients with metastatic colorectal cancer; Announce data from the Phase 1b/2 (NuTide:302) study of NUFIRI + bev and NUFOX + bev for the second-line treatment of patients with metastatic colorectal cancer; and Announce data from the Phase 1b/2 (NuTide:303) modular study of NUC-3373 in combination with pembrolizumab in patients with solid tumors and in..."

Commercial • P1/2 data • P2 data • Colorectal Cancer • Lung Cancer • Solid Tumor

A phase I open-label, dose-escalation study of NUC-3373, a targeted thymidylate synthase inhibitor, in patients with advanced cancer (NuTide:301). (PubMed, J Exp Clin Cancer Res) - P1 | "NUC-3373 was well-tolerated in a heavily pre-treated solid tumor patient population, including those who had relapsed on prior 5-FU. The MTD and RP2D was defined as 2500 mg/m2 NUC-3373 weekly. NUC-3373 is currently in combination treatment studies."

Journal • Metastases • P1 data • Hypotension • Oncology • Pain • Solid Tumor • Thymus Cancer

NuTide:302: A Safety, Pharmacokinetic and Efficacy Study of NUC-3373 in Combination With Standard Agents Used in Colorectal Cancer Treatment (clinicaltrials.gov) - P1/2 | N=107 | Completed | Sponsor: NuCana plc | Recruiting ➔ Completed | N=225 ➔ 107 | Trial completion date: Nov 2023 ➔ Mar 2024 | Trial primary completion date: Nov 2023 ➔ Mar 2024

Combination therapy • Enrollment change • Trial completion • Trial completion date • Trial primary completion date • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF • KRAS

A Study of NUC-3373 in Combination With Other Agents in Patients With Colorectal Cancer (clinicaltrials.gov) - P2 | N=182 | Active, not recruiting | Sponsor: NuCana plc | Recruiting ➔ Active, not recruiting

Enrollment closed • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF • KRAS • UGT1A1

A phase I open-label, dose-escalation study of NUC-3373, a targeted thymidylate synthase inhibitor, in patients with advanced cancer (NuTide:301) (J Exp Clin Cancer Res) - P1 | N=62 | NuTide:301 (NCT02723240) | "Fifty-nine patients received weekly NUC-3373 in 9 cohorts in Part 1 (n = 43) and 3 alternate-weekly dosing cohorts in Part 2 (n = 16). They had received a median of 3 prior lines of treatment (range: 0–11) and 74% were exposed to prior fluoropyrimidines. Four experienced dose-limiting toxicities: two Grade (G) 3 transaminitis; one G2 headache; and one G3 transient hypotension....NUC-3373 showed a favorable PK profile, with dose-proportionality and a prolonged half-life compared to 5-FU. A best overall response of stable disease was observed, with prolonged progression-free survival."

P1 data • Solid Tumor

A Study of NUC-3373 in Combination With Other Agents in Patients With Colorectal Cancer (clinicaltrials.gov) - P2 | N=171 | Recruiting | Sponsor: NuCana plc | Trial completion date: Dec 2024 ➔ Mar 2025 | Trial primary completion date: Jun 2024 ➔ Sep 2024

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF • KRAS • UGT1A1

NuCana Reports Third Quarter 2023 Financial Results and Provides Business Update (Yahoo Finance) - "2024 Anticipated Milestones...Announce data from the randomized Phase 2 (NuTide:323) study of NUFIRI-bev compared to the standard of care FOLFIRI-bev for the second-line treatment of patients with colorectal cancer; Announce data from the Phase 2 (NuTide:302) study of NUC-3373 in combination with irinotecan, leucovorin and bevacizumab (NUFIRI-bev) and in combination with oxaliplatin, leucovorin and bevacizumab (NUFOX-bev) for the second-line treatment of patients with colorectal cancer; and Announce data from the Phase 1b (NuTide:303) modular study of NUC-3373 in combination with pembrolizumab in patients with solid tumors and in combination with docetaxel in patients with lung cancer to identify additional indications for development....Announce data from the Phase 2 part of the NuTide:701 study of NUC-7738 in combination with pembrolizumab in patients with melanoma."

P1 data • P2 data • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Melanoma • Oncology • Skin Cancer • Solid Tumor

NuCana Presents Encouraging Data on NUC-3373 in Colorectal Cancer at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics 2023 (GlobeNewswire) - P2 | N=171 | NuTide:323 (NCT05678257) | Sponsor: NuCana plc | "The ongoing Phase 2 randomized NuTide:323 study is investigating NUFIRI-bev versus the global standard of care, 5-FU in combination with leucovorin, irinotecan and bevacizumab (FOLFIRI-bev), in 171 second-line patients with CRC. The study is recruiting well and aggregated safety data from the first 40 patients enrolled showed no new safety signals."

P2 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

NuCana Presents Encouraging Data on NUC-3373 in Colorectal Cancer at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics 2023 (GlobeNewswire) - P1/2 | N=225 | NuTide:302 (NCT03428958) | Sponsor: NuCana plc | "NuCana plc...announced presentations from two ongoing clinical studies with NUC-3373 in colorectal cancer (CRC) at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics 2023 taking place October 11-15, 2023 in Boston, Massachusetts....Data presented today showed that both regimens had favorable tolerability profiles. Furthermore, both NUFIRI-bev and NUFOX-bev demonstrated promising anti-tumor activity, including numerous patients with tumor volume reductions. Additionally, several patients achieved a longer progression-free survival (PFS) on NUC-3373-based regimens as compared to the PFS achieved in their first-line treatment with 5-FU-based therapy."

P1/2 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Phase Ib/II open label, multi-arm, parallel cohort dose finding and expansion study of NUC-3373 in combination with pembrolizumab in patients with advanced solid tumors or docetaxel in patients with lung cancer (NuTide:303). (AACR-NCI-EORTC 2023) - No abstract available

Clinical • Combination therapy • Metastases • P1/2 data • Lung Cancer • Oncology • Solid Tumor

Phase II study of NUC-3373, leucovorin, irinotecan (NUFIRI) + bevacizumab vs FOLFIRI + bevacizumab for the second-line treatment of patients with advanced/metastatic colorectal cancer (NuTide:323). (AACR-NCI-EORTC 2023) - No abstract available

Clinical • Metastases • P2 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

NUC-3373 in combination with irinotecan (NUFIRI) or oxaliplatin (NUFOX) and bevacizumab for second-line treatment of patients with advanced colorectal cancer (NuTide:302). (AACR-NCI-EORTC 2023) - No abstract available

Clinical • Combination therapy • Metastases • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

NuCana Announces Presentations at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics 2023 (GlobeNewswire) - "NuCana plc...nnounced four presentations at the upcoming AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics 2023 being held October 11-15, 2023 in Boston, Massachusetts."

P1/2 data • P2 data • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Melanoma • Oncology • Skin Cancer • Solid Tumor