NUC-3373 in Combination With Other Agents in Patients With Advanced Solid Tumours

NCT05714553 | Terminated Phase 1 FDA Drug

• 2 other identifiers: NuTide:3032022-000722-14
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 4

Brief Summary

This study is an open-label, multi-arm, parallel cohort, dose validation and expansion design. The study is modular in design, allowing evaluation of the safety, efficacy and pharmacokinetics (PK) of NUC-3373 in combination with other agents for the treatment of patients with different tumour types. Each module is designed to evaluate a different NUC-3373 combination and consists of a dose-validation phase (Phase Ib) and a dose-expansion phase (Phase II). Phase Ib of each module will determine the safety and tolerability of the combinations for further clinical evaluation in Phase II. Approximately 6-20 evaluable patients will be enrolled in the Phase Ib stage of each module to determine safety, tolerability, and preliminary efficacy of NUC-3373 in combination with other agents. Each module will then move into Phase II to enable a further assessment of safety and efficacy in approximately 20-40 patients. Module 1 will assess NUC-3373 + leucovorin (LV) in combination with pembrolizumab for the treatment of patients with advanced/metastatic solid tumours who have progressed on ≤2 prior therapies for metastatic disease, that may have included 1 prior immunotherapy-containing regimen (either monotherapy or in combination with chemotherapy) or who have not progressed but where addition of NUC-3373 + LV to standard pembrolizumab monotherapy may be appropriate (e.g., patients who could not tolerate post- immuno-oncology (IO) standard of care therapy). Module 2 will assess NUC-3373 + LV in combination with docetaxel for the treatment of patients with advanced/metastatic non-small cell lung cancer (NSCLC) or pleural mesothelioma who have progressed on, or were unable to tolerate, 1 or 2 prior lines of cytotoxic chemotherapy-containing regimens for advanced/metastatic disease. The opening of each module will be at the discretion of the Sponsor. Further modules may be added as non-clinical and clinical data become available to support additional NUC-3373 combinations and tumour types.

Conditions

Advanced Cancer; Advanced Solid Tumor; Neoplasm Malignant; Metastatic Cancer; Melanoma; Classical Hodgkin Lymphoma; Non Small Cell Lung Cancer; Renal Cell Carcinoma; Urothelial Carcinoma; Head and Neck Squamous Cell Carcinoma; Subungual Squamous Cell Carcinoma; Oesophageal Carcinoma; MSI-H Colorectal Cancer; Gastric Cancer; Triple Negative Breast Cancer; Endometrial Carcinoma; Pleural Mesothelioma

Keywords

NuCana plc; NUC-3373; Fosifloxuridine nafalbenamide; Leucovorin; Pembrolizumab; Docetaxel; Antineoplastic agents; Chemotherapy; Locally advanced; Metastatic

Outcome Measures

Primary Outcomes (3)

• Number of patients tolerating dose levels (maximum tolerated dose; MTD) in each of the combinations

  MTD of NUC-3373 in each of the combinations in each patient

  Assessed from baseline to 30 days after last dose of study drug

• Number of patients reporting treatment-emergent adverse events (TEAEs) in each of the combinations

  TEAEs in each patient, including clinically significant laboratory changes, and changes in physical exam, vital signs and serial electrocardiograms (ECGs)

  Assessed from baseline to 30 days after last dose of study drug

• Number of patients achieving a reduction in tumour volume (Objective response rate; ORR)

  ORR, defined as the percentage of patients achieving a confirmed complete or partial response to treatment, based on Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 criteria or immune-related RECIST criteria (iRECIST).

  Assessed from baseline to 30 days after last dose of study drug

Study Arms (2)

Module 1 (NUC-3373 + LV + pembrolizumab)

EXPERIMENTAL

This Module is designed to evaluate the tolerability and the overall safety profile of NUC-3373 (1875 mg/m2) + LV (400 mg/m2) + pembrolizumab (200 mg) in the treatment of patients with advanced solid tumours (dose validation phase). NUC-3373 and LV will be administered on Days 1, 8 and 15 and pembrolizumab will be administered on Day 1 of 21-day cycles. The dosing schedule may be adjusted based on emerging data with agreement from the Safety Review Committee. Following completion of the dose validation phase, expansion cohorts may be initiated at the selected dose level.

Drug: Fosifloxuridine Nafalbenamide; Drug: Leucovorin; Drug: Pembrolizumab

Module 2 (NUC-3373 + LV + docetaxel)

EXPERIMENTAL

This Module is designed to assess NUC-3373 (750 mg/m2) + LV (400 mg/m2) + docetaxel (55 mg/m2) for the treatment of patients with advanced/metastatic NSCLC or pleural mesothelioma who have progressed on, or were unable to tolerate, 1 or 2 prior lines of cytotoxic chemotherapy-containing regimens for advanced/metastatic disease (dose validation phase). NUC-3373 and LV will be administered on Days 1 and 22 and docetaxel will be administered on Day 8 of 28-day cycles. The dosing schedule may be adjusted based on emerging data with agreement from the Safety Review Committee. Following completion of the dose validation phase, expansion cohorts may be initiated at the selected dose level.

Drug: Fosifloxuridine Nafalbenamide; Drug: Leucovorin; Drug: Docetaxel

Interventions

Fosifloxuridine Nafalbenamide DRUG

Intravenous infusion

Also known as: NUC-3373, Nucleotide analogue

Module 1 (NUC-3373 + LV + pembrolizumab); Module 2 (NUC-3373 + LV + docetaxel)

Leucovorin DRUG

Intravenous infusion

Also known as: Folinic acid, Levo-leucovorin

Module 1 (NUC-3373 + LV + pembrolizumab); Module 2 (NUC-3373 + LV + docetaxel)

Pembrolizumab DRUG

Intravenous infusion

Also known as: Keytruda

Module 1 (NUC-3373 + LV + pembrolizumab)

Docetaxel DRUG

Intravenous infusion

Also known as: Taxotere, Docecad, Docefrez

Module 2 (NUC-3373 + LV + docetaxel)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provision of written informed consent.
• Confirmed diagnosis of one of the protocol-specified tumour types (refer to the relevant module for specific criteria).
• Age ≥18 years.
• Minimum life expectancy of ≥12 weeks.
• Eastern Cooperative Oncology Group (ECOG) Performance status 0 or 1.
• Measurable disease as defined by RECIST v1.1.
• Adequate bone marrow function as defined by absolute neutrophil count (ANC) ≥1.5×109/L, platelet count ≥100×109/L (with no evidence of bleeding), and haemoglobin ≥9 g/dL.
• Adequate liver function (refer to the relevant module for specific criteria).
• Adequate renal function assessed as serum creatinine \<1.5× upper limit of normal (ULN) and glomerular filtration rate ≥50 mL/min (calculated by the Cockcroft-Gault method).
• Serum albumin ≥3 g/dL.
• For the module in which the patient will participate, there are no contra-indications to receiving the approved partner combination drugs.
• Ability to comply with protocol requirements.
• Female patients of child-bearing potential must have a negative pregnancy test within 7 days prior to the first study drug administration. This criterion does not apply to patients who have had a previous hysterectomy or bilateral oophorectomy. Male patients and female patients of child-bearing potential must agree to practice true abstinence or to use two forms of contraception, one of which must be highly effective. These forms of contraception must be used from the time of signing consent, throughout the treatment period, and for 6 months following the last dose of any study medication. Oral or injectable contraceptive agents cannot be the sole method of contraception.
• Patients must have been advised to take measures to avoid or minimize exposure to ultraviolet (UV) light for the duration of study participation and for a period of 4 weeks following the last dose of study medication.
• Confirmed diagnosis of a solid tumour, with evidence of locally advanced/unresectable or metastatic disease, for which pembrolizumab treatment would be appropriate (e.g., melanoma, classical Hodgkin lymphoma, NSCLC, renal cell carcinoma (RCC), urothelial carcinoma, head and neck squamous cell carcinoma (HNSCC), cutaneous squamous cell carcinoma (cSCC), oesophageal carcinoma, microsatellite instability (MSI) high colorectal (CRC), gastric cancer, triple negative breast cancer (TNBC), and endometrial carcinoma).

You may not qualify if:

• History of hypersensitivity or current contra-indications to 5-fluorouracil (5-FU), floxuridine (FUDR), capecitabine (refer to latest package inserts), or the components of the NUC-3373 drug product formulation (super refined polysorbate 80 \[SRP80\], dimethylacetamide \[DMA\]).
• Symptomatic central nervous system or leptomeningeal metastases.
• Symptomatic ascites, ascites currently requiring drainage procedures or ascites requiring drainage over the 3 months prior to date of first dose of study drug.
• Chemotherapy, hormonal therapy, radiotherapy (other than a short cycle of palliative radiotherapy, e.g., for bone pain\*), immunotherapy, biological agents, or exposure to another investigational agent within 21 days (or four times the half-life for molecular targeted agents, whichever is shorter) of first administration of study treatment:
• For nitrosoureas and mitomycin C within 6 weeks of first administration of NUC-3373
• Corticosteroid treatment is allowed during screening but should be weaned to a dose of 10 mg prednisolone (or steroid equivalent) by Cycle 1 Day 1 \* Palliative radiotherapy during participation in the study is permitted, but should not be concurrent with study treatment and recovery should be allowed to prevent overlapping toxicity. It should not include a target lesion.
• Residual toxicities from prior chemotherapy, immunotherapy or radiotherapy which have not regressed to Grade ≤1 severity (Common Terminology Criteria for Adverse Events (CTCAE) v5.0), except for alopecia, peripheral neuropathy and ototoxicity (which are excluded if ≥Grade 3).
• Uncontrolled concurrent cancer other than the indication under investigation. Patients with a concurrent cancer whose natural history or treatment does not have the potential to interfere with safety or efficacy assessment are eligible.
• Presence of an active bacterial or viral infection (including severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2), Herpes Zoster or chicken pox), or known active hepatitis B or C.
• Presence of any uncontrolled concurrent serious illness, medical condition or other medical history, including laboratory results, which, in the Investigator's opinion, would be likely to interfere with the patient's ability to participate in the study or with the interpretation of the results, including any of the following:
• Congestive heart failure (New York Heart Association Class III or Class IV)
• Clinically significant coronary heart disease or myocardial infarction within 6 months of the first dose of study medication or high risk of uncontrolled arrythmia
• Unstable or poorly controlled angina pectoris
• Complete left bundle branch, bifascicular block or other clinically significant abnormal electrocardiogram (ECG) finding
• Corrected QT (QTc) interval \>470 milliseconds

Sponsors & Collaborators

• NuCana plc: lead

Study Sites (4)

Queen Elizabeth Hospital University Hospitals Birmingham NHS Foundation Trust

Birmingham, B15 2TH, United Kingdom

Location

The Beatson West of Scotland Cancer Centre

Glasgow, G12 0TN, United Kingdom

Location

Guy's and St Thomas NHS Foundation Trust

London, SE1 9RT, United Kingdom

Location

The Christie NHS Foundation Trust

Manchester, M20 4BX, United Kingdom

Location

MeSH Terms

Conditions

Neoplasms; Neoplasm Metastasis; Melanoma; Carcinoma, Non-Small-Cell Lung; Carcinoma, Renal Cell; Carcinoma, Transitional Cell; Squamous Cell Carcinoma of Head and Neck; Esophageal Neoplasms; Stomach Neoplasms; Triple Negative Breast Neoplasms; Endometrial Neoplasms; Mesothelioma, Malignant

Interventions

Leucovorin; Levoleucovorin; pembrolizumab; Docetaxel

Condition Hierarchy (Ancestors)

Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases; Carcinoma, Squamous Cell; Head and Neck Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Esophageal Diseases; Gastrointestinal Diseases; Stomach Diseases; Breast Neoplasms; Breast Diseases; Uterine Neoplasms; Genital Neoplasms, Female; Uterine Diseases; Genital Diseases, Female; Genital Diseases; Mesothelioma; Adenoma; Neoplasms, Mesothelial; Pleural Neoplasms

Intervention Hierarchy (Ancestors)

Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Coenzymes; Enzymes and Coenzymes; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 23, 2023
• First Posted: February 6, 2023
• Study Start: March 8, 2023
• Primary Completion: May 30, 2025
• Study Completion: May 30, 2025
• Last Updated: July 18, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

GB (4)