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

Phase 1

Recruiting

• 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
• Interventions: Drug: Fosifloxuridine Nafalbenamide; Drug: Leucovorin; Drug: Pembrolizumab; Drug: Docetaxel

• Registration Number: NCT05714553
• Lead Sponsor: NuCana plc

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2023-01-23
• Study First Submitted QC: 2023-02-01
• Study First Posted: 2023-02-06
• Study Start: 2023-03-08
• Status Verified: 2025-02
• Last Update Submitted: 2025-02-28
• Last Update Posted: 2025-03-03
• Primary Completion: 2025-12
• Study Completion: 2025-12

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 91

Inclusion Criteria

1. 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).
2. Must have progressed on ≤2 prior lines of therapy for advanced/metastatic disease, that may have included 1 prior line of an immunotherapy-containing regimen (either monotherapy or in combination with chemotherapy). Patients who have not progressed but where addition of NUC-3373 + LV to standard pembrolizumab monotherapy may be appropriate are also eligible (e.g., patients who could not tolerate post-IO standard of care therapy).
3. Patient must be willing to undergo a new tumour biopsy at Screening and during therapy on the study. Biopsies are mandatory for patient inclusion, except where taking a biopsy would be associated with unacceptable clinical risk due to the location of the disease. A prior (archival) biopsy that is less than 6 months old (from the date of Cycle 1Day 1; C1D1) may be substituted for a fresh tumour biopsy at Screening.
4. Adequate liver function, as defined by serum total bilirubin ≤1.5×ULN, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5×ULN (or ≤5×ULN if liver metastases are present).

Additional Module 2 Inclusion Criteria:

1. Confirmed diagnosis of NSCLC (any histology) or pleural mesothelioma (any histology) with evidence of locally advanced/unresectable or metastatic disease.
2. Must have progressed on, or were unable to tolerate, 1 or 2 prior lines of cytotoxic chemotherapy-containing standard of care regimens for advanced/metastatic disease (not including neoadjuvant or adjuvant therapy). Additional prior lines of treatment with targeted agents or immunotherapy are allowed as long as they were not given in combination with cytotoxic chemotherapy. Prior regimens in which one drug is substituted for another due to toxicity count as 1 line of treatment. Prior treatment with docetaxel for metastatic disease is not allowed.
3. Adequate liver function, as defined by serum total bilirubin <ULN, AST and ALT ≤2.5×ULN (or ≤5×ULN if liver metastases are present). In the event of concomitantly increased alkaline phosphatase (ALP) values >2.5×ULN, AST and ALT must be <1.5×ULN.

Exclusion Criteria (all modules):

1. 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]).

2. Symptomatic central nervous system or leptomeningeal metastases.

3. Symptomatic ascites, ascites currently requiring drainage procedures or ascites requiring drainage over the 3 months prior to date of first dose of study drug.

4. 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:

   1. For nitrosoureas and mitomycin C within 6 weeks of first administration of NUC-3373
   2. 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.

5. 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).

6. 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.

7. 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.

8. 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:

   1. Congestive heart failure (New York Heart Association Class III or Class IV)
   2. Clinically significant coronary heart disease or myocardial infarction within 6 months of the first dose of study medication or high risk of uncontrolled arrythmia
   3. Unstable or poorly controlled angina pectoris
   4. Complete left bundle branch, bifascicular block or other clinically significant abnormal electrocardiogram (ECG) finding
   5. Corrected QT (QTc) interval >470 milliseconds
   6. History of or current risk factor for torsade de pointes (e.g., heart failure, hypokalaemia, or a family history of long QT syndrome)
   7. History of severe skin reactions
   8. History of severe ocular disorders
   9. Interstitial pneumonitis or pulmonary fibrosis

9. Any condition (e.g., known or suspected poor compliance, psychological instability, geographical location, etc.) that, in the judgment of the Investigator, may affect the patient's ability to sign the informed consent and undergo study procedures.

10. Currently pregnant, lactating or breastfeeding.

11. Required concomitant use of drugs known to prolong QT/QTc interval.

12. Required concomitant use of strong CYP3A4 inducers or strong CYP3A4 inhibitors. The use of strong CYP3A4 inducers within 2 weeks of first receipt of study drug or the use of strong CYP3A4 inhibitors within 1 week of first receipt of study drug is also excluded.

13. Use of live attenuated vaccines against infectious diseases (e.g., measles mumps rubella [MMR combined vaccines], Rotavirus, Chickenpox, yellow fever) within 4 weeks of initiation of study treatment.

14. Known dihydropyrimidine dehydrogenase (DPD) or thymidine phosphorylase (TYMP) mutations associated with toxicity to fluoropyrimidines.

15. Full-dose anti-coagulation treatment is prohibited. Use of warfarin and other types of long-acting anti-coagulants (such as phenprocoumon and anti-Xa inhibitors with a half-life of >12 hours) is prohibited within 4 weeks of the first dose of study treatment. Patients requiring low dose anti-coagulant treatment should switch to low molecular weight heparin or anti-Xa inhibitors with a half-life of ≤12 hours.

Additional Module 1

Exclusion Criteria

1. Prior history of hypersensitivity or current contra-indication to immunotherapy with checkpoint inhibitors.
2. Any history of hypersensitivity or current contra-indication to the components of pembrolizumab (L-histidine, polysorbate 80, sucrose, sodium hydroxide, hydrochloric acid).
3. Any prior toxicity attributed to checkpoint inhibitors that resulted in discontinuation of therapy.
4. Patients previously exposed to checkpoint inhibitors who are not adequately treated for skin rash or have no replacement therapy for endocrinopathies.
5. Known neutralising antibodies against checkpoint inhibitors.
6. Patients who have received >2 prior lines of therapy or who have received >1 prior line of an immunotherapy-containing regimen for advanced/metastatic disease.
7. Systemic steroid therapy or any immunosuppressive therapy (≥10 mg/day prednisone or equivalent).
8. Congenital or acquired immunodeficiency (e.g., serious active infection with human immunodeficiency virus (HIV)).
9. Patients with a history of drug induced pneumonitis or current pneumonitis.
10. Active autoimmune disease or a documented history of autoimmune disease, including ulcerative colitis and Crohn's disease or any condition that requires systemic steroids.

Additional Module 2 Exclusion Criteria:

1. Prior history of hypersensitivity or current contra-indication to docetaxel, polysorbate 80, ethanol (anhydrous) or citric acid.
2. Total serum bilirubin >ULN and/or AST and ALT ≥1.5×ULN together with concomitantly increased ALP values >2.5×ULN.
3. Patients who have received >2 prior lines of cytotoxic chemotherapy-containing regimens for advanced/metastatic disease.
4. Patients who have received prior treatment with docetaxel for advanced/metastatic disease.
5. Congenital or acquired immunodeficiency (e.g., serious active infection with HIV). Patients with HIV who are healthy and have a low risk of acquired immunodeficiency syndrome (AIDS)-related outcomes are eligible.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Module 1 (NUC-3373 + LV + pembrolizumab)	Leucovorin	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.
Module 1 (NUC-3373 + LV + pembrolizumab)	Pembrolizumab	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.
Module 2 (NUC-3373 + LV + docetaxel)	Leucovorin	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.
Module 1 (NUC-3373 + LV + pembrolizumab)	Fosifloxuridine Nafalbenamide	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.
Module 2 (NUC-3373 + LV + docetaxel)	Docetaxel	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.
Module 2 (NUC-3373 + LV + docetaxel)	Fosifloxuridine Nafalbenamide	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.

Primary Outcome Measures

Name	Time	Method
Number of patients tolerating dose levels (maximum tolerated dose; MTD) in each of the combinations	Assessed from baseline to 30 days after last dose of study drug	MTD of NUC-3373 in each of the combinations in each patient
Number of patients reporting treatment-emergent adverse events (TEAEs) in each of the combinations	Assessed from baseline to 30 days after last dose of study drug	TEAEs in each patient, including clinically significant laboratory changes, and changes in physical exam, vital signs and serial electrocardiograms (ECGs)
Number of patients achieving a reduction in tumour volume (Objective response rate; ORR)	Assessed from baseline to 30 days after last dose of study drug	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).

Trial Locations

Locations (4)

The Beatson West of Scotland Cancer Centre; 🇬🇧 Glasgow, United Kingdom

Queen Elizabeth Hospital University Hospitals Birmingham NHS Foundation Trust; 🇬🇧 Birmingham, United Kingdom

Guy's and St Thomas NHS Foundation Trust; 🇬🇧 London, United Kingdom

The Christie NHS Foundation Trust; 🇬🇧 Manchester, United Kingdom