Trial Title:
NUC-3373 in Combination With Other Agents in Patients With Advanced Solid Tumours
NCT ID:
NCT05714553
Condition:
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
Conditions: Official terms:
Carcinoma
Neoplasms
Carcinoma, Squamous Cell
Triple Negative Breast Neoplasms
Mesothelioma
Squamous Cell Carcinoma of Head and Neck
Endometrial Neoplasms
Esophageal Neoplasms
Leucovorin
Pembrolizumab
Docetaxel
Levoleucovorin
Conditions: Keywords:
NuCana plc
NUC-3373
Fosifloxuridine nafalbenamide
Leucovorin
Pembrolizumab
Docetaxel
Antineoplastic agents
Chemotherapy
Locally advanced
Metastatic
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Fosifloxuridine Nafalbenamide
Description:
Intravenous infusion
Arm group label:
Module 1 (NUC-3373 + LV + pembrolizumab)
Arm group label:
Module 2 (NUC-3373 + LV + docetaxel)
Other name:
NUC-3373
Other name:
Nucleotide analogue
Intervention type:
Drug
Intervention name:
Leucovorin
Description:
Intravenous infusion
Arm group label:
Module 1 (NUC-3373 + LV + pembrolizumab)
Arm group label:
Module 2 (NUC-3373 + LV + docetaxel)
Other name:
Folinic acid
Other name:
Levo-leucovorin
Intervention type:
Drug
Intervention name:
Pembrolizumab
Description:
Intravenous infusion
Arm group label:
Module 1 (NUC-3373 + LV + pembrolizumab)
Other name:
Keytruda
Intervention type:
Drug
Intervention name:
Docetaxel
Description:
Intravenous infusion
Arm group label:
Module 2 (NUC-3373 + LV + docetaxel)
Other name:
Taxotere
Other name:
Docecad
Other name:
Docefrez
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.
Criteria for eligibility:
Criteria:
Inclusion Criteria (all modules):
1. Provision of written informed consent.
2. Confirmed diagnosis of one of the protocol-specified tumour types (refer to the
relevant module for specific criteria).
3. Age ≥18 years.
4. Minimum life expectancy of ≥12 weeks.
5. Eastern Cooperative Oncology Group (ECOG) Performance status 0 or 1.
6. Measurable disease as defined by RECIST v1.1.
7. 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.
8. Adequate liver function (refer to the relevant module for specific criteria).
9. 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).
10. Serum albumin ≥3 g/dL.
11. For the module in which the patient will participate, there are no
contra-indications to receiving the approved partner combination drugs.
12. Ability to comply with protocol requirements.
13. 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.
14. 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.
Additional Module 1 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 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.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Queen Elizabeth Hospital University Hospitals Birmingham NHS Foundation Trust
Address:
City:
Birmingham
Zip:
B15 2TH
Country:
United Kingdom
Status:
Recruiting
Facility:
Name:
The Beatson West of Scotland Cancer Centre
Address:
City:
Glasgow
Zip:
G12 0TN
Country:
United Kingdom
Status:
Not yet recruiting
Facility:
Name:
Guy's and St Thomas NHS Foundation Trust
Address:
City:
London
Zip:
SE1 9RT
Country:
United Kingdom
Status:
Recruiting
Facility:
Name:
The Christie NHS Foundation Trust
Address:
City:
Manchester
Zip:
M20 4BX
Country:
United Kingdom
Status:
Recruiting
Start date:
March 8, 2023
Completion date:
January 2025
Lead sponsor:
Agency:
NuCana plc
Agency class:
Other
Source:
NuCana plc
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05714553
