A Study of NUC-3373 in Combination With Other Agents in Patients With Colorectal Cancer

• ClinicalTrials.gov Identifier: NCT05678257
• Recruitment Status: Active, not recruiting
• First Posted: January 10, 2023
• Last Update Posted: April 3, 2024
• Sponsor: NuCana plc
• Information provided by (Responsible Party): NuCana plc

Tracking Information

• First Submitted Date: December 22, 2022
• First Posted Date: January 10, 2023
• Last Update Posted Date: April 3, 2024
• Actual Study Start Date: April 18, 2023
• Estimated Primary Completion Date: September 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 9, 2023)

Number of patients achieving progress-free survival (PFS) [ Time Frame: Assessed from baseline to 30 days after last dose of study drug ]

PFS assessed according to Response Evaluation Criteria in Solid Tumours (RECIST) v1.1, defined as the time from randomisation to the first observation of objective tumour progression or death from any cause

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: January 9, 2023)

• Number of patients achieving a reduction in tumour volume [ Time Frame: Assessed from baseline to 30 days after last dose of study drug ]
  Objective response rate, defined as the percentage of patients achieving a complete or partial (30%+) response to treatment
• Number of patients surviving [ Time Frame: Assessed from baseline to 30 days after last dose of study drug ]
  Overall survival, defined as the time from randomization to the time of death from any cause
• Number of patients reporting treatment-emergent adverse events (TEAEs) [ Time Frame: Assessed from baseline to 30 days after last dose of study drug ]
  TEAEs assessed and graded by CTCAE v5.0

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of NUC-3373 in Combination With Other Agents in Patients With Colorectal Cancer
• Official Title: A Randomised, Open-label, Phase II, Dose/Schedule Optimisation Study of NUC-3373/Leucovorin/Irinotecan Plus Bevacizumab (NUFIRI-bev) Versus 5-FU/Leucovorin/Irinotecan Plus Bevacizumab (FOLFIRI-bev) for the Treatment of Patients With Previously Treated Unresectable Metastatic Colorectal Cancer

Brief Summary

This is a randomized, open-label, dose/schedule optimization study comparing NUC-3373/leucovorin (LV)/irinotecan plus bevacizumab (NUFIRI-bev) to 5-FU/LV/irinotecan plus bevacizumab (FOLFIRI-bev) for the treatment of patients with unresectable metastatic colorectal cancer.

A total of 171 patients will be randomized 1:1:1 to either NUFIRI-bev on a weekly NUC-3373 schedule, NUFIRI-bev based on an alternate weekly NUC-3373 schedule, or FOLFIRI bev on an alternate weekly schedule. The main objectives are to assess and compare the efficacy and safety of the 3 regimens. Pharmacokinetics will be assessed on the 2 NUFIRI arms.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Colorectal Cancer
• Colorectal Neoplasms
• Colorectal Adenocarcinoma
• Colorectal Cancer Metastatic
• Neoplasm, Colorectal

Intervention

• Drug: Fosifloxuridine Nafalbenamide
  Intravenous infusion
  Other Names:

  • NUC-3373
  • Nucleotide analogue
• Drug: Leucovorin
  Intravenous infusion
  Other Names:

  • Folinic acid
  • LV
• Drug: Irinotecan
  Intravenous infusion
  Other Names:

  • Campto
  • Camptosar
• Biological: Bevacizumab
  Intravenous infusion
  Other Names:

  • Avastin
  • Zirabev
• Drug: 5-FU
  Intravenous infusion
  Other Names:

  • 5FU
  • 5-fluorouracil
  • Fluorouracil

Study Arms

• Experimental: NUFIRI-bev on a Q1W NUC-3373 schedule

  Arm A: Study treatment will be administered in 28-day cycles as follows:

  1. Bevacizumab 5 mg/kg on Days 1 and 15:

     • 90 minutes for the first dose
     • 60 minutes for the second dose (if first dose is tolerated)
     • 30 minutes for subsequent doses (if second dose is tolerated)
  2. LV 400 mg/m2 (or equivalent levo-LV) over 120 minutes on Days 1, 8, 15, and 22.
  3. Irinotecan 180 mg/m2 over 90 minutes (concurrently with the LV infusion) on Days 1 and 15.
  4. NUC-3373 1500 mg/m2 over 120 minutes on Days 1, 8, 15, and 22.
  Interventions:

  • Drug: Fosifloxuridine Nafalbenamide
  • Drug: Leucovorin
  • Drug: Irinotecan
  • Biological: Bevacizumab
• Experimental: NUFIRI-bev on a Q2W NUC-3373 schedule

  Arm B: Study treatment will be administered in 28-day cycles as follows:

  1. Bevacizumab 5 mg/kg on Days 1 and 15:

     • 90 minutes for the first dose
     • 60 minutes for the second dose (if first dose is tolerated)
     • 30 minutes for subsequent doses (if second dose is tolerated)
  2. LV 400 mg/m2 (or equivalent levo-LV) over 120 minutes on Days 1 and 15.
  3. Irinotecan 180 mg/m2 over 90 minutes (concurrently with the LV infusion) on Days 1 and 15.
  4. NUC-3373 1500 mg/m2 over 120 minutes on Days 1 and 15.
  Interventions:

  • Drug: Fosifloxuridine Nafalbenamide
  • Drug: Leucovorin
  • Drug: Irinotecan
  • Biological: Bevacizumab
• Active Comparator: FOLFIRI-bev on a Q2W schedule

  Arm C: Study treatment will be administered in 28-day cycles as follows:

  1. Bevacizumab 5 mg/kg on Days 1 and 15:

     • 90 minutes for the first dose
     • 60 minutes for the second dose (if first dose is tolerated)
     • 30 minutes for subsequent doses (if second dose is tolerated)
  2. LV 400 mg/m2 (or equivalent levo-LV) over 120 minutes on Days 1 and 15.
  3. Irinotecan 180 mg/m2 over 90 minutes (concurrently with the LV infusion) on Days 1 and 15.
  4. 5-FU 400 mg/m2 bolus on Days 1 and 15.
  5. 5-FU 2400 mg/m2 infusion over 46 hours on Days 1 and 15.
  Interventions:

  • Drug: Leucovorin
  • Drug: Irinotecan
  • Biological: Bevacizumab
  • Drug: 5-FU

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: April 2, 2024): 182
• Original Estimated Enrollment (submitted: January 9, 2023): 171
• Estimated Study Completion Date: March 2025
• Estimated Primary Completion Date: September 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Provision of written informed consent.
2. Histological or cytological confirmation of colorectal adenocarcinoma (excluding appendiceal and anal canal cancers, as well as signet-ring cell carcinoma) that is unresectable and metastatic.
3. Measurable disease (as defined by RECIST v1.1).
4. Received ≥2 months of a first-line fluoropyrimidine and oxaliplatin-containing regimen for metastatic disease or relapsed within 6 months of completing a fluoropyrimidine and oxaliplatin-containing neoadjuvant/adjuvant therapy. Previous treatment with standard of care chemotherapy regimens in combination with molecular targeted therapies (e.g., VEGF and EGFR pathway inhibitors and immuno-oncology agents) is permitted. Previous treatment with maintenance therapy (e.g., capecitabine) is also allowed. Patients who started on a fluoropyrimidine and oxaliplatin-containing regimen in any setting but must discontinue the oxaliplatin due to.toxicity or allergy (and are now unable to receive oxaliplatin) are considered eligible regardless of the number of cycles of oxaliplatin they received.
5. Known RAS and BRAF status. Patients with wild-type RAS tumours must have received prior treatment with an EGFR inhibitor, unless this was not standard of care according to relevant region-specific treatment recommendations.
6. Known UGT1A1 status, or patient consents to UGT1A1 status testing if unknown.
7. Known DPD activity status, or patient consents to DPD status testing if unknown. See exclusion criterion 1.
8. Age ≥18 years.
9. Minimum life expectancy of ≥12 weeks.
10. Eastern Cooperative Oncology Group (ECOG) Performance status 0 or 1.
11. Adequate bone marrow function as defined by: absolute neutrophil count (ANC) ≥1.5 × 109/L, platelet count ≥100 × 109/L, and haemoglobin ≥9 g/dL. Patients with benign neutropenia may be discussed on a case-by-case basis with the medical monitor.
12. Adequate liver function, as defined by: serum total bilirubin ≤1.5 × ULN), AST and ALT ≤2.5 × ULN (or ≤5 × ULN if liver metastases are present).
13. Adequate renal function assessed as serum creatinine <1.5 × ULN and glomerular filtration rate ≥50 mL/min (calculated by the Cockcroft-Gault method).
14. Serum albumin ≥3 g/dL.
15. Ability to comply with protocol requirements.
16. Female patients of child-bearing potential must have a negative serum 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 (defined in Section 10.3.1) 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
17. Patients must have been advised to take measures to avoid or minimize exposure of the skin and eyes to UV light, including avoiding sunbathing and solarium use, for the duration of study participation and for a period of 4 weeks following the last dose of study medication

Exclusion Criteria:

1. History of hypersensitivity or current contra-indications to 5-FU, FUDR, or capecitabine.
2. History of hypersensitivity or current contra-indication to any of the combination agents required for the study.
3. History of allergic reactions attributed to components of the NUC-3373 drug product formulation.
4. History of hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanised antibodies.
5. History of or known central nervous system or leptomeningeal metastases.
6. Symptomatic ascites, ascites currently requiring drainage procedures or ascites requiring drainage over the prior 3 months.
7. Mutant BRAF V600E status.
8. MSI high or dMMR.
9. Prior treatment with irinotecan.
10. 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:
11. Residual toxicities from prior chemotherapy or radiotherapy which have not regressed to Grade ≤1 severity (CTCAE v5.0), except for alopecia and residual Grade 2 neuropathy.
12. History of other malignancies, except adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, surgically excised or potentially curatively treated ductal carcinoma in situ of the breast, or low-grade prostate cancer or patients after prostatectomy. Patients with previous invasive cancers are eligible if treatment was completed >3 years prior to initiating the current study treatment, and the patient has had no evidence or recurrence since then.
13. Presence of an active bacterial or viral infection (including SARS-CoV-2, Herpes Zoster, Varicella Zoster or chickenpox), known Human Immunodeficiency Virus (HIV) positive or known active hepatitis B or C.
14. 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 (refer to protocol for further details).
15. Any condition that, in the judgment of the Investigator, may affect the patient's ability to provide informed consent and undergo study procedures.
16. Patients with a history of haemoptysis (1/2 teaspoon or more of red blood) within 6 months prior to enrolment.
17. Wound healing complications or surgery within 28 days of starting bevacizumab (wound healing must have been fully completed before starting bevacizumab). Investigators may allow patients to initiate treatment with the other study drugs (i.e., NUC-3373/5-FU, LV and irinotecan) on C1D1 but withhold bevacizumab for at least 15 days, but no longer than 28 days, to allow completion of wound healing in patients who would otherwise be eligible for the study, in line with standard local practice and after discussion with the Medical Monitor. Patients who have not received bevacizumab by C2D1 must be replaced.
18. Unhealed wound, active gastric or duodenal ulcer, or bone fracture.
19. Serious thromboembolic event in the 6 months before inclusion.
20. Patients with a history of haemorrhage within 6 months prior to enrolment.
21. Known inherited or acquired bleeding disorders.
22. Red blood cell (RBC) transfusion dependence, defined as requiring more than 2 units of packed RBC transfusions during the 4-week period prior to screening.
23. Uncontrolled hypertension.
24. Severe proteinuria or nephrotic syndrome.
25. Acute intestinal obstruction or sub-obstruction, history of inflammatory intestinal disease or extended resection of the small intestine. Presence of a colic prosthesis.
26. History of abdominal fistulas, trachea-oesophageal fistulas, any other Grade 4 gastrointestinal perforations, non-gastrointestinal fistulas, or intra-abdominal abscesses 6 months prior to screening.
27. Currently pregnant, lactating or breastfeeding.
28. Required concomitant use of brivudine, sorivudine and analogues.
29. Required concomitant use of St John's Wort.
30. Required concomitant use of drugs known to prolong QT/QTc interval.
31. 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: France, Germany, Italy, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT05678257
• Other Study ID Numbers: NuTide:323; 2022-001459-17 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: NuCana plc
• Original Responsible Party: Same as current
• Current Study Sponsor: NuCana plc
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Elisabeth Oelmann, MD, PhD; NuCana plc

• PRS Account: NuCana plc
• Verification Date: March 2024