| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed, unresectable, histologically or cytologically confirmed metastatic adenocarcinoma of colon or rectum with radiologically measurable disease. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Previously treated colorectal cancer that has spread from one part of the body to another and that cannot be removed surgically |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 27.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10052358 |
| E.1.2 | Term | Colorectal cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
• To compare progression-free survival (PFS) of NUC-3373 in combination with leucovorin (LV), irinotecan and bevacizumab (NUFIRI-bev) with 5-fluorouracil (5-FU) in combination with LV, irinotecan and bevacizumab (FOLFIRI-bev)
• To determine the optimal NUFIRI-bev dosing schedule |
|
| E.2.2 | Secondary objectives of the trial |
• To compare the efficacy of NUFIRI-bev to FOLFIRI-bev in terms of:
o Objective response rate (ORR)
o Duration of response (DoR)
o Disease control rate (DCR)
o Maximum percentage change in tumour size
o Overall survival (OS)
• To assess the safety and tolerability of NUFIRI-bev compared to FOLFIRI-bev
• To assess the pharmacokinetics (PK) of NUFIRI-bev |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 colorectal cancers of mixed histologies [e.g., mucinous adenocarcinoma, micropapillary, 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 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.
5. Known RAS and BRAF status. Patients with wild-type KRAS 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, see exclusion criterion 33. In the case of patients with blood uracil levels between ≥16 ng/mL and <150 ng/mL, the 5-FU dose must be adapted .
8. Age ≥18 years.
9. Minimum life expectancy of ≥12 weeks.
10. 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.
12. Adequate liver function, as defined by: serum total bilirubin ≤1.5×upper limit of normal (ULN), aspartate aminotransferase (AST) and alanine aminotransferase (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 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.
17. Patients must have been advised to take measures to avoid or minimize exposure to UV light for the duration of study participation and for a period of 4 weeks following the last dose of study medication. |
|
| E.4 | Principal 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 (super refined polysorbate 80 [SRP80], dimethylacetamide [DMA]).
4. History of hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanised antibodies.
5. Symptomatic 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:
a. For nitrosoureas and mitomycin C within 6 weeks of first administration of study treatment
b. 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
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.
15. 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 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).
18. Unhealed wound, active gastric or duodenal ulcer, or bone fracture.
19. Thromboembolic event in the 6 months before inclusion (e.g., transitory ischemic stroke, stroke, subarachnoid haemorrhage) except peripheral deep vein thrombosis treated with anticoagulants.
20. Known inherited or acquired bleeding disorders.
21. 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.
22. Uncontrolled hypertension.
23. Severe proteinuria or nephrotic syndrome (≥Grade 3 [≥3.5 g/day]).
24. Acute intestinal obstruction or sub-obstruction, history of inflammatory intestinal disease or extended resection of the small intestine. Presence of a colic prosthesis.
25. 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.
26. Currently pregnant, lactating or breastfeeding.
27. Required concomitant use of brivudine.
28. Required concomitant use of St John's Wort.
29. Required concomitant use of drugs known to prolong QT/QTc interval.
30. 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.
31. Use of strong UGT1A1 inhibitors within 1 week of first receipt of study drug.
32. Received a live vaccination within four weeks of first planned dose of study medication.
33. Patients with complete DPD deficiency, defined as a blood uracil level ≥150 ng/mL.
34. Known DPD or TYMP mutations associated with toxicity to fluoropyrimidines. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| PFS, 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 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Efficacy
• ORR, defined as the percentage of patients achieving a complete or partial response to treatment
• DoR, defined as the time from initial clinical response (partial response [PR] or complete response [CR]) to the first observation of tumour progression or death from any cause
• DCR, defined as the percentage of patients demonstrating a best overall response (BOR) of CR, PR or stable disease (SD)
• Maximum percentage change from baseline in tumour size according to RECIST v1.1
• OS, defined as the time from randomisation to the time of death from any cause
Safety
Safety and tolerability will be assessed by evaluation of:
• Treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs; per Common Terminology Criteria for Adverse Events [CTCAE] v5.0)
• Deaths due to TEAEs
• Treatment modifications due to TEAEs
• Clinically-significant laboratory changes (per CTCAE v5.0)
• Electrocardiograms (ECGs)
Pharmacokinetics
The PK of the NUFIRI-bev regimen will be assessed, including:
• Concentration at end of infusion (Cinf)
• Maximum concentration (Cmax)
• Area under the plasma concentration-time curve (AUC)
• Half-life (t1/2)
• Volume of distribution (Vd)
• Clearance (CL)
The analytes measured in plasma will include, but are not limited to:
• NUC-3373, 5-FU, α-fluoro-β-alanine (FBAL), deoxyuridine (dUrd), irinotecan, SN-38 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 24 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United Kingdom |
| United States |
| France |
| Germany |
| Italy |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The study will be considered complete when a total of 139 PFS events have occurred, unless the study is terminated early by decision of the Sponsor. In this case, the study will be considered complete after the last patient has completed their End of Treatment visit. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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