Colorectal Cancer, Colorectal Carcinoma, Colorectal Neoplasms, Colorectal Tumors, Neoplasms, Colorectal
Conditions
Keywords
Relapsed metastatic adenocarcinoma of colon/rectum
Brief summary
This is a three-part study of NUC-3373 administered by intravenous (IV) infusion across two administration schedules, either as monotherapy or as part of various combinations with agents commonly used to treat CRC (leucovorin, oxaliplatin, irinotecan, bevacizumab, cetuximab and panitumumab). The primary objective is to identify a recommended dose and schedule for NUC-3373 when combined with these agents.
Interventions
DRUGNUC-3373 + leucovorin
NUC-3373 + leucovorin
DRUGNUC-3373
NUC-3373
DRUGNUFOX
NUC-3373 + oxaliplatin
DRUGNUFOX + VEGF pathway inhibitor
NUC-3373 + oxaliplatin + bevacizumab
DRUGNUFOX + EGFR inhibitor
NUC-3373 + oxaliplatin + cetuximab/panitumumab
DRUGNUFIRI
NUC-3373 + irinotecan
DRUGNUFIRI + VEGF pathway inhibitor
NUC-3373 + irinotecan + bevacizumab
DRUGNUFIRI + EGFR inhibitor
NUC-3373 + irinotecan + cetuximab/panitumumab
DRUGNUC-3373 + bevacizumab
NUC-3373 + bevacizumab
Sponsors
NuCana plc
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a three-part study of NUC-3373 administered by IV across two administration schedules, either as monotherapy or as part of various combinations with agents commonly used to treat CRC (LV, oxaliplatin, irinotecan, bevacizumab, cetuximab and panitumumab). Part 1 will determine if NUC-3373 should be administered with LV. Part 2 consists of a dose escalation phase, to assess the safety/tolerability of different doses of NUC-3373 in combination with either oxaliplatin (NUFOX) or irinotecan (NUFIRI), and an expansion phase, to assess weekly schedules of NUFOX and NUFIRI regimens selected in the escalation phase. Part 3 will assess the safety/efficacy of NUFOX and NUFIRI regimens administered in combination with bevacizumab, cetuximab or panitumumab. Additional patients may be enrolled in all parts to replace patients who withdraw prior to completing the 28-day safety evaluation period to complete the min number patients per cohort. Enrolment may be expanded at the DSMCs discretion.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
All patients 1. Provision of written informed consent 2. Have histological confirmation of CRC with evidence of locally advanced/unresectable or metastatic disease 3. Age ≥18 years 4. Life expectancy of ≥12 weeks 5. ECOG Performance status 0 or 1 6. Measurable disease as defined by RECIST v1.1 7. Known RAS and BRAF status. Patients with wild-type KRAS tumours who are to be enrolled to a cohort that does not contain an EGFR pathway inhibitor (Arms 2a, 2b, 2c, 2d, 3a, 3b, 3c, 3d and 3e) must have received prior treatment with an EGFR inhibitor, unless this was not standard of care according to relevant region-specific treatment recommendations. Patients with BRAF V600E mutant tumours should have received prior treatment with encorafenib in combination with an EGFR inhibitor, unless this was not standard of care according to relevant region-specific treatment recommendations 8. Adequate bone marrow function as defined by: ANC ≥1.5×10\^9/L, platelet count ≥100×10\^9/L (with no evidence of bleeding), and haemoglobin ≥9 g/dL 9. Adequate liver function as defined by serum total bilirubin ≤1.5×ULN, AST and ALT ≤2.5×ULN (or ≤5×ULN if liver metastases present) 10. Adequate renal function assessed as serum creatinine \<1.5×ULN or glomerular filtration rate ≥50 mL/min. This criterion does not apply to Arm 1d. 11. Serum albumin ≥3 g/dL 12. For the cohort in which the patient will participate, there are no contra-indications to receiving the approved partner combination drugs 13. Ability to comply with protocol requirements 14. 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 or to use two highly effective forms of contraception, one of which must be a barrier method. 15. Patients must have been advised to take measures to avoid or minimise exposure to UV light for the duration of study participation and for a period of 4 weeks following the last dose of study medication 16. Male patients receiving oxaliplatin must have been offered advice on and/or sought counselling for conservation of sperm prior to the first dose of study medication \>3rd-line patients 1. Received at least two prior lines of therapy for locally advanced or metastatic CRC, including one fluoropyrimidine plus oxaliplatin and one fluoropyrimidine plus irinotecan containing regimen. Previous treatment with SoC regimens in combination with molecular targeted therapies is permitted and patients who received FOLFOXIRI-based regimens in 1st-/2nd-line settings may be included. 2. Patients due to receive NUFOX should be suitable for re-challenge with an oxaliplatin-based regimen 3. Patients due to receive NUFIRI should be suitable for re-challenge with an irinotecan-based therapy 2nd-/3rd-line patients 1. Received at least one but no more than two prior lines of fluoropyrimidine-containing therapy in combination with oxaliplatin and/or irinotecan for locally advanced or metastatic CRC. Previous treatment with SoC regimens in combination with molecular targeted therapies is permitted and patients who received FOLFOXIRI-based regimens in 1st-/2nd-line settings may be included. 3rd-line patients enrolled to Arms 2c and 2d must have received prior bevacizumab treatment, unless ineligible or unless bevacizumab was not standard of care according to relevant region-specific treatment recommendations 2. Patients in Part 2 due to receive NUFOX should be suitable for re-challenge with an oxaliplatin-based regimen 3. Patients in Part 2 due to receive NUFIRI should be suitable for re-challenge with an irinotecan-based regimen Combination chemotherapy ineligible patients 1. May have received one prior fluoropyrimidine-containing regimen for locally advanced or metastatic CRC 2. Ineligible to receive combination therapy for locally advanced or metastatic CRC 3. Creatinine clearance \>30mL/min Rapid progressors 1. Received no more than two prior lines of fluoropyrimidine-containing therapy in combination with oxaliplatin and/or irinotecan for locally advanced or metastatic CRC. Previous treatment with SoC regimens in combination with molecular targeted therapies is permitted and patients who received FOLFOXIRI-based regimens in 1st-/2nd-line settings may be included. 2. Have had tumour progression ≤3 months of starting the last fluoropyrimidine-containing regimen 3. Patients due to receive NUFOX should be suitable for re-challenge with an oxaliplatin-based regimen 4. Patients due to receive NUFIRI should be suitable for re-challenge with an irinotecan-based regimen 2nd-line patients 1\. Received one prior line of fluoropyrimidine-containing therapy in combination with oxaliplatin and/or irinotecan for locally advanced or metastatic CRC. Previous treatment with SoC regimens in combination with molecular targeted therapies is permitted and patients who received triplet chemotherapy based regimens is allowed. Maintenance patients 1. Received at least 12 weeks of 1st-line SoC therapy for locally advanced or metastatic CRC and achieved at least stable disease 2. Eligible for maintenance therapy
Exclusion criteria
All patients 1. Prior history of hypersensitivity or current contra-indications to 5-FU or capecitabine 2. Prior history of hypersensitivity or current contra-indications to any of the combination agents required for the study arm to which the patient is assigned 3. History of allergic reactions attributed to the components of the NUC-3373 drug product formulation 4. Symptomatic CNS or leptomeningeal metastases 5. Symptomatic ascites, ascites currently requiring drainage procedures or ascites requiring drainage over the prior 3 months 6. Chemotherapy, radiotherapy (other than short cycle of palliative radiotherapy \[e.g. for bone pain\]), immunotherapy or exposure to another investigational agent within 28 days (or five times half-life for a biological or molecular targeted agent or three times the half-life for an immunotherapy agent) of first receipt of study drug 7. Residual toxicities from prior chemotherapy or radiotherapy, which have not regressed to Grade ≤1 severity (CTCAE v5.0) except for alopecia. In cohorts not containing oxaliplatin, residual Grade 2 neuropathy is allowed. 8. History of another malignancy diagnosed within the past 5 years, with the exception of adequately treated non-melanoma skin cancer curatively treated carcinoma in situ 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 not requiring treatment. Patients with previous invasive cancers are eligible if treatment was completed more than 3 years prior to initiating the current study treatment and there is no evidence of recurrence. 9. Presence of active bacterial or viral infection (including SARS-CoV-2, Herpes Zoster or chicken pox), known HIV positive or known active hepatitis B or C 10. 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 their participation in the study, or with the interpretation of the results 11. Any condition (e.g. known or suspected poor compliance, psychological instability, geographical location) that, in the judgment of the Investigator, may affect the patient's ability to sign the informed consent and undergo study procedures 12. Currently pregnant, lactating or breastfeeding 13. QTc interval \>450 milliseconds for males and \>470 milliseconds for females 14. Required concomitant use of drugs known to prolong QT/QTc interval 15. Required concomitant use of strong CYP3A4 inducers or strong CYP3A4 inhibitors, or use of strong CYP3A4 inducers within 2 weeks of first receipt of study drug or use of strong CYP3A4 inhibitors within 1 week of first receipt of study drug 16. For patients receiving irinotecan: Use of strong UGT1A1 inhibitors within 1 week of first receipt of study drug 17. Has received a live vaccination within four weeks of first planned dose of study medication 18. Known DPD or TYMP mutations associated with toxicity to fluoropyrimidines 19. Use of warfarin and other types of long acting anti-coagulants is prohibited within 4 weeks of the first dose of study treatment Patients receiving bevacizumab 1. Patients with a history of haemoptysis (≥1/2 tsp of red blood) 2. Wound healing complications or surgery within 28 days of starting bevacizumab 3. Severe chronic wounds, ulcers or bone fracture 4. Arterial thromboembolic events or haemorrhage within 6 months prior to study entry (except for tumour bleeding surgically treated by tumour resection) 5. Bleeding diatheses or coagulopathy 6. Receiving full-dose anti-coagulation treatment 7. Uncontrolled hypertension 8. Clinically significant coronary heart disease or myocardial infarction within the last 12 months or high risk of uncontrolled arrhythmia 9. Severe proteinuria 10. Acute or subacute ileus, chronic inflammatory bowel disease or chronic diarrhoea 11. Any contraindications present in the bevacizumab Prescribing Information Patients receiving cetuximab or panitumumab 1. Clinically significant coronary heart disease or myocardial infarction within the last 12 months or high risk of uncontrolled arrhythmia 2. Acute or subacute ileus, chronic inflammatory bowel disease or chronic diarrhoea 3. Hypomagnesaemia or hypokalaemia not controlled by oral therapy 4. Any contraindications present in the cetuximab or panitumumab Prescribing Information
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change From Baseline in Tumour Size | Assessed every 8 weeks following Day 1 until the end of study (up to 25 months) | Efficacy (per RECIST v 1.1): defined as the best percentage change from baseline in tumour size (mm) |
| Disease Control Rate (DCR) | Assessed every 8 weeks following Day 1 until the end of study (up to 25 months) | Efficacy (per RECIST v 1.1): defined as the proportion of patients achieving confirmed response (CR and PR) or stable disease (SD) as the best overall response |
| Duration of Stable Disease (DoSD) | Assessed every 8 weeks following Day 1 until the end of study (up to 25 months) | Efficacy (per RECIST v 1.1): defined as the time from the time measurement criteria are first met for SD until the first date that recurrence or progressive disease (PD) is objectively documented |
| Progression Free Survival (PFS) | Assessed every 8 weeks following Day 1 until the end of study (up to 25 months) | Efficacy (per RECIST v 1.1): defined as the time from first dose of study treatment until the date of objective disease progression or death |
| Overall Survival (OS) | From the date of randomization until the date of death from any cause, until the end of study (up to 25 months)] | Efficacy: defined as the time from randomization until the date of death from any cause |
| Best Overall Response | Assessed every 8 weeks from Day 1 until the end of study (up to 25 months) | Best overall response to study treatment according to RECIST v1.1 |
Countries
France, United Kingdom, United States
Participant flow
Recruitment details
A total of 111 patients were recruited between July 2018 and June 2023.
Pre-assignment details
No participants were recruited in Arms 1d, 2c, 2d, 3b, 3d, 3e, 3f, and 3g
Participants by arm
| Arm | Count |
|---|---|
| NUC-3373 + Leucovorin (LV) Every Other Week Arm 1a: NUC-3373 administered IV followed by a 2-week washout period. The next dose of NUC-3373 administered in combination with LV at 400 mg/m2. All subsequent doses of NUC-3373 administered in combination with LV every 2 weeks in 28-day cycles.
NUC-3373 + leucovorin: NUC-3373 + leucovorin | 11 |
| NUC-3373 Every Other Week Arm 1b: LV 400 mg/m2 administered IV over 2 hours prior to NUC-3373 infusion followed by a 2-week washout period. Then, NUC-3373 administered IV every 2 weeks without LV in 28-day cycles.
NUC-3373: NUC-3373 | 11 |
| NUC-3373 (1500 mg/m2) + Leucovorin (LV) Weekly Arm 1c: LV 400 mg/m2 administered IV over 2 hours followed by NUC-3373 1500 mg/m2 administered IV weekly on Days 1, 8, 15 and 22 of 28-day cycles.
NUC-3373 + leucovorin: NUC-3373 + leucovorin | 12 |
| NUC-3373 (2500 mg/m2) + Leucovorin (LV) Weekly Arm 1c: LV 400 mg/m2 administered IV over 2 hours followed by NUC-3373 2500 mg/m2 administered IV weekly on Days 1, 8, 15 and 22 of 28-day cycles.
NUC-3373 + leucovorin: NUC-3373 + leucovorin | 6 |
| NUC-3373 + Leucovorin (LV); Combination Chemotherapy Ineligible Arm 1d: LV 400 mg/m2 administered IV over 2 hours followed by NUC-3373 administered IV on Days 1, 8, 15 and 22 of 28-day cycles.
NUC-3373 + leucovorin: NUC-3373 + leucovorin | 0 |
| NUC-3373 + Oxaliplatin Weekly Arm 2a: NUC-3373+LV (400 mg/m2) administered weekly on Days 1, 8, 15 and 22 of 28-day cycles in combination with oxaliplatin (85 mg/m2) administered on Days 1 and 15.
NUFOX: NUC-3373 + oxaliplatin | 23 |
| NUC-3373 + Irinotecan Weekly Arm 2b: NUC-3373+LV (400 mg/m2) administered weekly on Days 1, 8, 15 and 22 of 28-day cycles in combination with irinotecan (180 mg/m2) on Days 1 and 15.
NUFIRI: NUC-3373 + irinotecan | 25 |
| NUC-3373 + Irinotecan Weekly (PK Sub-study) Arm 2b (PK sub-study): NUC-3373+LV (400 mg/m2) administered weekly on Days 1, 8, 15 and 22 of 28-day cycles in combination with irinotecan (180 mg/m2) on Days 1 and 15.
NUFIRI: NUC-3373 + irinotecan | 9 |
| NUC-3373 + Oxaliplatin (NUFOX) Expansion Arm 2c: At the completion of Arm 2a, the recommended dose of NUC-3373 (+LV 400 mg/m2) administered weekly on Days 1, 8, 15 and 22 of 28-day cycles in combination with oxaliplatin (85 mg/m2) administered on Days 1 and 15.
NUFOX: NUC-3373 + oxaliplatin | 0 |
| NUC-3373 + Irinotecan (NUFIRI) Expansion Arm 2d: At the completion of Arm 2b, the recommended dose of NUC-3373 (+LV 400 mg/m2) administered weekly on Days 1, 8, 15 and 22 of 28-day cycles in combination with irinotecan (180 mg/m2) on Days 1 and 15.
NUFIRI: NUC-3373 + irinotecan | 0 |
| NUFOX + Bevacizumab Weekly Arm 3a: NUC-3373, LV and oxaliplatin at dose levels used in Arm 2a will be combined with bevacizumab. NUC-3373+LV will be administered weekly, oxaliplatin and bevacizumab will be administered every other week.
NUFOX + VEGF pathway inhibitor: NUC-3373 + oxaliplatin + bevacizumab | 5 |
| NUFOX + Bevacizumab Every Other Week Arm 3b: NUC-3373, LV and oxaliplatin at dose levels used in Arm 2a will be combined with bevacizumab. NUC-3373+LV+oxaliplatin+bevacizumab will be administered every other week.
NUFOX + VEGF pathway inhibitor: NUC-3373 + oxaliplatin + bevacizumab | 0 |
| NUFIRI + Bevacizumab Weekly Arm 3c: NUC-3373, LV and irinotecan at dose levels used in Arm 2b will be combined with bevacizumab. NUC-3373+LV will be administered weekly, irinotecan and bevacizumab will be administered every other week.
NUFIRI + VEGF pathway inhibitor: NUC-3373 + irinotecan + bevacizumab | 9 |
| NUFIRI + Bevacizumab Every Other Week Arm 3d: NUC-3373, LV and irinotecan at dose levels used in Arm 2b will be combined with bevacizumab. NUC-3373+LV+irinotecan+bevacizumab will be administered every other week.
NUFIRI + VEGF pathway inhibitor: NUC-3373 + irinotecan + bevacizumab | 0 |
| NUC-3373 + LV + Bevacizumab; Maintenance Patients Arm 3e: NUC-3373+LV (400 mg/m2) administered weekly on Days 1, 8, 15 and 22 of 28-day cycles in combination with bevacizumab (administered every other week).
NUC-3373 + bevacizumab: NUC-3373 + bevacizumab | 0 |
| NUFOX + Cetuximab Arm 3f: NUC-3373, LV and oxaliplatin at dose levels used in Arm 2a may be administered in subsequent cetuximab cohorts. NUC-3373+LV may be administered weekly or every other week, oxaliplatin will be administered every other week and cetuximab will be administered weekly.
NUFOX + EGFR inhibitor: NUC-3373 + oxaliplatin + cetuximab/panitumumab | 0 |
| NUFIRI + Cetuximab Arm 3g: NUC-3373, LV and irinotecan at dose levels used in Arm 2b may be administered in subsequent cetuximab cohorts. NUC-3373+LV may be administered weekly or every other week, irinotecan will be administered every other week and cetuximab will be administered weekly.
NUFIRI + EGFR inhibitor: NUC-3373 + irinotecan + cetuximab/panitumumab | 0 |
| Total | 111 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 | FG014 | FG015 | FG016 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 1 | 0 | 2 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Clinical Progression | 2 | 3 | 2 | 1 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Death | 2 | 2 | 0 | 0 | 0 | 7 | 9 | 6 | 0 | 0 | 3 | 0 | 4 | 0 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Physician/Sponsor Decision | 1 | 0 | 1 | 0 | 0 | 2 | 2 | 2 | 0 | 0 | 2 | 0 | 4 | 0 | 0 | 0 | 0 |
| Overall Study | Progression per RECIST | 6 | 6 | 7 | 4 | 0 | 7 | 8 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 2 | 0 | 0 | 2 | 4 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | NUC-3373 + Leucovorin (LV) Every Other Week | NUC-3373 Every Other Week | NUC-3373 (1500 mg/m2) + Leucovorin (LV) Weekly | NUC-3373 (2500 mg/m2) + Leucovorin (LV) Weekly | NUC-3373 + Oxaliplatin Weekly | NUC-3373 + Irinotecan Weekly | NUC-3373 + Irinotecan Weekly (PK Sub-study) | NUFOX + Bevacizumab Weekly | NUFIRI + Bevacizumab Weekly | Total |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 55.1 Years STANDARD_DEVIATION 13.2 | 59.1 Years STANDARD_DEVIATION 9.3 | 55.4 Years STANDARD_DEVIATION 10.2 | 56.0 Years STANDARD_DEVIATION 11 | 58.3 Years STANDARD_DEVIATION 10 | 56.7 Years STANDARD_DEVIATION 10.1 | 55.3 Years STANDARD_DEVIATION 10 | 65 Years STANDARD_DEVIATION 5.9 | 54.3 Years STANDARD_DEVIATION 14.2 | 57 Years STANDARD_DEVIATION 10.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 11 Participants | 10 Participants | 6 Participants | 21 Participants | 21 Participants | 8 Participants | 4 Participants | 7 Participants | 99 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 3 Participants | 0 Participants | 1 Participants | 2 Participants | 8 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants | 1 Participants | 1 Participants | 1 Participants | 7 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) White | 10 Participants | 10 Participants | 10 Participants | 5 Participants | 20 Participants | 19 Participants | 8 Participants | 4 Participants | 7 Participants | 93 Participants |
| Sex: Female, Male Female | 4 Participants | 5 Participants | 4 Participants | 4 Participants | 12 Participants | 10 Participants | 7 Participants | 2 Participants | 3 Participants | 51 Participants |
| Sex: Female, Male Male | 7 Participants | 6 Participants | 8 Participants | 2 Participants | 11 Participants | 15 Participants | 2 Participants | 3 Participants | 6 Participants | 60 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 11 | 4 / 11 | 1 / 12 | 0 / 6 | 11 / 23 | 11 / 25 | 6 / 9 | 3 / 5 | 4 / 9 |
| other Total, other adverse events | 10 / 10 | 11 / 11 | 11 / 11 | 6 / 6 | 23 / 23 | 23 / 23 | 8 / 8 | 5 / 5 | 9 / 9 |
| serious Total, serious adverse events | 6 / 10 | 2 / 11 | 3 / 11 | 2 / 6 | 11 / 23 | 8 / 23 | 2 / 8 | 4 / 5 | 4 / 9 |
Outcome results
Primary
Best Overall Response
Best overall response to study treatment according to RECIST v1.1
Time frame: Assessed every 8 weeks from Day 1 until the end of study (up to 25 months)
Population: Evaluable for Response (EFR): Patients with measurable disease at baseline who received at least two cycles of study treatment (receiving at least 75% of the planned doses over the two cycles) and had a post-treatment objective disease assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| NUC-3373 + Leucovorin (LV) Every Other Week | Best Overall Response | Complete Response | 0 percentage of participants |
| NUC-3373 + Leucovorin (LV) Every Other Week | Best Overall Response | Progressive Disease | 100.0 percentage of participants |
| NUC-3373 + Leucovorin (LV) Every Other Week | Best Overall Response | Stable Disease | 0 percentage of participants |
| NUC-3373 + Leucovorin (LV) Every Other Week | Best Overall Response | Not Evaluable | 0 percentage of participants |
| NUC-3373 + Leucovorin (LV) Every Other Week | Best Overall Response | Partial Response | 0 percentage of participants |
| NUC-3373 Every Other Week | Best Overall Response | Complete Response | 0 percentage of participants |
| NUC-3373 Every Other Week | Best Overall Response | Not Evaluable | 14.3 percentage of participants |
| NUC-3373 Every Other Week | Best Overall Response | Progressive Disease | 42.9 percentage of participants |
| NUC-3373 Every Other Week | Best Overall Response | Partial Response | 0 percentage of participants |
| NUC-3373 Every Other Week | Best Overall Response | Stable Disease | 42.9 percentage of participants |
| NUC-3373 (1500 mg/m2) + Leucovorin (LV) Weekly | Best Overall Response | Progressive Disease | 37.5 percentage of participants |
| NUC-3373 (1500 mg/m2) + Leucovorin (LV) Weekly | Best Overall Response | Partial Response | 0 percentage of participants |
| NUC-3373 (1500 mg/m2) + Leucovorin (LV) Weekly | Best Overall Response | Complete Response | 0 percentage of participants |
| NUC-3373 (1500 mg/m2) + Leucovorin (LV) Weekly | Best Overall Response | Stable Disease | 62.5 percentage of participants |
| NUC-3373 (1500 mg/m2) + Leucovorin (LV) Weekly | Best Overall Response | Not Evaluable | 0 percentage of participants |
| NUC-3373 (2500 mg/m2) + Leucovorin (LV) Weekly | Best Overall Response | Not Evaluable | 0 percentage of participants |
| NUC-3373 (2500 mg/m2) + Leucovorin (LV) Weekly | Best Overall Response | Progressive Disease | 50.0 percentage of participants |
| NUC-3373 (2500 mg/m2) + Leucovorin (LV) Weekly | Best Overall Response | Complete Response | 0 percentage of participants |
| NUC-3373 (2500 mg/m2) + Leucovorin (LV) Weekly | Best Overall Response | Partial Response | 0 percentage of participants |
| NUC-3373 (2500 mg/m2) + Leucovorin (LV) Weekly | Best Overall Response | Stable Disease | 50 percentage of participants |
| NUC-3373 + Oxaliplatin Weekly | Best Overall Response | Partial Response | 0 percentage of participants |
| NUC-3373 + Oxaliplatin Weekly | Best Overall Response | Complete Response | 0 percentage of participants |
| NUC-3373 + Oxaliplatin Weekly | Best Overall Response | Stable Disease | 46.7 percentage of participants |
| NUC-3373 + Oxaliplatin Weekly | Best Overall Response | Not Evaluable | 6.7 percentage of participants |
| NUC-3373 + Oxaliplatin Weekly | Best Overall Response | Progressive Disease | 46.7 percentage of participants |
| NUC-3373 + Irinotecan Weekly | Best Overall Response | Progressive Disease | 42.9 percentage of participants |
| NUC-3373 + Irinotecan Weekly | Best Overall Response | Partial Response | 0 percentage of participants |
| NUC-3373 + Irinotecan Weekly | Best Overall Response | Complete Response | 0 percentage of participants |
| NUC-3373 + Irinotecan Weekly | Best Overall Response | Not Evaluable | 14.3 percentage of participants |
| NUC-3373 + Irinotecan Weekly | Best Overall Response | Stable Disease | 42.9 percentage of participants |
| NUC-3373 + Irinotecan Weekly (PK Sub-study) | Best Overall Response | Not Evaluable | 0 percentage of participants |
| NUC-3373 + Irinotecan Weekly (PK Sub-study) | Best Overall Response | Complete Response | 0 percentage of participants |
| NUC-3373 + Irinotecan Weekly (PK Sub-study) | Best Overall Response | Partial Response | 0 percentage of participants |
| NUC-3373 + Irinotecan Weekly (PK Sub-study) | Best Overall Response | Progressive Disease | 66.7 percentage of participants |
| NUC-3373 + Irinotecan Weekly (PK Sub-study) | Best Overall Response | Stable Disease | 33.3 percentage of participants |
| NUFOX + Bevacizumab Weekly | Best Overall Response | Progressive Disease | 20.0 percentage of participants |
| NUFOX + Bevacizumab Weekly | Best Overall Response | Complete Response | 0 percentage of participants |
| NUFOX + Bevacizumab Weekly | Best Overall Response | Stable Disease | 80.0 percentage of participants |
| NUFOX + Bevacizumab Weekly | Best Overall Response | Not Evaluable | 0 percentage of participants |
| NUFOX + Bevacizumab Weekly | Best Overall Response | Partial Response | 0 percentage of participants |
| NUFIRI + Bevacizumab Weekly | Best Overall Response | Partial Response | 0 percentage of participants |
| NUFIRI + Bevacizumab Weekly | Best Overall Response | Not Evaluable | 0 percentage of participants |
| NUFIRI + Bevacizumab Weekly | Best Overall Response | Stable Disease | 88.9 percentage of participants |
| NUFIRI + Bevacizumab Weekly | Best Overall Response | Progressive Disease | 11.1 percentage of participants |
| NUFIRI + Bevacizumab Weekly | Best Overall Response | Complete Response | 0 percentage of participants |
Primary
Disease Control Rate (DCR)
Efficacy (per RECIST v 1.1): defined as the proportion of patients achieving confirmed response (CR and PR) or stable disease (SD) as the best overall response
Time frame: Assessed every 8 weeks following Day 1 until the end of study (up to 25 months)
Population: Evaluable for Response (EFR): Patients with measurable disease at baseline who received at least two cycles of study treatment (receiving at least 75% of the planned doses over the two cycles) and had a post-treatment objective disease assessment. Data are only available for patients in the EFR set achieving confirmed response (CR and PR) or stable disease (SD) as the best overall response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NUC-3373 + Leucovorin (LV) Every Other Week | Disease Control Rate (DCR) | 0 percentage of patients |
| NUC-3373 Every Other Week | Disease Control Rate (DCR) | 42.9 percentage of patients |
| NUC-3373 (1500 mg/m2) + Leucovorin (LV) Weekly | Disease Control Rate (DCR) | 62.5 percentage of patients |
| NUC-3373 (2500 mg/m2) + Leucovorin (LV) Weekly | Disease Control Rate (DCR) | 50 percentage of patients |
| NUC-3373 + Oxaliplatin Weekly | Disease Control Rate (DCR) | 46.7 percentage of patients |
| NUC-3373 + Irinotecan Weekly | Disease Control Rate (DCR) | 42.9 percentage of patients |
| NUC-3373 + Irinotecan Weekly (PK Sub-study) | Disease Control Rate (DCR) | 33.3 percentage of patients |
| NUFOX + Bevacizumab Weekly | Disease Control Rate (DCR) | 80.0 percentage of patients |
| NUFIRI + Bevacizumab Weekly | Disease Control Rate (DCR) | 88.9 percentage of patients |
Primary
Duration of Stable Disease (DoSD)
Efficacy (per RECIST v 1.1): defined as the time from the time measurement criteria are first met for SD until the first date that recurrence or progressive disease (PD) is objectively documented
Time frame: Assessed every 8 weeks following Day 1 until the end of study (up to 25 months)
Population: Evaluable for Response (EFR): Patients with measurable disease at baseline who received at least two cycles of study treatment (receiving at least 75% of the planned doses over the two cycles) and had a post-treatment objective disease assessment. Data are only available for patients in the EFR set who did not have a best response of progressive disease and who had evaluable post-dose target lesion data and had Stable Disease.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NUC-3373 Every Other Week | Duration of Stable Disease (DoSD) | 1.9 months |
| NUC-3373 (1500 mg/m2) + Leucovorin (LV) Weekly | Duration of Stable Disease (DoSD) | 2.6 months |
| NUC-3373 (2500 mg/m2) + Leucovorin (LV) Weekly | Duration of Stable Disease (DoSD) | 1.9 months |
| NUC-3373 + Oxaliplatin Weekly | Duration of Stable Disease (DoSD) | 3.7 months |
| NUC-3373 + Irinotecan Weekly | Duration of Stable Disease (DoSD) | 3.2 months |
| NUC-3373 + Irinotecan Weekly (PK Sub-study) | Duration of Stable Disease (DoSD) | 2.3 months |
| NUFOX + Bevacizumab Weekly | Duration of Stable Disease (DoSD) | 6.5 months |
| NUFIRI + Bevacizumab Weekly | Duration of Stable Disease (DoSD) | 4.6 months |
Primary
Overall Survival (OS)
Efficacy: defined as the time from randomization until the date of death from any cause
Time frame: From the date of randomization until the date of death from any cause, until the end of study (up to 25 months)]
Population: Full Analysis Set: All randomised patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NUC-3373 + Leucovorin (LV) Every Other Week | Overall Survival (OS) | 1.9 months |
| NUC-3373 Every Other Week | Overall Survival (OS) | 3.0 months |
| NUC-3373 (1500 mg/m2) + Leucovorin (LV) Weekly | Overall Survival (OS) | 3.6 months |
| NUC-3373 (2500 mg/m2) + Leucovorin (LV) Weekly | Overall Survival (OS) | 3.6 months |
| NUC-3373 + Oxaliplatin Weekly | Overall Survival (OS) | 3.4 months |
| NUC-3373 + Irinotecan Weekly | Overall Survival (OS) | 3.2 months |
| NUC-3373 + Irinotecan Weekly (PK Sub-study) | Overall Survival (OS) | 7.3 months |
| NUFOX + Bevacizumab Weekly | Overall Survival (OS) | 14.2 months |
| NUFIRI + Bevacizumab Weekly | Overall Survival (OS) | 12.8 months |
Primary
Percentage Change From Baseline in Tumour Size
Efficacy (per RECIST v 1.1): defined as the best percentage change from baseline in tumour size (mm)
Time frame: Assessed every 8 weeks following Day 1 until the end of study (up to 25 months)
Population: Evaluable for Response (EFR): Patients with measurable disease at baseline who received at least two cycles of study treatment (receiving at least 75% of the planned doses over the two cycles) and had a post-treatment objective disease assessment. Data are only available for patients in the EFR set who did not have a best response of progressive disease and who had evaluable post-dose target lesion data. All patients in Arm 1a had a best response of either progressive disease or non-evaluable.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NUC-3373 Every Other Week | Percentage Change From Baseline in Tumour Size | 8.3 Percent change |
| NUC-3373 (1500 mg/m2) + Leucovorin (LV) Weekly | Percentage Change From Baseline in Tumour Size | 2.9 Percent change |
| NUC-3373 (2500 mg/m2) + Leucovorin (LV) Weekly | Percentage Change From Baseline in Tumour Size | 3.2 Percent change |
| NUC-3373 + Oxaliplatin Weekly | Percentage Change From Baseline in Tumour Size | 2.3 Percent change |
| NUC-3373 + Irinotecan Weekly | Percentage Change From Baseline in Tumour Size | 7.9 Percent change |
| NUC-3373 + Irinotecan Weekly (PK Sub-study) | Percentage Change From Baseline in Tumour Size | 2.8 Percent change |
| NUFOX + Bevacizumab Weekly | Percentage Change From Baseline in Tumour Size | -13.9 Percent change |
| NUFIRI + Bevacizumab Weekly | Percentage Change From Baseline in Tumour Size | -11.1 Percent change |
Primary
Progression Free Survival (PFS)
Efficacy (per RECIST v 1.1): defined as the time from first dose of study treatment until the date of objective disease progression or death
Time frame: Assessed every 8 weeks following Day 1 until the end of study (up to 25 months)
Population: Patients who received at least one dose of NUC-3373
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NUC-3373 + Leucovorin (LV) Every Other Week | Progression Free Survival (PFS) | 1.7 months |
| NUC-3373 Every Other Week | Progression Free Survival (PFS) | 2.3 months |
| NUC-3373 (1500 mg/m2) + Leucovorin (LV) Weekly | Progression Free Survival (PFS) | 2.9 months |
| NUC-3373 (2500 mg/m2) + Leucovorin (LV) Weekly | Progression Free Survival (PFS) | 1.8 months |
| NUC-3373 + Oxaliplatin Weekly | Progression Free Survival (PFS) | 2.5 months |
| NUC-3373 + Irinotecan Weekly | Progression Free Survival (PFS) | 3.6 months |
| NUC-3373 + Irinotecan Weekly (PK Sub-study) | Progression Free Survival (PFS) | 2.0 months |
| NUFOX + Bevacizumab Weekly | Progression Free Survival (PFS) | 7.7 months |
| NUFIRI + Bevacizumab Weekly | Progression Free Survival (PFS) | 5.5 months |