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A Safety, Pharmacokinetic and Efficacy Study of NUC-3373 in Combination With Standard Agents Used in Colorectal Cancer Treatment

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.
Colon, Phase I, Rectal
Phase I
Adults
Chemotherapy - cytotoxic, Mol. targeted/Immunotherapy/Biologics
Bevacizumab, Cetuximab, Irinotecan, Leucovorin, NUC-3373, Oxaliplatin
Ciombor, Kristen
International
Vanderbilt University
11-12-2018
Treatment
VICCGIP1851
NCT03428958

Eligibility

18 Years
BOTH
NO
Inclusion Criteria:

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 8. Adequate bone marrow function as defined by: ANC 1.510^9/L, platelet count 10010^9/L (with no evidence of bleeding), and haemoglobin 9 g/dL 9. Adequate liver function as defined by serum total bilirubin 1.5ULN, AST and ALT 2.5ULN (or 5ULN if liver metastases present) 10. Adequate renal function assessed as serum creatinine 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 fluoropyrimide-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. 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 fluoropyrimide-containing regimen 3. Patients in Part 2 or 3 due to receive NUFOX should be suitable for re-challenge with an oxaliplatin-based regimen 4. Patients in Part 2 or 3 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 for bone pain), immunotherapy or exposure to another investigational agent within 28 days (or five times half-life for a biological 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. Irinotecan cohorts: use of strong CYP3A4 inducers within 2 weeks of first dose of study drug or use of strong CYP3A4 or UGT1A1 inhibitors within 1 week of first dose of study drug 16. Has received a live vaccination within four weeks of first planned dose of study medication 17. Known DPD or TYMP mutations associated with toxicity to fluoropyrimidines 18. 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

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