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

Phase 1

Completed

Conditions: Neoplasms, Colorectal
Colorectal Carcinoma
Colorectal Neoplasms
Colorectal Tumors
Colorectal Cancer

Interventions: Drug: NUFIRI
Drug: NUC-3373 + leucovorin
Drug: NUC-3373
Drug: NUFOX + VEGF pathway inhibitor
Drug: NUFOX
Drug: NUFIRI + VEGF pathway inhibitor
Drug: NUFIRI + EGFR inhibitor
Drug: NUC-3373 + bevacizumab
Drug: NUFOX + EGFR inhibitor

Registration Number: NCT03428958

Lead Sponsor: NuCana plc

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 111

Inclusion Criteria

All patients

Provision of written informed consent
Have histological confirmation of CRC with evidence of locally advanced/unresectable or metastatic disease
Age ≥18 years
Life expectancy of ≥12 weeks
ECOG Performance status 0 or 1
Measurable disease as defined by RECIST v1.1
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
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
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)
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.
Serum albumin ≥3 g/dL
For the cohort in which the patient will participate, there are no contra-indications to receiving the approved partner combination drugs
Ability to comply with protocol requirements
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.
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
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

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.
Patients due to receive NUFOX should be suitable for re-challenge with an oxaliplatin-based regimen
Patients due to receive NUFIRI should be suitable for re-challenge with an irinotecan-based therapy

2nd-/3rd-line patients

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
Patients in Part 2 due to receive NUFOX should be suitable for re-challenge with an oxaliplatin-based regimen
Patients in Part 2 due to receive NUFIRI should be suitable for re-challenge with an irinotecan-based regimen

Combination chemotherapy ineligible patients

May have received one prior fluoropyrimidine-containing regimen for locally advanced or metastatic CRC
Ineligible to receive combination therapy for locally advanced or metastatic CRC
Creatinine clearance >30mL/min

Rapid progressors

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.
Have had tumour progression ≤3 months of starting the last fluoropyrimidine-containing regimen
Patients due to receive NUFOX should be suitable for re-challenge with an oxaliplatin-based regimen
Patients due to receive NUFIRI should be suitable for re-challenge with an irinotecan-based regimen

2nd-line patients

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

Received at least 12 weeks of 1st-line SoC therapy for locally advanced or metastatic CRC and achieved at least stable disease
Eligible for maintenance therapy

Exclusion Criteria

All patients

Prior history of hypersensitivity or current contra-indications to 5-FU or capecitabine
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
History of allergic reactions attributed to the components of the NUC-3373 drug product formulation
Symptomatic CNS or leptomeningeal metastases
Symptomatic ascites, ascites currently requiring drainage procedures or ascites requiring drainage over the prior 3 months
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
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.
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.
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
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
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
Currently pregnant, lactating or breastfeeding
QTc interval >450 milliseconds for males and >470 milliseconds for females
Required concomitant use of drugs known to prolong QT/QTc interval
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
For patients receiving irinotecan: Use of strong UGT1A1 inhibitors within 1 week of first receipt of study drug
Has received a live vaccination within four weeks of first planned dose of study medication
Known DPD or TYMP mutations associated with toxicity to fluoropyrimidines
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

Patients with a history of haemoptysis (≥1/2 tsp of red blood)
Wound healing complications or surgery within 28 days of starting bevacizumab
Severe chronic wounds, ulcers or bone fracture
Arterial thromboembolic events or haemorrhage within 6 months prior to study entry (except for tumour bleeding surgically treated by tumour resection)
Bleeding diatheses or coagulopathy
Receiving full-dose anti-coagulation treatment
Uncontrolled hypertension
Clinically significant coronary heart disease or myocardial infarction within the last 12 months or high risk of uncontrolled arrhythmia
Severe proteinuria
Acute or subacute ileus, chronic inflammatory bowel disease or chronic diarrhoea
Any contraindications present in the bevacizumab Prescribing Information

Patients receiving cetuximab or panitumumab

Clinically significant coronary heart disease or myocardial infarction within the last 12 months or high risk of uncontrolled arrhythmia
Acute or subacute ileus, chronic inflammatory bowel disease or chronic diarrhoea
Hypomagnesaemia or hypokalaemia not controlled by oral therapy
Any contraindications present in the cetuximab or panitumumab Prescribing Information

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
NUC-3373 + irinotecan weekly	NUFIRI	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.
NUC-3373 + leucovorin (LV) every other week	NUC-3373 + leucovorin	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 every other week	NUC-3373	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.
NUFOX + bevacizumab every other week	NUFOX + VEGF pathway inhibitor	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.
NUC-3373 + oxaliplatin (NUFOX) expansion	NUFOX	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.
NUC-3373 + irinotecan (NUFIRI) expansion	NUFIRI	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 + bevacizumab weekly	NUFIRI + VEGF pathway inhibitor	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 + cetuximab	NUFIRI + EGFR inhibitor	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.
NUC-3373 + leucovorin (LV) weekly	NUC-3373 + leucovorin	Arm 1c: LV 400 mg/m2 administered IV over 2 hours followed by NUC-3373 administered IV weekly on Days 1, 8, 15 and 22 of 28-day cycles.
NUC-3373 + oxaliplatin weekly	NUFOX	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.
NUC-3373 + leucovorin (LV); combination chemotherapy ineligible	NUC-3373 + leucovorin	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 + LV + bevacizumab; maintenance patients	NUC-3373 + bevacizumab	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).
NUFOX + bevacizumab weekly	NUFOX + VEGF pathway inhibitor	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.
NUFIRI + bevacizumab every other week	NUFIRI + VEGF pathway inhibitor	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.
NUFOX + cetuximab	NUFOX + EGFR inhibitor	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.

Primary Outcome Measures

Name	Time	Method
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)
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
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

Secondary Outcome Measures

Name	Time	Method

Trial Locations

Locations (10): Dana Farber Cancer Institute
🇺🇸
Boston, Massachusetts, United States
Duke University Medical Center
🇺🇸
Durham, North Carolina, United States
Seattle Cancer Center
🇺🇸
Seattle, Washington, United States
Hopital Franco-Britannique
🇫🇷
Levallois-Perret, France
Vanderbilt University
🇺🇸
Nashville, Tennessee, United States
University College London Hospitals NHS Foundation Trust
🇬🇧
London, United Kingdom
Beth Israel Deaconess Medical Center
🇺🇸
Boston, Massachusetts, United States
The Beatson West of Scotland Cancer Centre
🇬🇧
Glasgow, United Kingdom
Compass Oncology
🇺🇸
Vancouver, Washington, United States
University of Oxford
🇬🇧
Oxford, United Kingdom