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

Sponsor

NuCana plc (Other)

Overall Status

Recruiting

CT.gov ID

NCT03428958

Collaborator

(none)

225

Enrollment

Locations

Arms

49.5

Anticipated Duration (Months)

37.5

Patients Per Site

0.8

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer Colorectal Neoplasms Colorectal Carcinoma Colorectal Tumors Neoplasms, Colorectal	Drug: NUC-3373 + leucovorin Drug: NUC-3373 Drug: NUFOX Drug: NUFOX + VEGF pathway inhibitor Drug: NUFOX + EGFR inhibitor Drug: NUFIRI Drug: NUFIRI + VEGF pathway inhibitor Drug: NUFIRI + EGFR inhibitor Drug: NUC-3373 + bevacizumab	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

225 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

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.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.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase Ib/II Open Label Study to Assess the Safety and Pharmacokinetics of NUC-3373, a Nucleotide Analogue, Given in Combination With Standard Agents Used in Colorectal Cancer Treatment

Actual Study Start Date :

Oct 16, 2018

Anticipated Primary Completion Date :

Dec 1, 2022

Anticipated Study Completion Date :

Dec 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: NUC-3373 + leucovorin (LV) fortnightly 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.	Drug: NUC-3373 + leucovorin NUC-3373 + leucovorin Other Names: folinic acid levoleucovorin Nucleotide analogue
Experimental: NUC-3373 fortnightly 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.	Drug: NUC-3373 NUC-3373 Other Names: Nucleotide analogue
Experimental: NUC-3373 + leucovorin (LV) weekly 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.	Drug: NUC-3373 + leucovorin NUC-3373 + leucovorin Other Names: folinic acid levoleucovorin Nucleotide analogue
Experimental: 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.	Drug: NUC-3373 + leucovorin NUC-3373 + leucovorin Other Names: folinic acid levoleucovorin Nucleotide analogue
Experimental: 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.	Drug: NUFOX NUC-3373 + oxaliplatin Other Names: Eloxatin Nucleotide analogue
Experimental: 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.	Drug: NUFIRI NUC-3373 + irinotecan Other Names: Campto Camptosar Nucleotide analogue
Experimental: 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.	Drug: NUFOX NUC-3373 + oxaliplatin Other Names: Eloxatin Nucleotide analogue
Experimental: 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.	Drug: NUFIRI NUC-3373 + irinotecan Other Names: Campto Camptosar Nucleotide analogue
Experimental: NUFOX + bevacizumab weekly Arm 3a: NUC-3373, LV and oxaliplatin at dose levels used in Arm 2c will be combined with bevacizumab. NUC-3373+LV will be administered weekly, oxaliplatin will be administered fortnightly and bevacizumab will be administered in accordance with standard local practice.	Drug: NUFOX + VEGF pathway inhibitor NUC-3373 + oxaliplatin + bevacizumab Other Names: Eloxatin Avastin Nucleotide analogue
Experimental: NUFOX + bevacizumab fortnightly Arm 3b: NUC-3373, LV and oxaliplatin at dose levels used in Arm 2c will be combined with bevacizumab. NUC-3373+LV+oxaliplatin will be administered fortnightly and bevacizumab will be administered in accordance with standard local practice.	Drug: NUFOX + VEGF pathway inhibitor NUC-3373 + oxaliplatin + bevacizumab Other Names: Eloxatin Avastin Nucleotide analogue
Experimental: NUFIRI + bevacizumab weekly Arm 3c: NUC-3373, LV and irinotecan at dose levels used in Arm 2d will be combined with bevacizumab. NUC-3373+LV will be administered weekly, irinotecan will be administered fortnightly and bevacizumab will be administered in accordance with standard local practice.	Drug: NUFIRI + VEGF pathway inhibitor NUC-3373 + irinotecan + bevacizumab Other Names: Campto Camptosar Avastin Nucleotide analogue
Experimental: NUFIRI + bevacizumab fortnightly Arm 3d: NUC-3373, LV and irinotecan at dose levels used in Arm 2d will be combined with bevacizumab. NUC-3373+LV+irinotecan will be administered fortnightly and bevacizumab will be administered in accordance with standard local practice.	Drug: NUFIRI + VEGF pathway inhibitor NUC-3373 + irinotecan + bevacizumab Other Names: Campto Camptosar Avastin Nucleotide analogue
Experimental: 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 and bevacizumab will be administered in accordance with standard local practice.	Drug: NUC-3373 + bevacizumab NUC-3373 + bevacizumab Other Names: Nucleotide analogue Avastin
Experimental: NUFOX + cetuximab Arm 3f: NUC-3373, LV and oxaliplatin at dose levels used in Arm 2c may be administered in subsequent cetuximab cohorts. NUC-3373+LV may be administered weekly or fortnightly, oxaliplatin will be administered fortnightly and cetuximab will be administered in accordance with standard local practice.	Drug: NUFOX + EGFR inhibitor NUC-3373 + oxaliplatin + cetuximab/panitumumab Other Names: Eloxatin Erbitux Nucleotide analogue Vectibix
Experimental: NUFIRI + cetuximab Arm 3g: NUC-3373, LV and irinotecan at dose levels used in Arm 2d may be administered in subsequent cetuximab cohorts. NUC-3373+LV may be administered weekly or fortnightly, irinotecan will be administered fortnightly and cetuximab will be administered in accordance with standard local practice.	Drug: NUFIRI + EGFR inhibitor NUC-3373 + irinotecan + cetuximab/panitumumab Other Names: Campto Camptosar Erbitux Nucleotide analogue Vectibix

Outcome Measures

Primary Outcome Measures

Number of patients reporting treatment-emergent adverse events (TEAEs) [Assessed from baseline to 30 days after last dose of study drug]
Treatment-emergent adverse events will be assessed and graded by CTCAE v5.0
Number of patients with treatment-emergent clinically significant changes in laboratory parameters, ECG changes, or changes in physical examinations [Assessed from baseline to 30 days after last dose of study drug]
Each will be assessed and graded by CTCAE v5.0

Secondary Outcome Measures

Tolerability of NUC-3373 in each combination cohort measured by dose intensity in Cycle 1 [Assessed from baseline to 30 days after last dose of study drug]
Dose intensity will be measured by the actual dose received as compared to the projected dose to be administered in Cycle 1

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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
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 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 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.
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 fluoropyrimide-containing regimen
Patients in Part 2 or 3 due to receive NUFOX should be suitable for re-challenge with an oxaliplatin-based regimen
Patients in Part 2 or 3 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 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
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
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
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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
2	Vanderbilt University	Nashville	Tennessee	United States	37232
3	Seattle Cancer Center	Seattle	Washington	United States	98109-1023
4	Hopital Franco-Britannique	Levallois-Perret		France	92300
5	The Beatson West of Scotland Cancer Centre	Glasgow		United Kingdom	G12 0YN
6	University of Oxford	Oxford		United Kingdom	OX3 7LE