NUC-3373 in Advanced Solid Tumours (NuTide: 301)
Research type
Research Study
Full title
A TWO-PART, PHASE 1 OPEN LABEL, DOSE ESCALATION AND EXPANSION STUDY TO ASSESS SAFETY, PHARMACOKINETICS AND CLINICAL ACTIVITY OF NUC-3373, A NUCLEOTIDE ANALOGUE, IN PARTICIPANTS WITH ADVANCED SOLID TUMOURS
IRAS ID
185166
Contact name
Sarah Blagden
Contact email
Sponsor organisation
University of Oxford
Eudract number
2015-002250-13
Clinicaltrials.gov Identifier
Duration of Study in the UK
2 years, 5 months, 4 days
Research summary
Summary of Research
Fluorouracil (5-FU) is the backbone of therapy for a variety of different solid tumours for the last fifty years, however there is still a significant demand for more efficacious and better tolerated systematic therapies.
NUC-3373 has been specifically designed to overcome the cancer resistance mechanism associated with 5-FU, it is likely to be more potent in tumour cells and therefore could be given at a lower dose to achieve efficacy with less off-target toxicity.
The primary purpose of this study is to establish the recommended phase 2 dose (RP2D) for NUC-3373 administered using a weekly schedule and as fortnightly schedule. This will be achieved by determining a recommended phase 2 dose (RP2D) for each administration schedule in Parts 1 and 2. Expansion cohorts for Parts 1 and 2 will then be opened using the RP2D's.Summary of Results
We would like to thank all the patients and their families and friends for their support and participation in this study.
A chemotherapy drug called fluorouracil (5-FU) is commonly used to treat many cancers including colorectal cancer. 5-FU is either given intravenously alone or in combination with other chemotherapy drugs like irinotecan and oxaliplatin. However, cancer cells often develop resistance to 5-FU which means that, after receiving 5-FU treatment for a few months or years, cancers stop shrinking (or may even start growing) after 5-FU is given. Scientists have shown why this resistance happens. They have shown that enzymes in the tumour cells can degrade or destroy 5-FU so it becomes ineffective.
The pharmaceutical company NuCana developed a form of 5-FU that cannot be degraded by these resistance enzymes. Their drug is called NUC-3373. It is designed to enter cancer cells in disguise (thanks to wearing a special chemical “cap”) and, once in the cancer cells, releases high concentrations of 5-FU to damage and kills the cancer cells. The purpose of the NuTide 301 clinical study was to test how safe and how effective NUC-3373 was in patients with cancers including colorectal cancer.
The study was funded by NuCana and led by researchers at the University of Oxford. Patients were recruited at the Churchill Hospital in Oxford, the Beatson West of Scotland Cancer Centre, Glasgow and Belfast City Hospital, Belfast. These centres are part of the UK’s Experimental Cancer Medicines Centres (ECMC) network. This was the first time that NUC-3373 had been tested in people.
The study was designed to test different doses of NUC-3373. Patients with advanced cancer were enrolled into groups (or cohorts). Those that enrolled first received NUC-3373 at its lowest dose. If they tolerated the dose, another cohort of patients was then enrolled at the next higher dose. NUC-3373 was given once a week (weekly) or on alternate weeks (fortnightly) to see if this made a difference to its side effects.
The main aims of the study were to:
• find the best safe dose
• find out how often to have treatment
• find out how well it works
• learn more about the side effects
In order to be selected to enter the study, each patient had a physical examination, blood tests, a heart trace (ECG), and a CT or MRI scan. The patient’s medical records were also checked to make sure they had no other conditions that could interfere with NUC-3373.
NUC-3373 was given by an intravenous infusion in hospital. Patients stayed in the hospital day unit for about 8 hours after the first dose of the study drug. Some patients stayed in overnight.
In the first 4 weeks of treatment, patients saw the study team for a check-up and had blood and urine tests once a week. Extra blood samples were taken at some of the visits. Every 2 months on the study, patients had a CT scan to measure their tumours. If their tumours had grown on NUC-3373, patients discontinued the study and, one month later, repeated their blood tests to make sure they did not have any lasting side effects.In total, 100 patients were considered (or screened) for the NuTide-301 study and 62 took part.
The NUC-3373 was given as a drip into a vein that took between 30 minutes to 4 hours depending on the dose given. Two treatment schedules were tested: NUC-3373 given weekly (Part 1) or fortnightly (Part 2). For people having treatment once a week (Part 1), treatment was given on days 1, 8, 15 and 22 of every month. For people having treatment once every 2 weeks (Part 2), treatment was given on days 1 and 15 of every month.
Patients continued treatment on the study unless they developed adverse side effects or they (or their doctors) made the choice to stop treatment.Weekly NUC-3373 (Part 1)
A total of 46 patients were given NUC-3373 weekly: 18 were women and 28 were men. Their average age was 59.5 years.
The first 4 patients to be enrolled were given NUC-3373 at its lowest dose (125mg/m2) every week for 4 weeks and checked to make sure they didn’t have any serious side effects. After a month, the patients on 125mg/m2 didn’t have any serious side effects, so 7 patients were given a slightly higher dose of NUC-3373 (250mg/m2) every week and checked to make sure they didn’t have any serious side effects.
When the doctors had checked that the patients given 250mg/m2 of NUC-3373 every week didn’t have any serious side effects 8 patients were given 500mg/m2 every week and so on for the following doses:
4 patients were given 750 mg/m2 every week
3 patients were given 1125 mg/m2 every week
3 patients were given 1500 mg/m2 every week
6 patients were given 1875 mg/m2 every week
7 patients were given 2500 mg/m2 every week
4 patients were given 3250 mg/m2 every weekFortnightly NUC-3373 (Part 2)
A total of 16 patients were given NUC-3373 fortnightly, 7 were women and 9 were man and their average age was 59.5 years. The patients in this part of the study were given the NUC-3373 every two weeks as a drip into a vein instead of every week and they were also checked for serious side effects:
4 patients were given 1500 mg/m2 every two weeks
6 patients were given 1875 mg/m2 every two weeks
6 patients were given 2500 mg/m2 every two weeksFor Part 1, from the side effects that the patients had it was decided that 2500mg/m2 NUC-3373 was the best dose to be given to patients every week. The most common side effects from NUC-3373 when given every week were tiredness, allergic reaction, feeling sick and diarrhoea.
For Part 2, there was not enough information to decide what the best dose was for treatment to be given every 2 weeks. The most common side effects from NUC-3373 when given every two weeks were tiredness, allergic reaction, feeling sick, being sick and a lower appetite. However, when given fortnightly, NUC-3373 was less effective than the weekly. The researchers decided to stop Part 2 and continue testing NUC-3373 as a weekly treatment.
The full results of what the researchers found will be available on ClinicalTrials.gov reference number NCT02723240.REC name
South Central - Oxford C Research Ethics Committee
REC reference
15/SC/0644
Date of REC Opinion
1 Dec 2015
REC opinion
Further Information Favourable Opinion