A Phase Ib/II open label study to assess NUC-3373 in colorectal cancer
Research type
Research Study
Full 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.
IRAS ID
242189
Contact name
Thomas Ronald Jeffry Evans
Contact email
Sponsor organisation
Nucana plc
Eudract number
2017-002062-53
Clinicaltrials.gov Identifier
Duration of Study in the UK
1 years, 7 months, 0 days
Research summary
Summary of Research
A phase 1b study of a new study drug, NUC-3373, when given in combination with standard agents used to treat colorectal cancer. NUC-3373 is a type of anti-cancer drug called a nucleotide analogue which kills cancer cell growth by preventing DNA replication. The study will look at the safety and tolerability of NUC-3373 and what happens to the study drug in the body and its effect on tumours when combined with standard agents. This information will identify a suitable dose when combined with each standard agent(s). The study will involve adult patients who have colorectal cancer that has spread to other parts of the body and which has come back after at least 2 lines of chemotherapy treatment.
There are two parts to this study. Eighteen patients will be recruited to Part 1 of the study and will receive NUC-3373 either alone or in combination with a drug called leucovorin (LV). LV is similar to folic acid and is often given with cancer treatments that include a drug called 5-FU. This is to enhance the anti-cancer effects of 5-FU.Once the most effective and well tolerated dose combination of NUC-3373 and LV is confirmed in Part 1, Part 2 will open. If the addition of LV demonstrates no benefit in Part 1, it will be omitted from Part 2. In Part 2, patients will receive NUC-3373 (with or without LV) plus one of the standard treatment combinations below:
- Oxaliplatin
- Oxaliplatin + bevacizumab
- Oxaliplatin + panitumumab
- Irinotecan
- Irinotecan + cetuximab
Up to 12 patients will be treated per treatment cohort (maximum of 60 patients). This is an open-label study so patients will know what drugs they are receiving.The study will recruit patients for 12 months in 9 hospital sites across Europe and the US.
Summary of Results
Why was the research needed?
Researchers do clinical studies to get information about how well a new treatment works and how safe it is before the treatment can become available to everyone.
The standard treatment for many people with previously treated colorectal cancer (CRC) that cannot be removed surgically (also known as advanced CRC) is a chemotherapy medicine called 5-FU, otherwise known as fluorouracil. 5-FU is used in combination with other medicines that are commonly used for the treatment of CRC.
The Sponsor of this study has developed a new type of chemotherapy drug called NUC 3373, which is similar to 5-FU. However, there are several factors that are known to limit the effectiveness of 5-FU and NUC-3373 has been designed to overcome these limitations.
The researchers in this study wanted to find the best dose and schedule for NUC-3373, and to learn about the safety and anti-cancer activity of NUC-3373, when given in combination with other standard medicines in people with CRC.What were the main questions studied?
The main questions the researchers wanted to answer in this study were:
• What is the best dose and schedule for NUC-3373 when it is given in combination with other standard medicines that are normally given with 5-FU in CRC?
• Do the NUC-3373 combinations shrink participants’ tumours or stabilise the disease?
• What side-effects did the study doctors think might be related to the study treatments?Who participated in the study?
There were a total of 106 people with advanced CRC who participated in this study. They were 33 to 81 years old.
The study was split into three parts and each part tested different study treatment combinations. The table in the section below shows how many people were included in each part of the study and which treatments they received.
The study took place in three countries: United Kingdom, United States, and France.
The study started in October 2018 and ended in March 2024.What treatments did the participants receive?
This was an open-label study, which means the study doctors and participants knew which treatments participants were receiving.
Participants were assigned to one of three study parts, depending on when they entered the study and on which prior treatments they had received for CRC:
• Part 1: participants received NUC-3373 either with or without a drug called leucovorin (LV), which is also known as folinic acid. LV is given in combination with certain cancer drugs to improve anti-cancer activity.
o Arm 1a: NUC-3373 + LV Every Other Week
o Arm 1b: NUC-3373 Every Other Week
o Arm 1c: NUC-3373 (1500 mg/m2) + LV Weekly
o Arm 1c: NUC-3373 (2500 mg/m2) + LV Weekly
• Part 2: participants received NUC-3373 + LV in combination with either oxaliplatin (referred to as NUFOX from now on) or irinotecan (referred to as NUFIRI from now on). Oxaliplatin and irinotecan are standard chemotherapy drugs for the treatment of CRC and are commonly combined with 5-FU. NUC-3373 and LV were given weekly and the other drugs every other week. There was also a sub-study in Part 2 (PK Sub-Study), in which participants received NUFIRI but with the drugs given in a different order during the first cycle to find out if the order matters.
o Arm 2a: NUFOX
o Arm 2b: NUFIRI
o PK Sub-study: NUFIRI
• Part 3: participants received either the NUFOX or NUFIRI treatments studied in Part 2 in combination with bevacizumab, which is a standard drug (known as a biological agent) used in combination treatments for CRC. NUC-3373 and LV were given weekly and the other drugs every other week.
o Arm 3a: NUFOX + Bevacizumab Weekly
o Arm 3c: NUFIRI + Bevacizumab Weekly
The doses of the study treatments were measured in milligrams (mg) per meter square (m2) of body surface area or in mg per kilogram (kg) of body weight. All study treatments were given by intravenous infusions in time periods called “cycles”. A cycle lasted 28-days. During a cycle, participants received the study treatments either once every week or once every two weeks.
All participants could continue to receive the study treatment they were assigned to until their cancer got worse, they had medical problems related to the study treatments that could not be managed, or they/their study doctors decided they should not participate anymore.What happened during the study?
This section shows how the study was planned to be done.Before joining the study, the participants visited their clinic to learn about the study and then decided to join. This is called "informed consent”. Then, the study doctors and staff asked the participants about their medical history and checked their health to make sure they could join the study. This part lasted up to 28 days.
During the treatment phase of the study, the participants visited the study clinic on Days 1 and 15 (in Arms 1a and 1b) or on Days 1, 8, 15 and 22 (in all other arms) of each 28-day cycle. On these visits, the participants received the study treatments and underwent a number of tests to make sure it was safe for them to continue in the study. These tests included physical exams, assessment of vital signs, and blood tests. The participants had a scan to measure their tumours every 8 weeks. The study doctors kept track of any medical problems reported by the participants or observed by the study doctors or staff.
After receiving their last treatment, the participants entered the follow-up period. Participants who finished study treatment before their cancer had progressed continued to visit the study clinic every 8 weeks to have scans. Participants whose finished study treatment because their cancer had progressed were contacted by phone every 12 weeks to find out about their health status.
What were the results of the study?
This is a summary of the main results from the study. These are the results from all the participants combined for each treatment arm. The individual results of each participant might be different and are not in this summary.What is the best dose and schedule for NUC-3373 when it is given in combination with other standard medicines?
NUC-3373 + LV
In Part 1 of this study, several important results helped researchers decide on the best dose and schedule for NUC-3373 in combination with LV:
• The once-a-week NUC-3373 schedule (Arm 1c 1500 and Arm 1c 2500) was associated with greater anti-cancer activity than the once every two weeks NUC-3373 schedule (Arm 1a and Arm 1b).
• When comparing NUC-3373 doses on the once-a-week schedule, the lower dose (Arm 1c 1500) was better tolerated by participants than the higher dose (Arm 1c 2500), while anti-cancer activity was very similar with both doses.
• The safety and pharmacokinetics (the way a drug is broken down in the body) of NUC-3373 were not affected by the addition of LV. Since LV is a standard combination treatment used with 5-FU for CRC, it was decided to continue using LV in Parts 2 and 3 of the study.
Based on these findings, it was decided that the following dose and schedule of NUC-3373 + LV should be used in Part 2 of the study:
NUC-3373 1500 mg/m2 + LV 400 mg/m2 given once a week on Days 1, 8, 15, and 22 of 28-day cycles.NUC-3373 + LV + Oxaliplatin (NUFOX) or Irinotecan (NUFIRI) In Part 2 of this study, different doses of NUC-3373 were studied when given in combination with LV and either oxaliplatin or irinotecan. To find the best dose, researchers checked how many participants had certain severe side-effects called dose-limiting toxicities (DLTs) in each dose group studied. The doctors were only allowed to increase the dose for the next group of participants if few of these severe side-effects occurred:
• Arm 2a (NUFOX): two participants had DLTs in the highest dose group (2250 mg/m2 NUC-3373 + 85 mg/m2 oxaliplatin). One participant had fatigue and one participant had increases in liver enzymes.
• Arm 2b (NUFIRI): two participants had DLTs in the highest dose group (1875 mg/m2 NUC-3373 + 180 mg/m2 irinotecan). One participant had fatigue and one participant had colitis.
Based on these findings, it was decided that the following NUFOX and NUFIRI doses should be used in Part 3 of the study:
NUFOX: NUC-3373 1875 mg/m2 + LV 400 mg/m2 given once a week on Days 1, 8, 15, and 22 with oxaliplatin 85 mg/m2 given once every two weeks on Days 1 and 15 of 28-day cycles.
NUFIRI: NUC-3373 1500 mg/m2 + LV 400 mg/m2 given once a week on Days 1, 8, 15, and 22 with irinotecan 180 mg/m2 given once every two weeks on Days 1 and 15 of 28-day cycles.Did the NUC-3373 combinations shrink participants’ tumours or stabilise the disease?
Yes. In this study, the researchers found that the combination treatments caused tumour shrinkages or stabilised the disease (also called disease control) in some participants in each part of the study.
To answer this question, the scans for each participant were evaluated by the study doctors, who measured the size of the tumours at each scan. From this, they could calculate how much the tumours had changed in size over the course of the study. Then, based on the change in size, participants were classified as follows:
• Complete responders: disappearance of all target tumours
• Partial responders: at least a 30% reduction in the size of the target tumours
• Progressive disease: at least a 20% increase in the size of the target tumours
• Stable disease: neither a big enough shrinkage to be a partial response or a big enough increase to be progressive disease. This is also known as disease control.
Although some participants in the study had tumour shrinkages, the shrinkages were not large enough to qualify for the first two categories in the list above. Therefore, all participants either had stable disease or progressive disease. The researchers then calculated the disease control rate (the percentage of participants with stable disease) as a percentage of all participants who were considered to be “evaluable” within each treatment arm.What side-effects did the study doctors think might be related to the study treatments?
This section is a summary of the side-effects the participants had during the study that the study doctors thought might be related to the study treatments. In this summary, these side-effects are called “adverse reactions”.
This summary also includes information about serious adverse reactions. An adverse reaction is considered “serious” when it is life-threatening, causes lasting problems, or requires hospital care.
Other studies may or may not show that these side-effects were related to the study treatments. The results from several studies are often needed to decide what side-effects are actually caused by a treatment. Always talk to a doctor before making any treatment decisions.What serious adverse reactions did the participants have?
The list below shows the serious adverse reactions that happened in at least 5% of participants in any treatment group. For each serious adverse reaction, the number and percentage of participants are shown for each treatment arm. Some of the participants had more than one adverse reaction.
• Nausea (feeling sick):
o 1 participant (4%) in Arm 2a
o 2 participants (9%) in Arm 2b
o 2 participants (40%) in Arm 3a
• Vomiting (being sick):
o 1 participant (4%) in Arm 2a
o 1 participant (4%) in Arm 2b
o 1 participant (20%) in Arm 3a
• Colitis (inflamed colon):
o 2 participants (9%) in Arm 2b
• Bilirubin increased (could indicate liver problems):
o 1 participant (9%) in Arm 1b
o 1 participant (4%) in Arm 2a
• Pyrexia (fever):
o 1 participant (9%) in Arm 1c (1500)
• Neutropenic colitis (inflamed colon with low white blood cells):
o 1 participant (13%) in the sub-study
• Pancreatitis (inflamed pancreas):
o 1 participant (11%) in Arm 3c
• Hypokalaemia (low potassium):
o 1 participant (20%) in Arm 3a
• Back pain:
o 1 participant (20%) in Arm 3aWhat adverse reactions did the participants have?
The lists below show the adverse reactions that happened in each part of the study. For each adverse reaction, the number and percentage of participants are shown for each treatment arm. Some of the participants had more than one adverse reaction.Part 1
The list below shows the adverse reactions that happened in at least 20% of participants in any treatment group in Part 1.
• Nausea
o 2 participants (20%) in Arm 1a
o 3 participants (27%) in Arm 1b
o 7 participants (64%) in Arm 1c (1500)
o 3 participants (50%) in Arm 1c (2500)
• Vomiting
o 1 participant (10%) in Arm 1a
o 2 participants (18%) in Arm 1b
o 6 participants (55%) in Arm 1c (1500)
o 4 participants (67%) in Arm 1c (2500)
• Diarrhoea
o 3 participants (30%) in Arm 1a
o 4 participants (36%) in Arm 1b
o 3 participants (27%) in Arm 1c (1500)
o 1 participant (17%) in Arm 1c (2500)
• Fatigue
o 2 participants (20%) in Arm 1a
o 2 participants (18%) in Arm 1b
o 6 participants (55%) in Arm 1c (1500)
o 5 participants (83%) in Arm 1c (2500)
• Feeling hot
o 2 participants (20%) in Arm 1a
o 2 participants (18%) in Arm 1b
o 1 participant (9%) in Arm 1c (1500)
• Bilirubin increased
o 1 participant (9%) in Arm 1b
o 2 participants (33%) in Arm 1c (2500)
• Flushing
o 4 participants (40%) in Arm 1a
o 1 participant (9%) in Arm 1b
o 1 participant (9%) in Arm 1c (1500)
o 3 participants (50%) in Arm 1c (2500)Part 2
The list below shows the adverse reactions that happened in at least 20% of participants in any treatment group in Part 2.
• Anaemia
o 6 participants (26%) in Arm 2a
o 5 participants (22%) in Arm 2b
o 3 participants (38%) in PK Sub-Study
• Nausea
o 13 participants (57%) in Arm 2a
o 8 participants (35%) in Arm 2b
o 4 participants (50%) in PK Sub-Study
• Vomiting
o 12 participants (52%) in Arm 2a
o 6 participants (26%) in Arm 2b
o 2 participants (25%) in PK Sub-Study
• Diarrhoea
o 10 participants (44%) in Arm 2a
o 8 participants (35%) in Arm 2b
o 3 participants (38%) in PK Sub-Study
• Fatigue
o 14 participants (61%) in Arm 2a
o 7 participants (30%) in Arm 2b
o 8 participants (100%) in PK Sub-Study
• Alanine aminotransferase increased*
o 5 participants (22%) in Arm 2a
o 5 participants (22%) in Arm 2b
o 1 participant (13%) in PK Sub-Study
• Aspartate aminotransferase increased*
o 5 participants (22%) in Arm 2a
o 3 participants (13%) in Arm 2b
o 1 participant (13%) in PK Sub-Study
• Decreased appetite
o 7 participants (30%) in Arm 2a
o 5 participants (22%) in Arm 2b
o 1 participant (13%) in PK Sub-Study
• Hot flush
o 2 participants (9%) in Arm 2a
o 1 participant (4%) in Arm 2b
o 3 participants (38%) in PK Sub-Study*Alanine aminotransferase and aspartate aminotransferase are liver enzymes that can be increased in the blood when there are problems with the liver.
Part 3
The list below shows the adverse reactions that happened in at least 30% of participants in any treatment group in Part 3.
• Anaemia
o 1 participant (20%) in Arm 3a
o 3 participants (33%) in Arm 3c
• Nausea
o 5 participants (100%) in Arm 3a
o 4 participants (44%) in Arm 3c
• Vomiting
o 5 participants (100%) in Arm 3a
o 3 participants (33%) in Arm 3c
• Diarrhoea
o 4 participants (80%) in Arm 3a
o 6 participants (67%) in Arm 3c
• Abdominal pain
o 1 participant (20%) in Arm 3a
o 3 participants (33%) in Arm 3c
• Constipation
o 1 participant (20%) in Arm 3a
o 1 participant (20%) in Arm 3c
• Fatigue
o 2 participants (40%) in Arm 3a
o 4 participants (44%) in Arm 3c
• Alanine aminotransferase increased*
o 5 participants (56%) in Arm 3c
• Aspartate aminotransferase increased*
o 5 participants (56%) in Arm 3c
• Headache
o 2 participants (40%) in Arm 3a
o 1 participant (11%) in Arm 3c
• Flushing
o 2 participants (40%) in Arm 3a
o 3 participants (33%) in Arm 3c*Alanine aminotransferase and aspartate aminotransferase are liver enzymes that can be increased in the blood when there are problems with the liver.
How has this study helped participants and researchers?
The results of this study have helped researchers learn more about using NUC-3373 in people with advanced CRC. The researchers learned the best dose and schedule for NUC-3373 when it is combined with other standard treatments for CRC.
Deciding which treatments work best for people almost always takes results from several studies. This summary shows only the main results from this one study. Other studies may provide new information or different results. The purpose of this summary is only to share information. If you need medical advice about your own health or situation, please contact your doctor.
Where can I learn more about this study?
You can find more information about this study at the website listed below:
• https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Fclick.pstmrk.it%2F3ts%2Fclinicaltrials.gov%252Fstudy%252FNCT03428958%2FNBTI%2FpCS8AQ%2FAQ%2F2a1dea30-257d-46cc-a552-8067b87b705c%2F2%2FNHjRj8plms&data=05%7C02%7Cnewcastlenorthtyneside1.rec%40hra.nhs.uk%7Cf2b331590d874f80799508dd686537c7%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638781506110174788%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=Tko5WLLW9srakKWhKgilZN%2B8I%2BDtcy5xeZPnHz%2Fh%2BbE%3D&reserved=0
If you have questions about the study, contact information for NuCana is available at https://gbr01.safelinks.protection.outlook.com/?url=http%3A%2F%2Fwww.nucana.com%2F&data=05%7C02%7Cnewcastlenorthtyneside1.rec%40hra.nhs.uk%7Cf2b331590d874f80799508dd686537c7%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638781506110188340%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=lYN0WlhsoZOdzyhV1iVKpQCiDtCIt79Yu2ts4dojk3o%3D&reserved=0REC name
North East - Newcastle & North Tyneside 1 Research Ethics Committee
REC reference
18/NE/0122
Date of REC Opinion
13 Jun 2018
REC opinion
Further Information Favourable Opinion