LNP3794 in Solid Tumours
Research type
Research Study
Full title
A Phase I Open-Label Study of LNP3794 (BI3011441) in Subjects With NRAS/KRAS\nMutated Advanced or Metastatic Refractory Solid Tumors.
IRAS ID
280561
Contact name
Louise Carter
Contact email
Sponsor organisation
Lupin Limited
Eudract number
2020-000643-32
Duration of Study in the UK
1 years, 11 months, 31 days
Research summary
Summary of Research
This Phase 1, dose escalation study will test a new investigational medication, LNP3794, in participants with advanced or metastatic (cancer that has spread) solid tumours with an NRAS or KRAS mutation. NRAS and KRAS are genes that are involved in controlling the way cells in the body grow, age and die. A change (mutation) in these genes can lead to uncontrolled cell growth, resulting in tumours. High levels of these mutations are seen in a number of cancers and there is an unmet need for treatment for these types of cancers. LNP3794 acts by blocking an enzyme called mitogen activated extracellular signal regulated kinase (MEK). An enzyme is a substance in the body that helps to speed up certain chemical reactions. MEK is an important enzyme for the growth of cancer cells and has been shown to be stimulated in solid tumours that have the change in the specific genes involved in cancer cell growth (NRAS and KRAS). \nThis study will look at the safety/tolerability, and pharmacokinetics (PK-what the body does to the study drug). and pharmacodynamics (PD- how the study drug affects the body). PD will be evaluated in tumour tissue from tissues biopsies, where available. Treatment results will be reviewed by a safety monitoring committee. The first 6 patients will be sequentially assigned to the 4 mg and 6 mg LNP374 dose cohorts; 3 patients in each dose cohort. After these 6 patients complete Cycle 1 (28 days) of treatment, the committee will review the treatment results. Based on the results, the committee will decide if participants should be enrolled to the 8mg LNP3794 cohort daily) or not or if a lower dose may be given (7 mg).\nApproximately 15 patients will be enrolled from 4-5 centres in Belgium, the Netherlands, Spain and the United Kingdom for up to 2 years.\nPatients will undergo physical exams, vital signs, blood/urine sampling, tumour scans, eye and heart examinations and other assessments.\nSummary of Results
RESULTS SUMMARY of a clinical study looking at an investigational medication in people with cancer that has spread to other areas of the body Sponsor of the study: Lupin Limited is the Sponsor of this study. It is the company that paid to carry out this research.
Full study name: A Phase I, Open-Label Study of LNP3794 (BI3011441) in Subjects with NRAS/KRAS Mutated Advanced or Metastatic Refractory Solid Tumors Study protocol number: LRP/LNP3794/2020/001 What was the study medicine? The investigational medicine (study medicine) is described using a number: LNP3794 (BI3011441). It is a ‘MEK inhibitor’. A MEK inhibitor is a type of medicine that blocks proteins in the body called MEK1 and MEK2. These proteins are involved in cell growth and survival, which means they can help cancer cells to grow and spread.
Who took part in the study? 15 people with NRAS/KRAS mutations in advanced or metastatic refractory solid tumours took part. ‘NRAS/KRAS mutations’ are specific changes in cells that can be found in tumours. ‘Advanced’ or ‘metastatic’ means that the cancer has spread to other areas of the body.What were the main results? This study tested 3 different doses (4 mg, 6 mg and 8 mg) of LNP3794. All 3 doses were considered safe, but 6 mg was found to be the safest dose. All participants in this study experienced side effects (adverse events), but only one of these adverse events was considered serious.
[H2] Thank you to all participants
If you participated in this study, Lupin Limited, the Sponsor, would like to thank you for your participation.
This summary will describe the study results. If you have any questions about the study or the results, please contact the doctor or staff at your study site.
[H2] About this clinical study results summaryThis summary was completed in September 2022.
This summary only describes the results from this one study. Please be aware that other studies of this study medicine may have different or conflicting results.
[H2] Where can I learn more about the study?
You can find more information about the study on the websites listed at the end of this summary.
[H2] Tell me more about this studyBefore a treatment can be approved for general use in people, researchers carry out clinical studies to better understand how safe it is and whether it works.
This was a Phase I study, which means that the study medicine was in the early stages of testing in people.
[H3] Why did the research happen?
Researchers are looking for ways to treat cancer in people whose tumours test positive for specific cell mutations. Mutations are certain changes that can happen to cancerous tumors. Some mutations can lead to uncontrolled cell growth, resulting in more tumours. Targeting these mutations may slow or stop the cancer from growing or spreading.
In this study, the mutations are NRAS and KRAS.
This study was conducted to check if different doses of the study medicine, LNP3794, are effective and safe for patients who have tumours with NRAS or KRAS mutations.
This information is important to know before other studies can be done to see if LNP3794 improves the health of people with advanced or metastatic cancer with certain mutations.
[H3] What was the purpose of the study?
In this study, the researchers wanted to find out:
• if LNP3794 is safe and tolerable at 3 different doses
• the safest dose of LNP3794 for people with advanced or metastatic tumours that have certain mutations
• if the participants experienced any medical problems (adverse events) during the study
• how LNP3794 acts in the body.[H2] Who took part in the study?
This study included 10 women and 5 men with advanced or metastatic tumours, which had all tested positive for specific mutations (NRAS or KRAS).
The participants in the study were aged 38–74 years.
People without NRAS or KRAS mutations in their tumours were not able to participate in the study.
The 15 participants were from 3 countries: Belgium, the Netherlands and the United Kingdom. All participants completed the study.
There were 4 study centres that each had at least one participant.[H2] What study medicine did participants receive?
The participants received capsules of LNP3794 (the study medicine). This study medicine has been tested in 2 previous clinical studies in people.
• This study was an ‘open-label’ study.
• Open-label means that the participants, the study doctor and study staff all knew which dose of LNP3794 each participant received.
• This was also a ‘dose-escalation’ study. Three different doses of LNP3794 were tested: 4 mg, 6 mg and 8 mg.
• Dose escalation means that the first few participants started out taking the 4 mg and 6 mg doses of LNP3794. Then the researchers looked at the results for these participants and decided whether to increase the dose to 8 mg for further participants. Researchers use dose-escalation studies to learn about the safety of higher doses.
• Participants were assigned to a dose based on when they joined the study.This table shows the dose of LNP3794 the participants received.
Group A Group B Group C
5 participants 5 participants 5 participants
4 mg 6 mg 8 mg
2 capsules of 2 mg once daily 3 capsules of 2 mg once daily 4 capsules of 2 mg once daily[H2] What happened during the study?
The study started in September 2020 and ended in December 2021.Before each participant received study medicine, the study doctor and study staff checked to make sure the study was suitable for them.
Participants received LNP3794 in 28-day cycles.
After the participants received their last dose of study medicine, they visited the study site 30 days later for a final health check.
Lupin Limited, the study Sponsor, reviewed the study data collected when the study ended and created a comprehensive report of the results. This document is a lay summary of that report.
A lay summary is a brief explanation of a clinical research study and its results written in plain language for a non-academic or non-scientific audience.
[H2] What were the main results of the study?
This section is about the main results from this study. The websites listed at the end of this summary may have additional information about the results of this study.[H3] Does LNP3794 have acceptable side effects at different doses?
• Yes. The study tested 3 different doses (4 mg, 6 mg and 8 mg) of LNP3794. All participants in the study had at least one adverse event. The adverse events experienced were similar to those that other people who have taken LNP3794, and other medicines like it, have experienced.[H3] What dose of LNP3794 is safest and tolerated by the body?
• The study found that all 3 doses were tolerated by the body. All participants experienced non-serious adverse events at all 3 doses.
• The most adverse events were experienced by participants taking the 8 mg dose of LNP3794. This study sought to find the maximum (highest) dose that was safest. Therefore, it was decided that the 6 mg dose was the best dose.The study was designed to get the most accurate answers to the 2 questions above. The results in the remainder of this section are for additional questions the researchers wanted to answer.
[H3] What does the body do to LNP3794?
• What the body does to a medicine is called ‘pharmacokinetics’. Part of pharmacokinetics research is looking at how long it takes the body to absorb a medicine into the blood. This study found that LNP3794 was absorbed quickly, taking between about 1 and 1.5 hours.[H3] How does LNP3794 affect the tumour?
• This study focused on the safety of LNP3794. However, it did look at the tumour status of 13 participants during the study. Seven participants had stable disease, meaning their tumour remained the same while taking LNP3794. Six participants had progressive disease, meaning their tumour got worse while taking LNP3794.[H3] Other comments on the main results of the study
This summary only shows the results from this one study. Other studies on this study medicine may have different results.
[H2] What medical problems happened during the study?
Medical problems that happen in clinical research studies are called ‘adverse events’. An adverse event is any unwanted sign or symptom that participants have during a study.
An adverse event is considered ‘serious’ when it is:
• life-threatening,
• causes lasting problems,
• causes a participant to need hospital care, or
• causes a participant’s hospital care to be extended.Adverse events may or may not be caused by the study medication. A lot of research is needed to know whether a medication causes an adverse event.
Doctors keep track of all the adverse events that happen in studies, even if they do not think the adverse events might be related to the study medications.
This section is a summary of the adverse events that happened during this study.
.
[H3] Did participants experience adverse events during the study?All participants had at least one adverse event during the study. A total of 281 adverse events were reported in this study. A total of 260 of these events were considered to be related to the study medicine.
• 10 out of 15 participants (66.7%) experienced a non-serious adverse event.
• No participants left the study because of a non-serious adverse event or because of a serious adverse event.
• 4 out of 15 participants (26.7%) experienced a serious adverse event.
• No participants died because of a serious adverse event.More adverse events were seen in the 8 mg dose group compared with the 4 mg and 6 mg dose groups.
[H3] What serious adverse events happened?
The table below shows the reported serious adverse events in each group that happened during the study.
Serious adverse event 4 mg dose group 6 mg dose group 8 mg dose group
COVID-19 infection 1 of 5 participants (20%) – –
A blockage of the intestines – 1 of 5 participants (20%) –
Build-up of fluid around the lungs – 1 of 5 participants (20%) –
Liver injury – – 1 of 5 participants (20%)Only the liver injury was considered to be related to the study medicine.
The liver injury was also considered an ‘adverse event of special interest’. An adverse event of special interest is a specific adverse event that researchers are interested in when testing a medicine.
In this study, one of the adverse events of special interest was increased levels of a protein in the body called ‘AST’. AST is mainly found in the liver. When cells containing AST are damaged in the liver, they release AST into the bloodstream. Therefore, when checked with a blood test, increased levels of AST in the blood can be used as a sign of liver damage.
[H3] What non-serious adverse events happened?
This table shows the most common non-serious adverse events that happened in more than 5 participants in the study:
Non-serious adverse event - Number of participants Diarrhoea - 9 of 15 participants (60%) A skin condition that causes small, raised, acne-like bumps to form, usually on the face, scalp, chest and upper back -9 of 15 participants (60%) Abnormal liver function (increased AST levels in the blood)- 8 of 15 participants (53.3%) Participants also reported the following adverse events during the study:
• abnormal blood test results,
• abnormal heart activity and
• abnormal eye examinations.
These are known to be side effects of MEK inhibitors.
]
[H2] What was learned from this study?
In this study, researchers learned about LNP3794 and its safety in patients with advanced or metastatic tumours with certain mutations, concluding that:
• LNP3794 is safe and tolerable when given to patients
• the safest dose of LNP3794 that will be used for future research is 6 mg.This summary shows only the main results from this one study. Other studies may provide new information or different results.
More research is needed to find out how the appropriate dose of LNP3794 can be used for patients with advanced or metastatic tumours with certain mutations.
The findings from this study will be used to make decisions about:
• further studies that may be needed to learn if LNP3794 helps people who have advanced or metastatic tumours with certain mutations
• the best way to use LNP3794 in people who have advanced or metastatic tumours with certain mutations.
The results of this study may also be used to seek approval from regulatory authorities for using LNP3794 in people who have advanced or metastatic tumours with certain mutations.[H2] Where can I find more information about this study?
If you have questions about the results of this study, please speak with the doctor or staff at your study site.For more details on this study, please visit:
• https://eur03.safelinks.protection.outlook.com/?url=https%3A%2F%2Fu2790089.ct.sendgrid.net%2Fls%2Fclick%3Fupn%3DXv3JSvJ-2B3M71ppf7N9agbRehJ-2Fi4xyo44sEgJVCl5BcbW9wgc64X2JjNxW-2BqMpAM-2B-2FcDLXTH22A-2Fo9V6-2FTMFidP8eT-2F6herK0sn8uFVM4wpsd94k8XTcUXQVcHLbuJbCitJW_E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YIidgaB-2BJx-2Bt1cWVPYHK6qqa48M5nU0uTN0cficpvGmdDt5FJt28na55Z44tJiuBj9cO-2BkN34cSK24AYcsU-2BBx0mQ8cxXaJhx1l20FyIj135eTiC7By2okinfNWD80R-2F65t7AlbuO9dJkiikUsKSGGPvjQ7s6vPwbu31ydLyDGzww-3D-3D&data=05%7C01%7Capprovals%40hra.nhs.uk%7C1e31a6aa89f44599388b08da843272e1%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C637967649454806358%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=Cg40Lh4huJcgCx4MP%2FqY1S6xsIhhzgSQ3HPTmlADmFU%3D&reserved=0For more details on your study protocol, please visit:
• https://eur03.safelinks.protection.outlook.com/?url=http%3A%2F%2Fwww.clinicaltrials.gov%2F&data=05%7C01%7Capprovals%40hra.nhs.uk%7C1e31a6aa89f44599388b08da843272e1%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C637967649454806358%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=ZcZP1vMgxo7iuBTa%2FjtzEYffmfoQKMPiJBX4en2TYos%3D&reserved=0
• Use the study identifier: NCT05187858
• Once you are on the website, type ‘NCT0518785’ into the ‘Other terms’ search box and click ‘Search’.To learn more about the study medicine, you can find more information on the Sponsor’s website:
• https://eur03.safelinks.protection.outlook.com/?url=https%3A%2F%2Fu2790089.ct.sendgrid.net%2Fls%2Fclick%3Fupn%3DXv3JSvJ-2B3M71ppf7N9agbVguC7fzfz-2BjWwehcEV4LW0QpyJNkM-2FAkNGa-2BH0NPJHhuko9eEe-2FEjEON9fAW4m6nUDISaN0iAYkDwiw-2F2lV30eMRIuDbdDT2NPBow3XYfP7OtIUQGqM3Q9BZcoboCfqNQ-3D-3DCaqE_E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YIidgaB-2BJx-2Bt1cWVPYHK6qq9N3VPL931L8qRbDd4fYW6kJOuFt9n-2BaB9PigVfguhLs2Fd7lq-2Ftodi7IHc6w65b8PEEluBP0xoS0oiS76gkopUwkakhZPMF1l3xhTYCMGAKd2hd7mfxw-2FIcCCOxcG9iUav55GE8nbV7iCBjFXbhMgg-3D-3D&data=05%7C01%7Capprovals%40hra.nhs.uk%7C1e31a6aa89f44599388b08da843272e1%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C637967649454806358%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=m1dBrVFbJM5%2F0HBZ20xT%2Ft%2B889naYLUwfIDNOm6S5HM%3D&reserved=0National Clinical Trial (NCT) identification number: NCT05187858
This study is registered in EudraCT and the identifier number is: 2020-000643-32
If there are more clinical studies with LNP3794, you can find them on the websites listed above. You can find them by searching for the words LNP3794 or BI3011441.
Again, thank you to everyone who took part in this study. Clinical study participants belong to a large community of people who take part in clinical research all around the world. They help researchers answer important health questions and find new medical treatments.
REC name
Wales REC 3
REC reference
20/WA/0246
Date of REC Opinion
22 Oct 2020
REC opinion
Further Information Favourable Opinion