GEN1029 in patients with malignant solid tumours
Research type
Research Study
Full title
First-in-human, open-label, dose-escalation trial with expansion cohorts to evaluate safety of GEN1029 in patients with malignant solid tumors
IRAS ID
236908
Contact name
Jacob Vemb Hansen
Contact email
Sponsor organisation
Genmab B.V.
Eudract number
2017-001394-16
Duration of Study in the UK
3 years, 0 months, 1 days
Research summary
Summary of Research
This is a trial to determine if trial drug (GEN1029) is safe and well tolerated by patients who have tried but have not had an acceptable response from available standard therapy or are not suitable candidates for the standard therapy for the following relapsed (re‐emerging) solid tumour cancer types (colorectal, gastric, pancreatic, urothelial, non‐small cell lung, renal cell or triple negative breast). The trial consists of two parts: a dose‐escalation part,
where small groups of patients will be given increasingly higher doses of the trial drug (GEN1029), and an expansion part that will be initiated once the dose‐escalation part is ended and a suitable dose level has been determined.This trial will also measure the level of GEN1029 in blood during the trial to see how the body processes and gets rid of the drug. Samples of blood and tumour tissue will be analysed for possible cancer biomarkers to obtain a better understanding of the action of the trial drug on the cancer types. The trial drug (GEN1029) is a mixture of two antibodies. When the trial drug binds to a tumour cell a process is activated that kills the tumour cell. The medical need is high for new innovative anti‐cancer therapies with improved efficiency and safety profiles, including therapies for patients with the mentioned cancer types. This trial will be a multi‐centre trial conducted in UK, Spain, and USA and possibly more countries. The participants will continue to receive treatment with the trial drug (GEN1029) until their disease progresses (worsens) or they decide to leave the study.
Summary of Results
Why was the research needed?
Researchers are looking for new drugs to treat cancer patients for whom currently available therapies do not work. In this study, researchers studied a drug called GEN1029.
GEN1029, also called HexaBody®-DR5/DR5, is a mixture of two antibodies, 1029-01 and 1029-05. Antibodies are part of the natural immune system in the human body. The GEN1029 antibodies are designed in the laboratory to specifically bind a molecule that is present on the surface of cancer cells, namely the protein called Death Receptor 5 (DR5). The mixture of the GEN1029 antibodies has in test models been shown to be better than any of the single antibodies in starting the chain of reactions that finally kill the cancer cell. In addition, GEN1029 is based on a technology called the HexaBody® antibody format, that brings the antibodies into groups of six. This results in an even more efficient killing of cancers cells.
The main questions to be answered by the study were:
• What is the highest GEN1029 dose one can take without having many side effects?
• What medical problems did the participants have during treatment with GEN1029?
Who participated in the study?
The study included 48 people with different kinds of advanced and/or metastatic cancers. The most common type was colon cancer: 37 of the 48 participants had this (77%). Examples of other cancers that were studied were non-small cell lung cancer, gastric cancer, pancreatic cancer, and a type of breast cancer called triple negative.
All participants were adults: the youngest was 32 years and the oldest 76. Most of them were older than 65 years. There were more women than men in the study: 27 women and 21 men.
The study was ongoing in 3 countries:
• the UK (2 sites)
• the US (2 sites)
• Spain (2 sites)
What kind of study was it?
Phase 1/2: The researchers wanted to learn if patients with cancer can take GEN1029 without having too many or serious side effects. They also wanted to learn if GEN1029 worked against cancer.
The study included 2 parts. The first part of the study was the Phase 1, which means first time that people are treated with this new drug. This requires extra attention to look for side effects. The drug is tested in a small group of study participants and the first dose is low. The doses are then increased slowly to be sure that side effects remain few and not serious before moving on to test higher doses. Phase 2 of the study means that dose(s) from Phase 1 is tested in a larger group of study participants. The focus is now also to show efficacy and learn more about the drug and what the body does with the drug.
Open-label study: Each study participant knew what they were taking, and the study doctor and their study staff also knew.
What happened in the study?
The study was ongoing for approximately 3 ½ years. On average, the participants stayed in the study for 98 days. The study ended earlier than planned. It was stopped after Phase 1 was completed and Phase 2 never started. The reason for stopping the study was because of harmful liver values in combination with GEN1029 dose levels that did not have enough activity against the cancer.
Before the study began, the doctors did tests to make sure each patient could join the study. All participants were treated with GEN1029. GEN1029 was given as an intravenous infusion, which is a slow injection into a vein. Study participants were treated according to one of 3 dosing alternatives:
• one dose every 2nd week: called the Biweekly schedule
• a lower dose the first time, followed by the main dose after two weeks and every 2nd week onwards: called the Priming schedule
• one dose every week for 8 weeks, followed by the main dose every 2nd week onwards: called the Intensified schedule
Most participants (46 of 48) were treated with the Biweekly schedule. Both the Priming and Intensified schedules were stopped early.
The participants came to their clinic to get the drug infusions. Throughout the study, the doctors:
• checked each participant’s health and asked how they were feeling and what medicines they took
• took blood samples and scanned each participant to see if the cancer tumor changed in size
Participants received treatment until their cancer got worse, they had unacceptable medical problems, they died, or they decided to leave the study.
Participants who stopped treatment or completed the study had safety follow-up visits within 30 and 70 days of their last dose. Researchers stayed in contact with participants, if they agreed to, to see how they were doing until the entire study ended.
When the study ended, the sponsor reviewed the data and created a report of the results. This is a summary of that report.
What were the key results?
The information below tells what the researchers learned while trying to answer their main questions. Since Priming and Intensified dosing schedules were stopped, all results are based on the Biweekly dosing schedule and the 46 study participants.What is the highest GEN1029 dose one can take without having many side effects?
The table below shows number of participants that started and completed the study. It also shows the number of participants that had a so-called DLT. DLT stands for dose-limiting toxicity. It refers to side effects occurring within the first 28 days of treatment that make the participants having to stop taking the drug.
In total, 6 Biweekly dose levels were investigated. The lowest dose level was 0.1 mg/kg and the highest was 3.0 mg/kg.Analyses of the DLTs while the study was ongoing led to the decision not to go higher than
3.0 mg/kg. It was also decided to close the study earlier than planned.
Three (3) out of 46 participants completed the study, meaning they were treated with GEN1029 until their cancer got worse and after that, were contacted for follow-ups as planned.
Forty-three (43) participants left the study before it ended. The main reason was death (17) followed by starting a new cancer treatment (11). Eight (8) participants decided themselves to leave the study.
None of the deaths were considered by the study doctor to be related to GEN1029 treatment, but they were due to the cancer the participants had.
What medical problems did the participants have during treatment with GEN1029?
Medical problems in a study may or not be caused by the study drug. In addition, not everyone participating in studies experience medical problems.
For the purpose of this summary, “side effects” are defined as medical problems that the study doctor thought might be caused by GEN1029. The results from several studies are usually needed to help decide if a drug actually causes a side effect.
In scientific literature, medical problems that happen in a study are called Adverse Events. A medical problem/Adverse Event is considered ‘serious’ when it results in death, is life-threatening, causes lasting problems or requires hospital care.
Medical problems in the study
Most of the participants in this study suffered from medical problems (95.7%). Almost 6 of 10 participants (58.7%) had a serious medical problem. The table below shows how many participants on each dose level had medical problems during the study. It also shows how many had events that were thought to be caused by GEN1029 (meaning side effects).
Most common medical problems & side effects The most common adverse events were increased levels of liver proteins in the blood, diarrhoea, and extreme tiredness.
Medical problems that occurred in at least 30% of the participants are presented in the table below.
Most of the cases of increased levels of liver proteins in the blood and diarrhoea were considered as being side effects of GEN1029. Extreme tiredness often happens in connection with treatment of cancer.
Where is more information available?
To learn more about the study, its methods and the results, please visit the public registries, Home - ClinicalTrials.gov and Clinical Trials Register and search by using the specific study identifiers available on the first page of this summary.
No further clinical studies with GEN1029 are planned.REC name
North East - Newcastle & North Tyneside 1 Research Ethics Committee
REC reference
18/NE/0003
Date of REC Opinion
29 Mar 2018
REC opinion
Further Information Favourable Opinion