First-in-human, trial of HuMax-AXL-ADC in patients with solid tumours
Research type
Research Study
Full title
First-in-human, open-label, dose-escalation trial with expansion cohorts to evaluate safety of Axl-specific antibody-drug conjugate (HuMax®-AXL-ADC) in patients with solid tumours.
IRAS ID
211258
Contact name
Juanita Lopez
Contact email
Sponsor organisation
Genmab A/S
Eudract number
2016-002243-42
Duration of Study in the UK
3 years, 10 months, 31 days
Research summary
Summary of Research
This is an open label, multi-center Phase I/IIa safety trial of HuMax AXL ADC in a mixed population of patients with solid tumours known from the literature to have an increased production of proteins directed by the gene Axl (overexpression). HuMax AXL ADC is a human antibody which acts to interfere with cell division, ultimately resulting in tumour cell death. The trial consists of two parts; a dose escalation part (phase I, first-in-human (FIH)) and an expansion part (phase IIa). The dose escalation part has two dose escalation arms: the first one investigates a once every 3 weeks (1Q3W) dose schedule and the second one investigates a three administrations over 4 weeks (3Q4W) dose schedule. The primary objective is to determine the maximum tolerated dose (MTD) and to establish the safety profile of HuMax AXL ADC, given as an intravenous infusion, in a mixed population of patients with specified solid tumours. Secondary objectives encompass: i) evaluation of the PK profile of HuMax AXL ADC ii) evaluate the safety parameters of HuMax AXL ADC in a mixed population of patients with solid tumours iii) evaluate the antitumour activity of HuMax AXL ADC in a mixed population of patients with solid tumours and iv) evaluate Axl expression in tumour biopsies from a mixed population of patients with solid tumours. In total, up to 165 patients can be enrolled.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 GEN1021.
GEN1021, also called enapotamab vedotin, is a molecule that consists of 3 parts:
• an antibody
• an anti-cancer drug
• a linker between antibody and drug
Antibodies are part of the natural immune system in the human body. The GEN1021 antibody is designed in the laboratory to specifically bind a molecule that is over-represented on the surface of some type of cancer cells. This cell-surface molecule is called AXL. When GEN1021 binds to AXL, GEN1021 is transferred into the inside of the cell. A chemical reaction happens, and the drug (monometyl auristatin E) gets released from the antibody part and can kill the cancer cell.
The main questions to be answered by the study were:
• What is the highest GEN1021 dose one can take without having unacceptable side effects?
• What medical problems did the participants have during treatment with GEN1021?
A medical problem in a study may or may not be caused by the study drug.
WHAT KIND OF STUDY WAS IT?
Phase 1/2: The researchers wanted to learn if patients with cancer can take GEN1021 without having too many or serious side effects. They also wanted to learn if GEN1021 worked against cancer.
The study included 2 parts. Part 1 of the study was the Phase 1, which is a scientific term and means first time that people are treated with this new drug. 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 acceptable before moving on to test higher doses. Phase 2 (Part 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 knows what they were taking, and the study doctor and their study staff also know.
WHO PARTICIPATED IN THE STUDY?
The study totally included 306 people with different kinds of advanced and/or metastatic cancers:
• 47 people with cancer were included in Part 1
• 259 people with cancer were included in Part 2.
Patients in Part 1 suffered from either ovarian cancer, melanoma, cervical cancer, endometrial cancer, or non-small cell lung cancer (NSCLC). Participants in Part 2 were included based on their cancer type. The most common cancer type in Part 2 was NSCLC.
All participants were adults: the youngest was 23 years and the oldest 81. Most of them were younger than 65 years. There were more women than men in the study: 174 women and 132 men.
The study took place in 6 countries:
• Belgium
• Denmark
• Spain
• the Netherlands
• the UK
• the US
Spain and the Netherlands were included only in Part 2.
WHAT HAPPENDED IN THE STUDY?
The study was ongoing for close to 5 years. As the drug was not working well enough, it was decided to stop further research with GEN1021 but to let ongoing study participants continue. At the time of this decision, Part 1 had completed and Part 2 had stopped including new patients.
Before the study began, the doctors did tests to make sure each patient could join the study. All participants were treated with GEN1021. GEN1021 was given as an intravenous infusion, which is a slow injection into a vein. Both Part 1 and Part 2 investigated 2 dosing frequencies. The participants were either treated with:
• one dose every 3rd week: called the 1Q3W-dosing, or
• one dose every week for 3 weeks, followed by 1 week without dosing: called 3Q4W-dosing.
Of the 47 patients that started in Part 1:
• 32 were treated with the 1Q3W-dosing
• 15 with the 3Q4W-dosing
Of the 259 patients that started in Part 2:
• 189 were treated with the 1Q3W-dosing
• 70 with the 3Q4W-dosing
The study 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 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 getting treatment came back to the clinical within 30 days of their last dose to see how they were doing. Researchers then continued to stay in contact with the participants to follow how they were doing until the entire study ended. On average, the participants in Part 1 stayed in the study for 263 days (1Q3W group) and 205 days (3Q4W group). Participants in Part 2 stayed in the study on average for 356 days (1Q3W group) and 376 days (3Q4W group).
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.
This summary distinguishes between medical problems and side effects. Medical problems in a study may or may not be caused by the study drug. In addition, not everyone participating in studies experience new or worsening of their medical problems. In scientific literature, medical problems that happen or get worse 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 complication or requires hospital care.
In this summary, side effects are defined as medical problems that the study doctors thought might be caused by GEN1021. The results from several studies are usually needed to help decide if a drug actually causes a side effect.
What is the highest GEN1021 dose one can take without having unacceptable side effects?
The highest GEN1021 dose one can take without having unacceptable side effects was decided in Part 1. The lowest dose level investigated for the 1Q3W group was 0.3 mg/kg and the highest was 2.4 mg/kg. The lowest dose level investigated for the 3Q4W group was 0.6 mg/kg and the highest was 1.2 mg/kg.
Based on how many so-called DLTs that the study participants had, the highest tolerated GEN1021 dose was decided. DLT stands for dose-limiting toxicity. It refers to side effects occurring within the first 21 days (1Q3W) or 28 days (3Q4W) of treatment, leading to that the participant had to stop taking more drug. In total, 6 participants had DLTs.
The highest GEN1021 dose without unacceptable side effects was determined to be:
• 2.2 mg/kg if the dosing frequency was 1Q3W, and
• 1.0 mg/kg if the dosing frequency was 3Q4W
What medical problems did the participants have during treatment with GEN1021?
All 306 participants had at least one medical problem (new or worsening) during the study. Close to half of the participants, 151 (49.3%) had a serious medical problem. Almost one of every 4th participant (24.2%) had a medical problem that led to that they stopped to take the study treatment. Nine (9) of every 10th participant (90.8%) had side effects, meaning medical problems that were thought to be caused by GEN1021.
The most common medical problem for the two dosing frequencies in both Part 1 and Part 2 was:
• Extreme tiredness
It was also common to have:
• uncomfortable or infrequent bowel movements, hard poo
• feeling sickness with involuntary impulse to vomit
The most common side effect by GEN1021 was extreme tiredness.
Two-hundred (200) participants died during the 5 years of the study:
• 32 in Part 1
• 168 in Part 2
Most of the participants died after they had stopped taking study treatment. Approximately 1 of 10 deaths happened due to a medical problem. The other deaths were due to the cancer the participants had.
Two (2) of the deaths were considered by the study doctor to be related to GEN1021. Both deaths were because of sepsis which is a body's extreme response to a bacterial infection. The 2 deaths occurred in Part 2 and with 1Q3W dosing frequency, at the dose level 2.2 mg/kg:
• One participant suffering from a particular type of lung cancer, NSCLC
• One participant suffering from ovarian cancer.
WHERE IS MORE INFORMATION AVAILABLE?
To learn more about the study, its methods, and the results, please use the specific study identifier, NCT02988817 to search www.clinicaltrials.gov.
No further clinical studies with GEN1021 are planned.The results presented here are from a single study. Many studies are needed to prove that a drug is acceptably safe and has effects in the disease that it is studied for. Do not make changes to your therapy based on these results without first consulting a doctor.
REC name
London - Central Research Ethics Committee
REC reference
16/LO/1637
Date of REC Opinion
14 Oct 2016
REC opinion
Further Information Favourable Opinion