AIPAC
Research type
Research Study
Full title
AIPAC (Active Immunotherapy PAClitaxel): A multicentre, Phase IIb, randomised, double blind, placebo-controlled study in hormone receptor-positive metastatic breast carcinoma patients receiving IMP321 (LAG-3Ig fusion protein) or placebo as adjunctive to a standard chemotherapy treatment regimen of paclitaxel.
IRAS ID
209938
Contact name
Anne Armstrong
Contact email
Sponsor organisation
Immutep S.A.S.
Eudract number
2015-002541-63
Clinicaltrials.gov Identifier
Duration of Study in the UK
2 years, 6 months, 31 days
Research summary
Summary of Research
The proposed Phase IIb clinical study aims to investigate the safety and efficacy of the active immunotherapy IMP321 in combination (adjunctive) with paclitaxel chemotherapy in patients with hormone receptor-positive metastatic breast cancer. This is the tenth clinical study of IMP321. The principal aim of this study is to obtain safety and efficacy data when IMP321 is administered as adjunctive to a standard first line chemotherapy regimen of paclitaxel in patients with hormone receptor-positive metastatic breast cancer. This information, together with pharmacokinetic and pharmacodynamic data, will help establish the treatment regimen suitable for subsequent Phase III clinical studies in the target population. Treatment of patients with IMP321 may result in improvement of their disease state.Summary of Results
CLINICAL TRIALS LAY SUMMARY OF AIPAC STUDY (IMP321-P011) Study that tested the combination of 2 medicines for women with advanced breast cancer; a new drug IMP321 (also known as eftilagimod or efti) with a marketed drug called paclitaxel.
Welcome
Researchers need many studies to decide which medicines work best and are safest. This summary explains how this particular study was done and what the results were.
1 WHAT WAS THE BACKGROUND AND OBJECTIVES OF THE STUDY?
Breast cancer is a disease where breast cells grow out of control and form a mass (tumour) that may spread to other parts of the body. This is also called metastasis, and the cancer is known as metastatic breast cancer.
IMP321, or eftilagimod, boosts the immune response to fight tumours. It does this by activating a type of immune cell known as dendritic cells. Once activated, dendritic cells then help to switch on other immune cells that kill cancer cells such as T cells, monocytes and natural killer cells.
Paclitaxel is a chemotherapy drug that works by stopping cancer cells from separating into two other new cells. This blocks the growth of the cancer. It also leads to death of the cancer cells. The remains of the dying cancer cells trigger the body’s immune system. When both drugs (IMP321 and paclitaxel) are given together, their combined effects boost the action of the body’s immune cells. This combined activity triggers the killing by T cells of any remaining cancer cells that are resistant to chemotherapy.
Prior to the start of this study, the safety of IMP321 was successful tested in healthy volunteers during the phase 1 study. This study was phase 2, meaning that IMP321 was tested in a small number of patients to assess its safety, how the drug was processed in the body and to get some data on its effectiveness.
The main objectives of the phase 2 study were:
● To find the recommended dose of IMP321 to use in the combined treatment with paclitaxel in the second stage of the study.
● To compare the anti-cancer effectiveness of IMP321 and paclitaxel to placebo plus paclitaxel.
In addition, this study tested:
● The safety of the drug combination and how well the treatment was tolerated.
● How the drugs were taken up by the body, their effects on the body, and the cells of the body’s immune system.
● How the drug combination affected the patient’s quality of life.
2 WHAT HAPPENED DURING THE STUDY?
This study included two parts:
1. The first part of this study (Run-in Stage) had 2 groups receiving 2 different doses of IMP321 (6 mg and 30 mg) together with paclitaxel. A patient who showed improvement or no worsening after two months could continue on monthly IMP321 (without paclitaxel) for another 11 months of maintenance therapy. Maintenance therapy means a treatment that is given to stop cancer from coming back after tumour shrinkage following an initial treatment.Among the 15 patients included in the Run-in Stage:
• 6 patients received 6 mg IMP321 together with paclitaxel.
• 9 patients received 30 mg IMP321 together with paclitaxel.2. During the second part of the study (Randomisation Stage), a different group of patients were assigned by chance to receive either paclitaxel 3 times a month with IMP321 or with placebo. Both the patient and the doctor providing treatment did not known which drug (IMP321 or placebo) was given to the patient.
After at least 6 months of treatment, a patient who showed improvement or no worsening of disease was allowed to continue on monthly IMP321 or placebo (without paclitaxel) for up to 11 months more for maintenance therapy.
A total of 226 patients took part in the Randomisation Stage:
● 114 patients received IMP321/paclitaxel treatment.
● 112 patients received placebo/paclitaxel treatment.Contact in both stages was kept with all patients as long as they lived or until their disease worsened or until withdrawal from the study, loss of contact, or the end of the study, whichever occurred first.
3 WHEN AND WHERE DID THIS STUDY TAKE PLACE?
When was the study performed?
The study started on 12 January 2016 and ended on 14 May 2021.Where did the study take place?
Run-in Stage (total 15 patients):
Belgium: 12 patients (80%)
Netherlands: 3 patients (20%)
Randomisation Stage (total 226 patients):
Belgium: 88 patients (39%)
Netherlands: 55 patients (16%)
France: 25 (11%)
Germany: 33 (15%)
Hungary: 12 (5%)
Poland: 5 (2%)
United Kingdom: 28 (12%)4 WHO PARTICIPATED IN THE STUDY?
What kind of patients were included in the study?
Potential patients were evaluated by the study doctors to make sure they met criteria to participate. This was known as the “screening period” and the main selection criteria are listed below:
● Women who were 18 years or older.
● Diagnosed with metastatic breast cancer.
● Diagnosed with breast cancer that does not have the HER2 protein on the surface of the cancer cells.
● Diagnosed with breast cancer that grows with the help of hormones.
● Whose cancer worsened after previous treatments and were prescribed to receive paclitaxel for the first time.
● Had a life expectancy of longer than 3 monthsHow old were the patients?
Run-in Stage:
<45 years: 13%
45-54 years: 47%
55-64 years: 27%
65-74 years: 13%Randomisation Stage:
<45 years: 12%
45-54 years: 25%
55-64 years: 27%
65-74 years: 27%
75+ years: 8%5 WHAT TREATMENTS DID PATIENTS RECEIVE?
The study drug IMP321 was given as an injection under the skin. Patients were injected on Days 2 and 16 of each monthly cycle.
The chemotherapy drug paclitaxel was in solution for injection into the veins. It was injected on Days 1, 8, and 15 of each monthly cycle.
6 WHAT WERE THE SIDE EFFECTS?
The researchers recorded any side effects patients had during the study. Side effects could happen for reasons not related to the study treatment (for example, caused by an underlying disease or by chance). Or, side effects could also have been caused by a study treatment, or by another medicine the patient was taking. Sometimes the cause of a side effect is unknown. By comparing side effects across many treatment groups in many studies, doctors try to understand what the side effects of an experimental drug might be.
In this study, side effects were unwanted events thought to be related to IMP321 and/or to paclitaxel.
What were the most common side effects?
The most common side effects caused by the study drugs that were reported in at least 15% of the patients during the Randomisation Stage of the study are presented below. These side effects are generally comparable to the published safety profile of paclitaxel.
Side effects related to IMP321 and/or paclitaxel:
• Tiredness (44%),
• Nausea (34%),
• Pain, swelling and redness at the site of injection (34%),
• Injection site redness (30%),
• Diarrhoea (24%),
• Damage of nerves outside of the brain and spinal cord (20%),
• Damage of nerves outside of the brain and spinal cord that carry messages of sensation (18%)Side effects related to placebo and/or paclitaxel:
• Tiredness (45%),
• Nausea (30%),
• Injection site redness (30%),
• Diarrhoea (32%),
• Damage of nerves outside of the brain and spinal cord (24%),
• Damage of nerves outside of the brain and spinal cord that carry messages of sensation (19%)
• Weakness (18%)The main difference between the IMP321/paclitaxel and placebo/paclitaxel groups were local pain, redness, and swelling at the site of the injection. These side effects occurred more frequently in the IMP321/paclitaxel group. They were usually limited to the area around the injection site, mild, and of brief duration.
What is a serious side effect and how many of them occurred?
A side effect is serious when:
● The patient needs to be hospitalized or needs to stay in hospital for a longer period.
● The patient’s life is in danger.
● It causes permanent damage or death.
● It puts the patient at risk and requires the care of a doctor to prevent the situation mentioned above.
● It causes a birth defect.
In this study, 11 patients (10%) experienced serious side effects related to IMP321 and/or paclitaxel treatment. These included:
● Diarrhoea
● Inflammation of the bowel
● Fever
● Vomiting
● Severe allergic reactions. These patients stopped the study and recovered a day later.
● Loss of liver function
● Injection related reactions (redness at the site of injection, and light fever and shivering, and nausea)
● Skin infection
● High blood sugar
● Sudden loss of kidney function
How many deaths occurred during the study?
Run-in Stage
1 death occurred because of general deterioration in the patient’s health that was not considered related to IMP321 or paclitaxel.
Randomisation Stage
2 patients died during IMP321/paclitaxel treatment. 1 patient died due to liver failure which was considered possibly related to paclitaxel and one died due to a blood clot in the lung. Neither event was due to IMP321 treatment.
3 patients died during treatment with placebo/paclitaxel. 1 patient died because of a blood clot in the lung that was considered possibly related to paclitaxel treatment. 1 patient in this group died due to her cancer spreading to the brain, and 1 patient died due to hepatic encephalopathy (brain dysfunction due to liver injury). These deaths were caused by the cancer of these patients.
How many patients stopped IMP321/paclitaxel treatment because of side effects?
6 patients, all of them in the Randomisation Stage of the study, stopped treatment with IMP321/paclitaxel because of side effects that were related to IMP321 and/or paclitaxel:
● 1 patient with sensations of numbness, tingling, pins and needles
● 1 patient with the heart not pumping enough blood
● 1 patient with bowel inflammation
● patients with allergic reactions (2 patients with overreacting immune responses and 1 patient with an anaphylactic reaction)
7 WHAT WERE THE STUDY RESULTS?
Did adding IMP321 to paclitaxel increase the length of time it takes for advanced breast cancer to worsen (progress)?
The final results showed that the combined treatment of IMP321/paclitaxel was not better at stopping the cancer from getting worse compared to the treatment with placebo/paclitaxel. The length of time that half the patients didn’t have tumour growth or spread (median progression free survival; PFS) was the same in both treatment groups (7.3 months).Did adding IMP321 to paclitaxel increase the length of time that patients survived on the study?
The number of months after which half of the patients were still alive (median overall survival; OS) was higher in the IMP321/paclitaxel group (20.4 months) compared with the placebo/paclitaxel group (17.5 months).Did adding IMP321 to paclitaxel increase significant tumour shrinkage on the study?
The percentage of patients whose breast tumour greatly reduced in size and number (objective response rate; ORR) was higher in the IMP321/paclitaxel group (51.4%) compared with the placebo/paclitaxel group (40.6%).How were patients’ quality of life impacted by being on the study?
Quality of life was measured according to standard questionnaires filled out by the patient. Some deterioration was observed in the paclitaxel/placebo group after 6 months. There was no worsening of quality of life reported by the patients in the IMP321/paclitaxel group at this very same timepoint.Did any subgroups benefit from IMP321/paclitaxel?
To explore the data more, researchers looked into subgroups of the study population that showed improvements in median PFS (gains of 0.1 to 1.8 months), in median overall survival (gains of 4.2 up to almost 20 months), and in ORR (gains of 10% to 19%).
These subgroups included women:
● Under the age of 65, or
● Who had less than 5 years since their cancer diagnosis, or
● Who had low numbers of certain blood cells (monocytes), or
● Who had luminal B disease (this is an aggressive type of breast cancer), or
● Who had a high neutrophil to lymphocyte ratio (the numbers of special types of blood cells that help to predict the chances of recovery from cancer), or
● Who had no prior taxane therapy (a type of anti-cancer drug similar to paclitaxel).How did the cells of patient’s immune system respond to IMP321/paclitaxel?
For patients treated with IMP321/paclitaxel, the number of certain immune cells like T cells was boosted in the blood compared to placebo/paclitaxel. This boost lasted long-term and was mainly seen in patients who lived longer on the study.What do the results mean?
Although IMP321/paclitaxel does not prolong median PFS compared to placebo/paclitaxel, there was some benefit was seen in OS and ORR for advanced breast cancer patients.
Certain subgroups of patients who received the combination treatment of IMP321/paclitaxel responded better with longer overall survival, ORR and/or PFS without worsening than in paclitaxel and placebo.
There was no negative effect on life quality with IMP321/paclitaxel unlike placebo/paclitaxel, which did show a decline in life quality after 6 months of treatment.
Other than general paclitaxel-related side effects, the most common side effects of IMP321/paclitaxel treatment were swelling, redness, and pain at the injection site. These events were usually mild and of brief duration and were contained to the area around the injection site.
IMP321 was shown to work as predicted in humans to boost the immune system.
These results mean that the combined treatment of IMP321 and paclitaxel was generally safe and well tolerated.8 HOW HAS THE STUDY HELPED PATIENTS AND RESEARCHERS?
The additional benefits seen for certain subgroups of patients identified potential interesting groups to study in future studies. The study helped researchers in understanding the effect of IMP321 on the immune system and how this affects the survival of patients.9 ARE THERE PLANS FOR FURTHER STUDIES?
Yes, planning is underway for further investigation of IMP321 in patients with certain types of breast cancer who receive chemotherapy for the first time.10 FURTHER INFORMATION
The full title of the study is:
AIPAC (Active Immunotherapy PAClitaxel): A multicentre, Phase IIb, randomised, double blind, placebo-controlled study in hormone receptor-positive metastatic breast carcinoma patients receiving IMP321 (LAG-3Ig fusion protein) or placebo as adjunctive to a standard chemotherapy treatment regimen of paclitaxelWhat are the identification details of the clinical study?
Protocol Number: IMP321-P011
EudraCT Number: 2015-002541-63
Clinicaltrials.gov Number: NCT02614833What is the name of the Sponsor of the study?
The company organizing and funding the research is called Immutep S.A.S. based in France.How can you contact the Sponsor of the study?
You can reach them on the Immutep website: https://eur03.safelinks.protection.outlook.com/?url=https%3A%2F%2Fu2790089.ct.sendgrid.net%2Fls%2Fclick%3Fupn%3DXv3JSvJ-2B3M71ppf7N9agbSXR0ElK0N8o4vrZfCd-2FKamp9a8n6r-2BqhJr7oqMCWOIDD7kcT9xrw-2BdyNVN1YjnQyw-3D-3D7g7z_E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YJTqgebX0WrG3IObO5pPyOzCgDYJBGAdBS5plHJY7-2ByATPKibFKDTqjYBAkT-2Ft-2Fx9tiZG1EKc7AmaAGNWmE3-2Fo6BSMSzrd19U9MDpyfyNiM0aoXBLvByRXD2GDxfxOg5I2PNEc8urZJiQF8KQwWgDmsm1aVqJlwn-2Fryn5Kr3zUn5A-3D-3D&data=05%7C01%7Capprovals%40hra.nhs.uk%7Ccb5596de83bd45e0a75708da5f41a57c%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C637927032790613454%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=XGxW7gVx4f2hIt6tkGz4qsZD7ZKRjFXyE7fAwGhmhFI%3D&reserved=0Where can you learn more about the study?
The scientific summary is available on the EudraCT website.REC name
North West - Haydock Research Ethics Committee
REC reference
16/NW/0671
Date of REC Opinion
11 Nov 2016
REC opinion
Further Information Favourable Opinion