Phase1 Study of AMG994 alone and with AMG404 in Advanced Solid Tumours

• Research type

  Research Study

• Full title

  A Phase 1, Multicenter, Open-label, Dose Exploration and Dose Expansion Study Evaluating the Safety, Tolerability, Pharmacokinetics and Efficacy of AMG 994 Monotherapy and Combination of AMG 994 and AMG 404 in Subjects with Advanced Solid Tumors

• IRAS ID

  290868

• Contact name

  Rowan Miller

• Contact email

  rowan.miller1@nhs.net

• Eudract number

  2020-003937-40

• Duration of Study in the UK

  3 years, 2 months, 10 days

• Research summary

  Research Summary

  Antibodies are molecules that enhance the attack on cancer cells by the body's immune system. AMG994 antibody tags a protein called mesothelin which is in tumour cells of multiple cancer types. Once tagged, AMG994 signals to specific immune cells called T cells to attack and destroy the tumour cell.
  
  Tumor cells can bind a ligand to the PD-1 receptor on T-cells to prevent the tumour cell's destruction by T-cells.
  
  AMG 404 is another antibody that blocks the PD-1 receptor and ensures that the destruction signal is not switched off by tumour cells.
  
  This is a first in human study to determine the side effects and best dose of AMG 994 in combination with AMG404 in patients with advanced solid tumours in a total of approximately 214 participants.
  
  There are two parts to this study: part 1 is dose exploration and part 2 is dose expansion.
  
  Part 1 is where best dose is established for AMG994 in patients with advanced solid tumours. This will be across 8 groups of patients at different dose levels.
  
  In these cohorts, participants will also be treated with a combination therapy of AMG 994 and AMG404. AMG404 will be administered intravenously once every 4 weeks.
  
  Part 2 is where the best dose level will be expanded to more patients who have specific types of tumours.
  
  The safety and research evaluation of the study product/s will be through analysing their blood and urine samples, archival tumour blocks archival and fresh biopsy tumour blocks and radiographic scans through CT or MRI (as appropriate).

  Summary of Results

  1. Study Name Title of the Study: A Phase 1, Multicenter, Open-label, Dose Exploration and Dose Expansion Study Evaluating the Safety, Tolerability, Pharmacokinetics and Efficacy of AMG 994 Monotherapy and Combination of AMG 994 and AMG 404 in Subjects with Advanced Solid Tumours

  Brief Title: Study of AMG 994 Monotherapy and AMG 994 and AMG 404 Combination Therapy in Participants With Advanced Solid Tumours

  Protocol Number: 20190136
  EU Trial Number: 2020-003937-40
  Other Identifiers: NCT04727554

  Date of This Summary: 23 April 2024

  What does this summary cover?
  This summary shows the main results from one clinical study. The results are only for this study. Other studies may find different results. Researchers and health authorities look at the results of many studies to decide which medicines work best and are safest for patients.

  Amgen has committed to make research results available to the public. This summary has been provided as part of that commitment and should not be used for any other purpose. It should not be considered to make a claim for any product or to guide treatment decisions.

  2. Who Sponsored This Study?
  Amgen Inc.
  One Amgen Center Drive
  Thousand Oaks, CA 91320-1799 USA
  Phone (United States): +1 805-447-1000
  Phone (United Kingdom): +44 1223 436441
  Amgen Inc. is the sponsor of the study who made AMG 994 and AMG 404, the medicines tested in the study. Amgen would like to thank everyone who participated in this study and feels it is important to share the results of this study.

  3. General Information About the Clinical Study Where and when was the study done?
  • This study took place in Belgium, France, Japan, Poland, Spain, and the United States.
  • The study began in April 2021 and ended in September 2023.
  • The study was stopped earlier than planned because Amgen decided not to continue the development of AMG 994 for business strategy reasons. The study was not stopped because of safety reasons or because of how well the medicine worked.

  Why was the study done?
  • This was a phase 1 study conducted as part of the early process to develop new medicines for humans to treat cancer. Researchers looked at how these medicines that are still being tested work in the body and the effect that they have in the body, including side effects.
  • The main purpose of this study was to find out information about the safety of the study medicine AMG 994 alone and a combination of AMG 994 and a different study medicine AMG 404 for the treatment of advanced solid tumors with the protein mesothelin on the cell surface. To do this, researchers looked at:
  - The number of participants who developed medical problems considered significant enough to stop any further increase in the dose of study medicine (called dose-limiting toxicities). The list of medical problems considered as dose-limiting toxicities was decided before the study started and included death not due to worsening cancer, severe medical problems requiring hospitalization, and severe low blood cell count.
  - The number of participants who developed adverse events at any time after being given their first dose of study medicine. An adverse event is any unwanted medical problem that may or may not have been caused by the study medicine(s).
  - Changes in vital signs (eg, blood pressure and heart rate), recordings of how the heart is working (electrocardiograms), and clinical laboratory tests
  • (eg, blood and urine tests).
  • This study was planned in 2 parts:
  - Part 1 (dose exploration): The purpose of part 1 was to determine if AMG 994 alone and a combination of AMG 994 and AMG 404 are safe and tolerable, what the body does to the drug(s) (pharmacokinetics), and what the drug(s) do to the body (pharmacodynamics). Part 1 also looked at what doses of AMG 994 alone and a combination of AMG 994 and AMG 404 are safe for participants to take and how they affect advanced solid tumors with the protein mesothelin on the cell surface.
  - Part 2 (dose expansion): The purpose of part 2 was to determine if the selected dose of AMG 994 from part 1 in combination with AMG 404 is safe and tolerable and whether it causes any side effects. Part 2 was not started as the study was stopped early for business strategy reasons.

  4. Who Was Included in This Study?
  Who took part in the study?

  This study included 11 participants with advanced solid tumors. 3 participants (27%] were women and 8 participants (73%) were men. They ranged in age from 37 to 72 years. 5 participants (45%) were younger than 65 years old and 6 participants (55%) were older than 65 years.

  This study took place at 7 study centers across Belgium, France, Japan, Poland, Spain, and the United States. The numbers of participants in each country are listed below:
  • Belgium: 3 participants
  • France: 1 participant
  • Japan: 1 participant
  • Poland: 2 participants
  • Spain: 2 participants
  • United States: 2 participants

  Participants were examined by a study doctor and chosen to be in the study if they:
  • were 18 years or older
  • had an advanced solid tumor with the protein mesothelin on the cell surface

  5. Which Medicines Were Studied?
  • AMG 994 is a type of medicine called an immunotherapy, which is designed to help the body’s immune system find and destroy cancer cells. AMG 994 is designed to target cancer cells with the protein mesothelin on the cell surface.
  • AMG 404 is also a type of immunotherapy medicine. AMG 404 blocks a type of protein (called programmed cell death protein 1) on the cell surface. Blocking this protein is thought to help the body’s immune system destroy cancer cells.
  • Both AMG 994 and AMG 404 were given by short-term intravenous infusion, where a tube is placed into a blood vessel (usually a vein in the participant’s arm) and the medicine is given over a short period of time. AMG 994 was given once every week by a 60-minute infusion. AMG 404 was given once every 4 weeks by a 30-minute infusion.
  • The first group of participants in part 1 of the study (called “cohort 1”) were given AMG 994 alone at a dose of 5 mg once every week for the first 4 weeks, followed by a combination of AMG 994 at a dose of 5 mg once every week and AMG 404 at a dose of 480 mg once every 4 weeks until the end of the study.
  • The next group of participants in part 1 of the study (called “cohort 2”) received AMG 994 alone at a dose of 15 mg once every week for the first 4 weeks, followed by a combination of AMG 994 at a dose of 15 mg once every week and AMG 404 at a dose of 480 mg once every 4 weeks until the end of the study.
  • The study was stopped before any further dose levels of AMG 994 were tested.
  • Part 2 of the study was not done because the study was stopped early for business strategy reasons.

  6. What Were the Side Effects?
  What is a side effect?
  All medicines can cause side effects, or unwanted medical problems that may happen when you take a medicine. In this study, doctors reported all the medical problems participants had. Doctors believed some of the problems could have been caused by the study medicine(s). These possible side effects are listed below.

  What side effects were seen?
  The tables below show how many participants had AMG 994-related side effects and how many participants had AMG 404-related side effects.

  AMG 994-related Side Effects During the Study

  How many participants had serious side effects?
  Cohort 1: 5 mg AMG 994 + AMG 404 (3 participants) 0 participants (0%) Cohort 2: 15 mg AMG 994 + AMG 404 (8 participants) 0 participants (0%) Total (11 participants) 0 participants (0%)

  How many participants had non-serious side effects?
  Cohort 1: 5 mg AMG 994 + AMG 404 (3 participants) 2 participants (67%) Cohort 2: 15 mg AMG 994 + AMG 404 (8 participants) 4 participants (50%) Total (11 participants) 6 participants (55%)

  How many participants died from side effects?
  Cohort 1: 5 mg AMG 994 + AMG 404 (3 participants) 0 participants (0%) Cohort 2: 15 mg AMG 994 + AMG 404 (8 participants) 0 participants (0%) Total (11 participants) 0 participants (0%)

  How many participants stopped taking the study medicine because of side effects?
  Cohort 1: 5 mg AMG 994 + AMG 404 (3 participants) 0 participants (0%) Cohort 2: 15 mg AMG 994 + AMG 404 (8 participants) 0 participants (0%) Total (11 participants) 0 participants (0%)

  AMG 404-related Side Effects During the Study

  How many participants had serious side effects?
  Cohort 1: 5 mg AMG 994 + AMG 404 (3 participants) 0 participants (0%) Cohort 2: 15 mg AMG 994 + AMG 404 (8 participants) 0 participants (0%) Total (11 participants) 0 participants (0%)

  How many participants had non-serious side effects?
  Cohort 1: 5 mg AMG 994 + AMG 404 (3 participants) 1 participant (33%) Cohort 2: 15 mg AMG 994 + AMG 404 (8 participants) 4 participants (50%) Total (11 participants) 5 participants (46%)

  How many participants died from side effects?
  Cohort 1: 5 mg AMG 994 + AMG 404 (3 participants) 0 participants (0%) Cohort 2: 15 mg AMG 994 + AMG 404 (8 participants) 0 participants (0%) Total (11 participants) 0 participants (0%)

  How many participants stopped taking the study medicine because of side effects?
  Cohort 1: 5 mg AMG 994 + AMG 404 (3 participants) 0 participants (0%) Cohort 2: 15 mg AMG 994 + AMG 404 (8 participants) 0 participants (0%) Total (11 participants) 0 participants (0%)

  If a participant had to stay in the hospital or died because of a side effect, the doctor reported that the side effect was serious. No participant had to stay in the hospital or died due to an AMG 994- or AMG 404-related side effect. No AMG 994- or AMG 404-related serious side effects were reported.

  The table below shows the AMG 994-related non-serious side effects that occurred.

  AMG 994-related Non-serious Side Effects During the Study

  Non-serious side effect
  Weakness
  Cohort 1: 5 mg AMG 994 + AMG 404 (3 participants) 0 participants (0%) Cohort 2: 15 mg AMG 994 + AMG 404 (8 participants) 2 participants (25%) Total (11 participants) 2 participants (18%)

  Tiredness
  Cohort 1: 5 mg AMG 994 + AMG 404 (3 participants) 1 participant (33%) Cohort 2: 15 mg AMG 994 + AMG 404 (8 participants) 1 participant (13%) Total (11 participants) 2 participants (18%)

  Chills
  Cohort 1: 5 mg AMG 994 + AMG 404 (3 participants) 0 participants (0%) Cohort 2: 15 mg AMG 994 + AMG 404 (8 participants) 1 participant (13%) Total (11 participants) 1 participant (9%)

  Dry mouth
  Cohort 1: 5 mg AMG 994 + AMG 404 (3 participants) 1 participant (33%) Cohort 2: 15 mg AMG 994 + AMG 404 (8 participants) 0 participants (0%) Total (11 participants) 1 participant (9%)

  Changes in the sound or tone of the voice Cohort 1: 5 mg AMG 994 + AMG 404 (3 participants) 1 participant (33%) Cohort 2: 15 mg AMG 994 + AMG 404 (8 participants) 0 participants (0%) Total (11 participants) 1 participant (9%)

  Inflammation of the moist body surfaces
  Cohort 1: 5 mg AMG 994 + AMG 404 (3 participants) 0 participants (0%) Cohort 2: 15 mg AMG 994 + AMG 404 (8 participants) 1 participant (13%) Total (11 participants) 1 participant (9%)

  Muscle weakness
  Cohort 1: 5 mg AMG 994 + AMG 404 (3 participants) 0 participants (0%) Cohort 2: 15 mg AMG 994 + AMG 404 (8 participants) 1 participant (13%) Total (11 participants) 1 participant (9%)

  Muscle pain
  Cohort 1: 5 mg AMG 994 + AMG 404 (3 participants) 1 participant (33%) Cohort 2: 15 mg AMG 994 + AMG 404 (8 participants) 0 participants (0%) Total (11 participants) 1 participant (9%)

  Pain in arm or leg
  Cohort 1: 5 mg AMG 994 + AMG 404 (3 participants) 0 participants (0%) Cohort 2: 15 mg AMG 994 + AMG 404 (8 participants) 1 participant (13%) Total (11 participants) 1 participant (9%)

  Buildup of fluid around the heart
  Cohort 1: 5 mg AMG 994 + AMG 404 (3 participants) 0 participants (0%) Cohort 2: 15 mg AMG 994 + AMG 404 (8 participants) 1 participant (13%) Total (11 participants) 1 participant (9%)

  Itching
  Cohort 1: 5 mg AMG 994 + AMG 404 (3 participants) 0 participants (0%) Cohort 2: 15 mg AMG 994 + AMG 404 (8 participants) 1 participant (13%) Total (11 participants) 1 participant (9%)

  Red patches on the tongue
  Cohort 1: 5 mg AMG 994 + AMG 404 (3 participants) 0 participants (0%) Cohort 2: 15 mg AMG 994 + AMG 404 (8 participants) 1 participant (13%) Total (11 participants) 1 participant (9%)

  The table below shows the AMG 404-related non-serious side effects that occurred.

  AMG 404-related Non-serious Side Effects During the Study

  Non-serious side effect
  Weakness
  Cohort 1: 5 mg AMG 994 + AMG 404 (3 participants) 0 participants (0%) Cohort 2: 15 mg AMG 994 + AMG 404 (8 participants) 2 participants (25%) Total (11 participants) 2 participants (18%)

  Chills
  Cohort 1: 5 mg AMG 994 + AMG 404 (3 participants) 0 participants (0%) Cohort 2: 15 mg AMG 994 + AMG 404 (8 participants) 1 participant (13%) Total (11 participants) 1 participant (9%)

  Loss of appetite
  Cohort 1: 5 mg AMG 994 + AMG 404 (3 participants) 0 participants (0%) Cohort 2: 15 mg AMG 994 + AMG 404 (8 participants) 1 participant (13%) Total (11 participants) 1 participant (9%)

  Tiredness
  Cohort 1: 5 mg AMG 994 + AMG 404 (3 participants) 0 participants (0%) Cohort 2: 15 mg AMG 994 + AMG 404 (8 participants) 1 participant (13%) Total (11 participants) 1 participant (9%)

  Overactive thyroid gland
  Cohort 1: 5 mg AMG 994 + AMG 404 (3 participants) 0 participants (0%) Cohort 2: 15 mg AMG 994 + AMG 404 (8 participants) 1 participant (13%) Total (11 participants) 1 participant (9%)

  Inflammation of the moist body surfaces
  Cohort 1: 5 mg AMG 994 + AMG 404 (3 participants) 0 participants (0%) Cohort 2: 15 mg AMG 994 + AMG 404 (8 participants) 1 participant (13%) Total (11 participants) 1 participant (9%)

  Muscle weakness
  Cohort 1: 5 mg AMG 994 + AMG 404 (3 participants) 0 participants (0%) Cohort 2: 15 mg AMG 994 + AMG 404 (8 participants) 1 participant (13%) Total (11 participants) 1 participant (9%)

  Muscle pain
  Cohort 1: 5 mg AMG 994 + AMG 404 (3 participants) 1 participant (33%) Cohort 2: 15 mg AMG 994 + AMG 404 (8 participants) 0 participants (0%) Total (11 participants) 1 participant (9%)

  Pain in arm or leg
  Cohort 1: 5 mg AMG 994 + AMG 404 (3 participants) 0 participants (0%) Cohort 2: 15 mg AMG 994 + AMG 404 (8 participants) 1 participant (13%) Total (11 participants) 1 participant (9%)

  Buildup of fluid around the heart
  Cohort 1: 5 mg AMG 994 + AMG 404 (3 participants) 0 participants (0%) Cohort 2: 15 mg AMG 994 + AMG 404 (8 participants) 1 participant (13%) Total (11 participants) 1 participant (9%)

  Red patches on the tongue
  Cohort 1: 5 mg AMG 994 + AMG 404 (3 participants) 0 participants (0%) Cohort 2: 15 mg AMG 994 + AMG 404 (8 participants) 1 participant (13%) Total (11 participants) 1 participant (9%)

  This section only shows the side effects considered by the study doctor as related to study medicine in this study. No single clinical study can give a complete picture of the benefits and risks of a medicine. Information about other side effects may be available at the websites listed at the end of this summary.

  7. What Were the Overall Results of the Study?
  Unless noted otherwise, the results presented below include all adverse events regardless of whether or not doctors believed they could have been caused by the study medicine(s).
  • Overall, 3 out of 11 participants (27%), all from cohort 2, had dose-limiting toxicities.
  • At any time after being given their first dose of medicine:
   All 11 participants (100%) had at least 1 adverse event.
   9 out of 11 participants (82%) had a serious adverse event.
   8 out of 11 participants (73%) passed away during the study, all related to worsening cancer.
  • There were no clinically relevant changes in laboratory test results or vital signs related to the study medicines.
  • No new safety concerns were identified.
  • More results may be available at the websites listed at the end of this summary.

  8. How Has This Study Helped Participants and Researchers?
  What else is important to know about these results?
  These results are only for this clinical study, which looked at a sample of 11 people with an advanced solid tumor with the protein mesothelin on the cell surface. Not all participants in each group of the study had the same results. The results for any single participant could have been better or worse than the results for their group. Other studies may find different results. These results do not explain how a study medicine may work in a single person. Many studies are needed to show the benefits and risks of a medicine that is still being tested. This research may help future participants and families by helping doctors understand more about the study medicine being studied.

  9. Are There Plans for Further Studies?
  If more clinical studies are done, they may be listed on public websites, such as those below. Search for study medicine name AMG 994 or AMG 404 on the websites below.

  10. Where Can I Find More Information About This Study?
  To find out more about this study, check these websites:

  • https://gbr01.safelinks.protection.outlook.com/?url=http%3A%2F%2Fwww.clinicaltrialsregister.eu%2F&data=05%7C02%7Cedgbaston.rec%40hra.nhs.uk%7C6d7a7a6c302e4ae21db608dceeb4857f%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638647706311468342%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C0%7C%7C%7C&sdata=09sxjjE6%2B%2FNITS5ixreufe%2F0sWEwQsULECFAY2hJvHI%3D&reserved=0. Use the study identifier 2020-003937-40.

  • https://gbr01.safelinks.protection.outlook.com/?url=http%3A%2F%2Fwww.clinicaltrials.gov%2F&data=05%7C02%7Cedgbaston.rec%40hra.nhs.uk%7C6d7a7a6c302e4ae21db608dceeb4857f%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638647706311496963%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C0%7C%7C%7C&sdata=kfM%2FchjvqMGwXhrBN5zTE1QbFK5Q2MyKWJWRgtrHTZc%3D&reserved=0. Use the study identifier NCT04727554.

  If you participated in the study and have questions about the study results, the doctor or staff at your study center may be able to answer them.

• REC name

  West Midlands - Edgbaston Research Ethics Committee

• REC reference

  21/WM/0114

• Date of REC Opinion

  1 Jul 2021

• REC opinion

  Further Information Favourable Opinion