A Phase I trial of AZD3965 in patients with advanced cancer.
Research type
Research Study
Full title
A Cancer Research UK Phase I Trial of AZD3965, a monocarboxylate transporter 1 inhibitor (MCT1) in patients with advanced cancer.
IRAS ID
93752
Contact name
Elizabeth Ruth Plummer
Sponsor organisation
Cancer Research UK, Centre for Drug Development
Eudract number
2010-024463-41
ISRCTN Number
N/A
Clinicaltrials.gov Identifier
Research summary
Summary of Research
This study is looking at a new drug called AZD3965. This is a type of drug called a monocaryboxylate transporter 1 inhibitor which is being used to stop the growth of cancer cells and kill cancer cells by blocking the action of one of the proteins involved in moving chemical compounds in and out of the cells of the body. This will be the first time that this type of drug has been given to patients. The drug is a capsule and is taken daily. The study is in two parts. In Part 1, small groups of patients will be treated at increasing doses to find the highest safe dose and best dose to give to patients in Part 2 of the study. Approximately 18 patients with advanced solid tumours or lymphomas will be treated in this part. In Part 2, the dose found to be safe in Part 1 will be given to three groups of patients with either prostate cancer, gastric cancer or diffuse large B cell lymphoma. 15 patients will be treated in each group. Patients will need to visit the hospital weekly for two months and then every fortnight. Patients will have regular blood and urine tests, scans, heart traces and eye tests amongst other clinical tests. Research blood samples will also be taken to look at what happens to the drug inside the body. Treatment will continue until a patient's cancer starts growing but can continue for up to a maximum of 12 months if the cancer is responding to the drug. It is important to explain that this is the first study of this drug and patients will have advanced cancer so it is unlikely that patients will benefit directly from taking part but the study may help improve future treatment of cancer.Summary of Results
This is a summary of a clinical trial in patients with cancer. It is written for the general reader. We have included information about how the researchers did the trial and the results of the trial.
Researchers look at the results of many clinical trials to decide which drugs work best and are safest for patients. This summary only shows the results from this one trial. Other trials using AZD3965 may find different results.
We thank all patients who took part in this clinical trial. By taking part you helped the researchers answer important questions and find out more about AZD3965 and cancer.1. GENERAL INFORMATION ABOUT THE TRIAL
The trial started on 23 April 2013 and lasted for 7 years and 7 months, ending on 17 November 2020 when the last patient had their final trial visit.
The trial was carried out at 7 places in the UK. Professor Elizabeth Ruth Plummer at The Sir Bobby Robson Cancer Research Trials Centre in Newcastle was the Chief Investigator. The Chief Investigator is the main person who works with Cancer Research UK to make sure the trial is run correctly.2. BACKGROUND
This clinical trial looked at a new drug called AZD3965. Before this trial, AZD3965 had been looked at in laboratory studies but had not been looked at in people. This was the first time this type of drug was given to patients.
Cancer cells often make more of a substance called ‘lactate’ than normal cells when they make energy. One of the proteins that transports lactate in and out of cells is called monocarboxylate transporter 1 (MCT1). AZD3965 is an MCT1 inhibitor, which means it blocks movement of substances like lactate in and out of the cells of the body. If cancer cells build up too much of these substances, it could stop them growing or cause them to die.
Laboratory studies showed that AZD3965 was most effective against cancer cells that had high levels of MCT1 and low levels of another transporter, MCT4. AZD3965 was effective in several types of cancer in the laboratory, particularly in certain types of lymphoma.Clinical Trial Phase
Before drugs are made available to use, they usually go through 3 phases of testing. With each phase, the number of patients taking part goes up and we learn more about the drug. This trial was the earliest phase, a Phase 1 trial, and it was the first time AZD3965 was given to patients.
In Phase 1 trials, the drug is first tested at increasing doses in groups of patients. This is called ‘dose escalation’. The first few patients that take part are given a very small dose of the drug. If no major side effects are seen, the next group have a slightly higher dose. The dose is increased with each group. The researchers monitor the side effects people have and how they feel, until they find the highest dose that can be given without unmanageable side effects. In this part of the trial, the lower doses are unlikely to be high enough to affect the patients’ cancer. Part 1 of this trial was a dose escalation and aimed to find the highest dose that can be given safely. Cancer drugs are usually tested in patients rather than healthy volunteers, so patients with solid tumours or lymphoma took part in Part 1 of the trial. A solid tumour is any type of cancer that forms a lump. Lymphoma is a cancer of white blood cells.
This Phase 1 trial also had a second part: Part 2. In Part 2, the highest safe dose from Part 1 was planned to be used in cancers that have high levels of MCT1 and low levels of MCT4 in laboratory studies. It was decided during the trial that Part 2 would include patients with certain types of lymphoma that usually have high levels of MCT1 and low levels of MCT4.
We want to develop new treatments to help cancer patients who don’t get better after being given the standard treatments. The patients who took part in this clinical trial had advanced forms of these cancers that were no longer responding to current treatments or had come back after previous treatments.3. AIMS
The aims of this clinical trial were to:
(a) Find the highest dose of AZD3965 that could be given safely to patients with advanced cancer and find the best dose of AZD3965 to test in more patients
(b) Learn more about the side effects of AZD3965 and how they can be managed
(c) Look at what happens to AZD3965 inside the body
(d) See if AZD3965 can make cancer cells die
(e) Find out if AZD3965 can make DLBCL or Burkitt’s lymphoma shrink4. THE TRIAL DRUG, AZD3965
AZD3965 is the drug that was tested in this trial. It was taken as a capsule. Some patients took it once a day and some patients took it twice a day.
Most of the patients in the trial took their first dose of AZD3965 then had a 7-day break. The break after the first dose was to check if the patient had severe side effects or too many side effects. Patients who did not have too many or major side effects after the first dose started to take AZD3965 every day after the break. The last few patients started taking AZD3965 every day straightaway.
Patients could continue to take AZD3965 every day for up to 6 months. If they were still benefitting from taking AZD3965 at 6 months, they could take it for longer.5. TRIAL PATIENTS
Every patient who took part in the clinical trial was given a patient information sheet to read and an agreement form to sign. These explained to the patients what AZD3965 was and what would happen if they took part in the trial.
Once a patient had agreed to take part in the trial, they had some tests to make sure their health status and cancer met the requirements needed to take part. All patients had to meet the criteria to go onto the trial and receive AZD3965.
The main criteria were that patients:
• were adults (aged 18 years or over)
• had a solid tumour or lymphoma (Part 1 of the trial) or DLBCL or Burkitt’s lymphoma (Part 2 of the trial)
• had cancer that was getting worse despite having other available treatments, or there were no other treatments they could have
• were well enough to take part from the results of their health tests
• did not have health conditions that could put them at greater risk of side effects from taking AZD3965
• were not pregnant or breastfeeding
• were willing to use 2 types of contraception if they were able to become pregnant or father a child77 patients agreed to take part in this trial but only 53 patients met all the criteria above and were enrolled into the trial. 42 were enrolled in Part 1 and 11 were enrolled in Part 2.
The patients in Part 1 had many different types of solid tumour. 25 of the patients in Part 1 were men and 17 were women. They were aged between 18 and 79 years old, with an average age of 65 years old.
The patients in Part 2 all had DLBCL. No patients with Burkitt’s lymphoma enrolled in the trial. There were 7 men and 4 women in Part 2. The 11 patients were aged between 48 and 82 years old, with an average age of 70 years old.6. DESIGN OF THE TRIAL
This trial was in 2 parts.
Part 1 consisted of 42 patients in total, but 2 patients withdrew before they took any AZD3965. The other 40 patients were treated in 6 groups. The first group had a dose of AZD3965 that was predicted to be safe based on laboratory studies. The dose of AZD3965 was gradually increased with each patient group for the next 3 groups. The patients in the first 4 groups all took AZD3965 once a day. The next 2 groups had their dose of AZD3965 split in 2, so they took AZD3965 twice a day.
• Group 1 had an AZD3965 dose of 5 mg once a day
• Group 2 had an AZD3965 dose of 10 mg once a day
• Group 3 had an AZD3965 dose of 20 mg once a day
• Group 4 had an AZD3965 dose of 30 mg once a day
• Group 5 had an AZD3965 dose of 15 mg twice a day
• Group 6 had an AZD3965 dose of 10 mg twice a dayThe highest safe dose from Part 1 was then used in Part 2 of the trial.
There were 11 patients in Part 2. All these patients had the same dose of AZD3965, which was 10 mg twice a day (the same as Group 6 in Part 1).Changes to the Trial Design
There were a few changes during the trial. Changes to the eligibility criteria and how side effects were assessed and managed were made as needed based on the side effects the patients had.
In Part 1, one of the main changes was that the number of patients that could be included in each group for a certain dose was changed during the trial. This was done to help the trial enrol enough patients to get the information needed to meet the aims of the trial.
There was also a change to the tests used for the main aim of the trial. It had been planned to measure the amount of lactate in patients’ blood before and after they took AZD3965. This was done for Part 1, but the tests did not give enough information to be able to compare lactate levels before and after having AZD3965. So, these tests were removed as part of the main aim of the trial.
In Part 2, it had been planned to test the highest safe dose in 3 groups of patients with different types of cancer. However, only one group with lymphoma was included because laboratory research found that they were most likely to benefit from AZD3965. It was also decided that patients who were benefitting from taking AZD3965 could continue for more than 6 months.Completing the Trial
Patients were seen by the trial team again one month after their last dose of AZD3965, if possible. If they still had side effects, they were then seen once a month until the side effects got better.
Patients should have continued to take AZD3965 for at least 6 months as long as it was stopping their cancer getting worse and they were not having unmanageable side effects. However, they could withdraw from the trial at any time for any reason.
2 patients took AZD3965 for at least 6 months. 1 of these patients was in Part 1 of the trial and took AZD3965 for 6 months. The other patient was in Part 2 of the trial and took AZD3965 for 17 months. Both patients then withdrew from the trial because their cancer started getting worse. The remaining 49 patients took AZD3965 for less than 6 months.
Overall, most of the patients who withdrew from the trial did so because their cancer was getting worse. This included 23 of 40 patients (55%) in Part 1 and 7 of 11 patients (64%) in Part 2. However, 13 of 40 patients (31%) and 1 of 11 patients (9%) in Part 2 withdrew because of side effects. The other patients withdrew for other reasons.7. SIDE EFFECTS
Side Effects
We collect information on side effects and use it to check the safety of the drug. Side effects are unwanted medical effects, such as vomiting. If they happen because of a trial drug, side effects are known as ‘adverse reactions’. We included all 51 patients who had AZD3965 in the tests for safety.
In Part 1 of this trial, a total of 111 adverse reactions were reported by 29 of the 40 patients (73%) who had AZD3965.
6 of the adverse reactions in 5 patients were classed as serious as the patient needed hospital care or because they were considered to be particularly important in this trial:
• 2 patients had changes on an eye test called an ‘electroretinogram’
• 1 patient had a problem where blood cells do not mature, called ‘myelodysplastic syndrome’
• 1 patient had lung inflammation, which is known as ‘pneumonitis’
• 1 patient had a serious adverse reaction of vomiting (being sick). This patient also had a problem where too much acid builds up in the body, called ‘metabolic acidosis’The serious adverse reaction of metabolic acidosis caused a change to the eligibility criteria of the trial. The researchers noticed that the patient’s tests from before they started taking AZD3965 showed they had very high levels of substances called lactate and ketones. These levels got even higher when they took 1 dose of AZD3965, and this increase was diagnosed as metabolic acidosis. The patient was withdrawn from the trial because of this problem. Tests were added to the eligibility criteria to make sure that other patients with high levels of such substances did not enter the trial.
In Part 2 of this trial, a total of 30 adverse reactions were reported by 9 of the 11 patients (82%) who had AZD3965.
7 of the adverse reactions in 4 patients were classed as serious as the patient needed hospital care or because they were considered to be particularly important in this trial:
• 1 patient had an infection of the lower respiratory tract (lung or airways). This patient also had high levels of calcium in the blood, which is known as ‘hypercalcaemia’
• 1 patient had serious adverse reactions of headache and vomiting
• 1 patient had an extreme response to infection, known as ‘sepsis’. This patient also had urinary retention, which is a problem with emptying the bladder
• 1 patient had increased troponin, which is a marker of heart damage
No patients died due to adverse reactions to AZD3965.Dose Limiting Toxicities
Dose limiting toxicities (DLTs) are side effects that the researchers think are important. They might be serious enough that a patient may have to stop having the drug completely or may have to have a break from the drug. They might also mean that the patient needs to have a lower dose of the drug. In early Phase 1 trials, it is not always known if the side effect is caused by the drug. In some cases, it may be that the patient already had a condition that made the side effect worse. So, we would normally expect to see 2 patients at the same dose have a DLT before deciding to reduce the dose for future patients or stop the trial completely.
DLTs are important to learn about in Phase 1 trials because they help us understand what dose of the drug to give to future patients.
In this trial, 7 of 40 patients in Part 1 (17.5%) experienced one or more DLTs. Most of the patients who had DLTs received the highest doses of AZD3965 tested, which were 30 mg once a day or 15 mg twice a day (4 patients with DLTs had these doses). These doses were therefore thought to cause too many major side effects.
• The dose of 10 mg twice a day was considered to be the highest safe dose of AZD3965 and was given to patients in Part 2 of the trial.1 of the 11 patients (9%) in Part 2 had a DLT.
Non Serious Side Effects
In Part 1 of the trial, the most common non-serious adverse reactions that happened in more than 1 in every 10 patients (10%) were:
• changes on an eye test called an ‘electroretinogram’, 14 patients (35%)
• fatigue (worse than usual tiredness), 9 patients (23%)
• nausea (feeling sick), 7 patients (18%)
• anorexia (losing weight), 7 patients (18%)
• ketonuria (substances called ‘ketones’ in the urine), 6 patients (15%)
• anaemia (low levels of red blood cells in the blood), 5 patients (13%)In Part 2 of the trial, the most common non-serious adverse reactions that happened in more than 1 in every 10 patients (10%) were:
• fatigue, 3 patients (27%)
• hypophosphataemia (low levels of phosphate in the blood), 2 patients (18%)
• blurred vision, 2 patients (18%)
• decreased appetite, 2 patients (18%)
• hypokalaemia (low levels of potassium in the blood), 2 patients (18%)Side Effects of Interest in this Trial
Based on laboratory studies, adverse reactions to the retina of the eyes, the heart and the testicles were of particular interest in this trial.
There were no adverse reactions affecting the testicles during the trial. Side effects affecting the retina and the heart were seen. Because it was thought AZD3965 might affect the eyes and heart, people with certain eye and heart problems could not enter this trial.• Retinal changes that were common in patients who received the highest doses of AZD3965 but did not cause symptoms. These changes were one of the reasons the 10 mg twice daily dose was chosen.
The retina is a thin layer at the back of your eye. In this trial, a type of eye test called an electroretinogram was used to look for changes in the retina. Changes in the retina detected on these tests were the most common adverse reactions in Part 1 of this trial, affecting 16 of 40 patients (40%). However, none of the patients with these changes had any symptoms.
Patients who had changes that were above a certain level stopped taking AZD3965. They could start taking AZD3965 again if the changes got better within 2 weeks. 6 patients in Part 1 of the trial stopped taking AZD3965 completely because of changes on their electroretinogram tests. These adverse reactions happened most often at the highest doses tested.
Only 1 of 11 patients (9%) in Part 2 of the trial had changes on their electroretinogram tests. This patient was able to carry on taking AZD3965.• Overall, 3 patients in the trial had adverse reactions to AZD3965 affecting their heart. These adverse reactions were all high levels of a marker in blood that indicates heart damage.
Heart tests were done regularly in this trial. They included blood tests for troponin levels. Troponin is a protein found in the muscles of your heart. If you have heart damage, troponin is released into your blood. People with more heart damage have more troponin in their blood.2 of 40 patients (5%) in Part 1 of the trial had high troponin levels that were considered adverse reactions to AZD3965. 1 of these patients had high troponin levels twice and both times the increases were considered DLTs. The patient stopped taking AZD3965 and their troponin levels improved. It was not known if the other patient’s troponin levels improved as the patient’s cancer got worse and they were withdrawn from the trial.
1 of 11 patients (9%) in Part 2 had high troponin levels that were considered a serious adverse reaction to AZD3965. This patient’s troponin levels improved, and they kept taking AZD3965. There were no other heart problems considered related to AZD3965 in the trial.8. OVERALL RESULTS OF THE CLINICAL TRIAL
The sections below explain the overall results for each of the aims of this trial.(a) AIM: Find the highest dose of AZD3965 that could be given safely to patients with advanced cancer and find the best dose of AZD3965 to test in more patients
• HOW IT WAS ASSESSED: Researchers looked at the adverse reactions in each patient and each group of patients. They also took blood samples to look at how AZD3965 behaved in the body.
• RESULTS: The highest dose of AZD3965 that could be given to patients with advanced cancer on this trial without unmanageable side effects was 10 mg twice a day. The adverse reactions at this dose were manageable. As well as information about side effects, information from blood tests was also used to decide what the best dose was for treating more patients. This was also 10 mg twice daily. See (c) for more about this.(b) AIM: Learn more about the side effects of AZD3965 and how they can be managed
• HOW IT WAS ASSESSED: Researchers monitored what side effects happened throughout the trial. They looked at how these could be managed and if patients with certain medical problems or test results should not take AZD3965.
• RESULTS: Some of the adverse reactions seen on this trial happened more often at the highest doses tested. The most common adverse reaction was changes in eye tests that did not cause any symptoms. These adverse reactions could be managed by stopping taking AZD3965 for up to 2 weeks then starting it again when the eye changes got better. In this trial, researchers learnt that these changes happen less often at the chosen dose of 10 mg twice a day. Adverse reactions at the chosen dose could generally be managed. This was usually done with treatments and by stopping taking AZD3965 until the adverse reaction got better.
The researchers also learned that patients with high levels of substances such as lactate in their blood and urine should not take AZD3965 as this could cause serious adverse reactions.(c) AIM: Look at what happens to AZD3965 inside the body
• HOW IT WAS ASSESSED: The researchers took blood samples to find out what happens to AZD3965 inside the body. They measured how much AZD3965 was left at certain times.
• RESULTS: They found that patients who had higher doses of AZD3965 had more AZD3965 in their bodies, as was expected. They also found that giving AZD3965 twice a day instead of once a day meant that levels of AZD3965 did not dip too low before the next dose was due. These results were used with the safety results to decide on the best dose of 10 mg twice a day.(d) AIM: See if AZD3965 can make cancer cells die
• HOW IT WAS ASSESSED: Blood samples were taken and tested to see if AZD3965 caused cancer cells to die.
• RESULTS: Unfortunately, there were too many differences in the results between patients to be able to find any pattern. There were also some problems getting reliable results from these tests.(e) AIM: Find out if AZD3965 can make DLBCL or Burkitt’s lymphoma shrink
• HOW IT WAS ASSESSED: As the patients in Part 2 were given the highest safe dose identified from Part 1, researchers looked at whether or not their cancer improved after having AZD3965. They did this using scans. Each patient had a scan before and after taking AZD3965 to measure the size of their cancer. This helped researchers see if a patient’s cancer was getting better or worse. The before and after measurements were compared to see if AZD3965 affected the amount of cancer.
• RESULTS: 5 of the 11 patients in this part of the trial received most of their first month of AZD3965 (75%) but 2 of them were withdrawn before they had a scan to look at their cancer. The other 6 patients stopped taking AZD3965 before they had taken 75% of the first month’s doses so there was not enough information about their cancer after taking AZD3965.
There was enough information about their cancer before and after AZD3965 to look at differences for 3 patients. 1 had progressive disease, which means their cancer got worse. 1 had cancer that stayed the same until they withdrew from the trial to have treatment on a different trial after taking AZD3965 for 5 months. 1 patient had a complete response, which means their cancer disappeared completely on scans. The patient’s cancer later got worse, and they withdrew from the trial after taking AZD3965 for 17 months.A complete list of outcomes based on all aims is available in the technical results summary for each clinical trial on the clinicaltrials.gov website (see Section 12 for clinicaltrials.gov website link).
The trial was completed as planned on 17 November 2020. Results were analysed in the Clinical Study Report, which was finalised on 18 October 2021.9. COMMENTS ON WHAT WE FOUND
In this trial, information from 40 patients with advanced cancer who took AZD3965 was used to find the highest safe dose that can be given to patients.
The researchers also found out:
• helpful information about the side effects caused by AZD3965 (adverse reactions) and how to manage them
• what the body does to the drug, which helped them decide that taking AZD3965 twice daily should work better than taking it once dailyThe best dose of AZD3965 found in Part 1 was tested in 11 patients with cancers more likely to be affected by AZD3965. Most patients did not take AZD3965 for long enough to look at differences in their cancer before and after taking AZD3965, but 1 patient with DLBCL had a complete response to AZD3965.
• The dose tested in Part 2 would be recommended for any future trials of AZD3965. This dose was 10 mg AZD3965 taken twice daily
A drug tested in a Phase 1 trial does not always get taken further, but anything we have learned from this trial will be useful for future research. As AZD3965 was also only tested by itself, it is possible that combining AZD3965 with other treatments for cancer might increase the effects of both treatments.
This summary only shows the results from this one trial. Other trials using AZD3965 may find different results.10. FUTURE PLANS
• At the moment, there are no further trials planned for AZD3965.
• Details about the patient who had an adverse reaction of metabolic acidosis have been published in a medical journal and can be read at the following link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156442/11. PATIENT INVOLVEMENT
This results summary has been reviewed by people affected by cancer and updated based on their comments.
We thank all those affected by cancer who gave their time to improve our trial information.12. WHERE TO FIND MORE INFORMATION AND OFFICIAL IDENTIFIERS
• To learn more about this trial, look up the official number or title for the trial, or visit the Cancer Research UK trial website: https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-azd3965-for-advanced-cancer
• The technical results summary is available at https://clinicaltrials.gov/ct2/show/NCT01791595
• For general information about clinical trials, visit https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/what-clinical-trials-are
Full Trial Title: A Cancer Research UK Phase I Trial of AZD3965, a Monocarboxylate Transporter 1 Inhibitor (MCT1) in Patients with Advanced Cancer Protocol Number: CRUKD/12/004 EudraCT Number: 2010-024463-41 ClinicalTrials.gov Identifier: NCT01791595Name and Contact of Sponsor (organiser, responsible for how the trial is run and how results are used):
• Cancer Research UK (CRUK), Centre for Drug Development (CDD), 2 Redman Place, London E20 1JQ
• Phone: 020 7242 0200
• Email: regulatory@cancer.org.uk
• Cancer Research UK Information Nurses: Freephone 0808 800 4040REC name
North East - Newcastle & North Tyneside 2 Research Ethics Committee
REC reference
12/NE/0345
Date of REC Opinion
7 Nov 2012
REC opinion
Further Information Favourable Opinion