DREAM3R: A phase 3 trial of durvalumab with chemotherapy as first line treatment in mesothelioma | DREAM3R
Treatment: Chemotherapy
Treatment: Targeted and biological therapies
The purpose of this study is to see whether adding durvalumab, a type of immunotherapy, to standard chemotherapy will improve overall survival in patients with pleural mesothelioma (PM).
Who is it for?
Participants may be eligible to join this study if they are aged 18 years or above, and have had a diagnosis of PM that cannot be surgically removed.
Study details:
The study involves allocating participants to receive treatment with standard chemotherapy given with durvalumab (experimental arm), or physician's choice of: chemotherapy alone OR Ipilimumab and Nivolumab immunotherapy (control arm) . These treatments are allocated by chance. Treatment will be given by infusion until disease worsens or you experience unmanageable side effects.
Study treatment:
Chemotherapy and durvalumab (experimental group):
This group will receive standard chemotherapy for mesothelioma (cisplatin or carboplatin and pemetrexed) every 3 weeks (one cycle) for a maximum of 6 cycles (about 18 weeks) plus the experimental treatment durvalumab every 3 weeks on the same day as the chemotherapy.
After combination treatment has been completed, participants will continue treatment with durvalumab alone every 4 weeks for as long as they are tolerating the treatment well and the mesothelioma is under control.
Physician's choice of (control group):
Chemotherapy alone:
This group will receive standard chemotherapy for mesothelioma (cisplatin or carboplatin and pemetrexed) every 3 weeks (one cycle) for a maximum of 6 cycles (about 18 weeks).
OR
Ipilumumab and Nivolumab immunotherapy: This group will receive Ipilimumab every 6 weeks and Nivolumab every 3 weeks or 2 weeks until disease progression, unacceptable toxicity, or up to 2 years.
After treatment has been completed, participants will receive the same care as they would if they were not on a clinical trial.
After stopping treatment, we would like to follow participants up every 6 weeks for the rest of their life.
Durvalumab is an antibody (a type of human protein) that works by blocking a body substance called Programmed Death-Ligand 1 (PD-L1). Blocking PD-L1 helps the body's immune system attack cancer cells. Research has shown that durvalumab can slow tumour growth and shrink tumours in some people with cancer. Previous studies of combining durvalumab and chemotherapy showed that this combination is active in advanced mesothelioma.
We plan to enrol 480 participants in this study from hospitals and clinics throughout Australia, New Zealand and the United States of America (USA). Durvalumab is not approved in Australia or any other country for treatment of advanced mesothelioma. Durvalumab is approved for locally advanced lung cancer and advanced bladder cancer in Australia and USA.
It is hoped this research will demonstrate that durvalumab is safe and effective for the treatment of advanced mesothelioma, and that the results of this study will lead to improved outcomes for future mesothelioma patients.
Overall Survival
Defined as the time from randomisation to the date of death due to any cause. Minimum follow-up is 18 months after randomisation.
Progression-Free Survival (PFS; by mRECIST 1.1 for MPM and iRECIST) - defined as the interval from date of randomisation to the date of first evidence of disease progression or death, whichever occurs first.
CT scans performed at baseline, then at weeks 6, 12, 18, 26, 34, 42, 50 and then every 12 weeks until disease progression (minimum follow-up is 18 months after randomisation).
Objective Tumour Response Rate (OTRR) - Defined as the percentage of participants with either Complete Response (CR) or Partial Response (PR) assessed by mRECIST 1.1 for MPM and iRECIST.
CT scans performed at baseline, then at weeks 6, 12, 18, 26, 34, 42, 50 and then every 12 weeks until disease progression (minimum follow-up is 18 months after randomisation).
Frequency and severity of adverse events as assessed by CTCAE V5.0.
Adverse events will be assessed every 3-4 weeks from the first dose of study treatment until 90 days after last dose of durvalumab or 30 days after last dose of chemotherapy, whichever is longer.
Health-Related Quality of Life (QOL) assessed using EORTC QLQ-C30 (all recruitment sites), EORTC QLQ-LC29 (all recruitment sites), and EuroQol EQ-5D-5L (Australian sites only).
Performed at baseline, then at weeks 6, 12, 18, 26, 34, 42, 50 and then every 12 weeks until disease progression (minimum follow-up is 18 months after randomisation).
Healthcare Resource use (Australian sites only), assessed using hospitalisation data and collection of Medicare Benefits Schedule (MBS) and Pharmaceutical Benefits Schedule (PBS) information.
Details of hospitalisations collected continuously from enrolment to end of study. MBS and PBS data collected once at end of study. Minimum follow-up is 18 months after randomisation.
Incremental cost effectiveness, assessed using hospitalisation data (all recruiting sites) and MBS/PBS data (Australian sites only).
Details of hospitalisations collected continuously from enrolment to end of study. MBS and PBS data collected once at end of study. Minimum follow-up is 18 months after randomisation.
Participants may experience some, all or none of the following side effects reported by people treated with durvalumab in clinical trials. These side effects are listed below; some of these may be due to the underlying cancer.
Very common (experienced by more than 1 in 10 patients):
• Diarrhoea
• Rash/ dry itchy skin
• Tiredness
• Nausea, vomiting
• Pain in the joints and back
• Low red blood count
• Decreased appetite
• Shortness of breath, cough and fever
Common (experienced by 1 in 100 to 1 in 10 patients):
• Liver problems- may present as abnormal liver function on blood tests. This may rarely lead to jaundice (yellowing of the skin and whites of eyes) and be severe or life-threatening
• Accumulation of fluid causing swelling
• Headache
• Inflammation in the lungs: which could cause shortness of breath, chest pain, or new or worsening cough. This could be serious and/or life threatening.
• Low thyroid function: A decrease in thyroid function as seen on blood tests may cause you to feel tired, cold or gain weight while an increase in thyroid function may cause you to feel shaky, have a fast pulse or lose weight.
• High thyroid function: An increase in thyroid function as seen on blood tests may cause you to feel nervous/ anxious, breathless, hot and experience palpitations.
• Kidney problems: changes in kidney function, which may lead to changes in blood tests and protein in your urine and if severe (rarely), decreased urine output and fatigue. This may be life threatening.
• Nervous system problems: Symptoms can include unusual weakness of legs, arms, or face, numbness or tingling in hands or feet. In rare situations there is the potential for the inflammation of the nervous system to be severe and cause damage to the nerve cells or breakdown in the communication between nerves and muscles.
• Infusion related reactions: Reactions may occur during or after the infusion of study medication. The reaction may cause fever or chills and a change in blood pressure or difficulty in breathing which might be serious.
• Inflammation of the intestine. It may cause abdominal pain and diarrhoea with or without blood. Fever may be present. It may require you to receive additional fluids. If left untreated, in rare occasions this may lead to a tear in the wall of the intestine which can be serious and life threatening. Tell your study doctor right away if you have any of these symptoms.
• Infection in the chest/ lungs
• Urinary tract infection causing painful urination
• Others: a hoarse voice, night sweats, pneumonia, oral thrush, difficulty sleeping, dental and oral soft tissue infection, pain in muscles, bones and limbs, influenza, low level of sodium (salt) in blood, high level of calcium in blood, low level of potassium in blood.
Uncommon (experienced by between 1 in 1000 and 1 in 100 patients):
• Inflammation of the pancreas that results in increased levels of digestive enzymes (lipase, amylase) seen in blood tests and which may cause abdominal pain
• Allergic reaction/hypersensitivity reaction
• Low levels of cortisol (a stress hormone), which can make you tired, light-headed, nauseous and unwell, and can become life-threatening if not detected
• Inflammation of the lungs (including fluid in the lungs) which could cause shortness of breath, chest pain, or new or worse cough. This could be serious and/or life threatening.
• Inflammation of the muscles or associated tissues, such as blood vessels that supply the muscles (myositis/polymyositis). Symptoms can include muscle weakness and aches, tired feeling when standing or walking, muscle pain and soreness that does not resolve after a few weeks.
• Irregular heart rhythms
Rare (experienced by less than 1 in 1000 patients)
• Type 1 Diabetes mellitus which may cause increased blood glucose levels. Symptoms may include weight loss, increased urination, increased thirst, infection, confusion and increased hunger requiring insulin administration and/or hospitalisation.
• Inflammation of a gland in the brain (hypophysitis) which can cause headaches and lead to hormone imbalances which require life-long replacement and can make you very unwell if unrecognised
• Inflammation of the heart muscle (myocarditis). Symptoms can include chest pain, rapid or abnormal heart beat, shortness of breath and swelling of your legs.
• Others: inflammation of the membrane surrounding the heart, growths of tiny collections of inflammatory cells in different parts of the body, inflammation of the middle layer of the eye and other events involving the eye (e.g. Inflammation of the cornea and optic nerves), inflammation of the brain or the membranes that cover the brain and spinal cord, hardening and tightening of the skin and connective tissues and loss of skin color, and haematological events (e.g. abnormal breakdown of the red blood cells and low levels of platelets), inflammation of the blood vessels, large skin blisters and rheumatological events (inflammatory disorder causing muscle pain and stiffness and autoimmune arthritis).
• Severe skin rash including large skin blisters.
Side effects of standard chemotherapy:
Participants will be asked to consult their specialist regarding specific side effects of the chemotherapy that they are receiving.
The most common side-effects of standard chemotherapy with cisplatin, pemetrexed, and carboplatin include tiredness, nausea and vomiting (which is usually minimal with standard anti-nausea medication), numbness in fingers and toes, hair loss, rash, changes in kidney function, constipation or diarrhoea, sore mouth, loss of appetite and altered taste. Blood counts (white blood cells, red blood cells, and platelets) may also be lowered, increasing the risk of infection, fatigue, and bleeding.
Some cancer treatments such as chemotherapy or other drugs may slightly increase the risk of blood clots in your veins. Please tell your study doctor if you have any new swelling in a leg or arm or have a sudden problem with your breathing. These may be signs of a clot forming or a clot moving to your lungs. Clots can be treated with blood thinners. If you experience any of these symptoms you should go to the nearest medical clinic or hospital and contact your study doctor as soon as possible.
Before chemotherapy, participants will be given standard premedication with drugs to help reduce some of these side-effects. They will be given some medication to take at home after treatment to help prevent and manage any nausea and vomiting. These medications can sometimes cause temporary problems with headache, constipation and trouble sleeping.
Side effects for combination ipilimumab and nivolumab
Please consult your specialist regarding specific side effects of the immunotherapy that you are receiving.
If you experience any of these symptoms you should go to the nearest medical clinic or hospital and contact your study doctor as soon as possible.
Ipilimumab and nivolumab combination
Very common (experienced by more than 1 in 10 patients):
• Overactive thyroid gland, which can cause rapid heart rate, sweating and weight loss
• Underactive thyroid gland, which can cause tiredness or weight gain
• Decreased appetite
• Headache
• Shortness of breath (dyspnoea)
• Inflammation of the intestines (colitis), diarrhoea (watery, loose or soft stools), vomiting, nausea, stomach pain
• Skin rash sometimes with blisters, itching
• Pain in the joints, muscles and bones
• Feeling tired or weak
• Fever
Common (may affect up to 1 in 10 people)
• Serious lung infection (pneumonia), infections of the upper respiratory tract Increase in some white blood cells most commonly the lungs (sarcoidosis)
• Decreased secretion of hormones produced by adrenal glands (glands situated above the kidneys); underactive function (hypopituitarism) or inflammation (hypophysitis) of the pituitary gland situated at the base of the brain; overactive thyroid gland, which can cause rapid heart rate, sweating and weight loss; inflammation of the thyroid gland (hyperthyroidism); swelling of the thyroid gland
• Dehydration; Inflammation of the nerves causing numbness, weakness, tingling or burning pain of the arms and legs; dizziness; Inflammation of the eye, which causes pain and redness, blurred vision
• Fast heart rate
• High blood pressure (hypertension)
• Inflammation of the lungs (pneumonitis), characterised by coughing and difficulty breathing, blood clots, cough
• Mouth ulcers and cold sores (stomatitis), inflammation of the pancreas (pancreatitis), constipation, dry mouth Inflammation of the liver
• Skin colour change in patches (vitiligo), dry skin, redness of the skin, unusual hair loss or thinning, hives (itchy rash)
• Pain in the muscles and bones
• Kidney failure (including abrupt loss of kidney function)
• Oedema (swelling), pain
• Allergic reaction, reactions related to the infusion of the medicine
Uncommon (may affect up to 1 in 100 people)
• Inflammation of the brain
• Bronchitis
• Chronic diseases associated with a build-up of inflammatory cells in various organs and tissues most commonly the lungs (sarcoidosis)
• Acid in the blood produced from diabetes (diabetic ketoacidosis)
• A temporary inflammation of the nerves that causes pain, weakness and paralysis in the extremities (Guillain-Barré syndrome); damage to nerves causing numbness and weakness (polyneuropathy); inflammation of the nerves; foot drop (peroneal nerve palsy); inflammation of the nerves caused by the body attacking itself, causing numbness, weakness, tingling or burning pain (autoimmune neuropathy)
• Changes in the rhythm or rate of the heart beat, abnormal heart rhythm
• Fluid around the lungs
• Intestinal perforation, inflammation of the stomach (gastritis), inflammation of the duodenum (duodenitis)
• Skin disease with thickened patches of red skin, often with silvery scales (psoriasis)
• Chronic disease of joints (spondyloarthropathy)
• Disease in which the immune system attacks the glands that make moisture for the body, such as tears and saliva (Sjogren's syndrome)
• Inflammation of the joints (arthritis) Inflammation of muscles (myositis) causing pain or stiffness Inflammation of the kidney (nephritis)
• Chest pain Inflammation of the heart (myocarditis) characterised by shortness of breath, fatigue, palpitations or chest pain.
• Muscle breakdown/injury (rhabdomyolysis) characterised by muscle pain, weakness, nausea or vomiting.
Rare (may affect up to 1 in 1000 people)
• Severe and possibly fatal peeling of the skin (toxic epidermal necrolysis, Steven-Johnson syndrome)
Changes in test results
Ipilimumab in combination with nivolumab may cause changes in the results of tests carried out by your doctor. These include
• Abnormal liver function tests
• Abnormal kidney function tests
• A decreased number of red blood cells (which carry oxygen), white blood cells (which are important in fighting infection) or platelets (cells which help the blood to clot)
• An increased level of the enzyme that breaks down fats and of the enzyme that breaks down starch.
• Abnormal levels of calcium, potassium, magnesium or sodium in your blood
• Higher blood levels of bilirubin
• Decrease in body weight
• Higher (hyperglycaemia) or lower (hypoglycaemia) levels of sugar in your blood
Child-bearing:
Chemotherapy may cause temporary or permanent sterility. Participants will be asked to discuss this with their study doctor if they have any concerns about future fertility.
The effects of the combination of durvalumab and chemotherapy on the unborn child and on the newborn baby are not known. Because of this, it is important that study participants are not pregnant or breast-feeding and do not become pregnant during the course of the study. Females should also refrain from egg cell donation and males from sperm donation. Participants must not take part in the study if they are pregnant or trying to become pregnant, or are breast-feeding. Female participants in whom child-bearing is a possibility will be required to undergo a pregnancy test prior to starting the study. Male participants should not father a child or donate sperm for at least 90 days after the last dose of study medication.
Both men and women are strongly advised to use effective contraception during the course of the study and for a period of 90 days after the final dose of durvalumab. Participants should discuss methods of effective contraception with their study doctor.
Cost and Time Commitments
Similar cost as usual care
More time commitment than usual care
Additional travel commitments
Primary Sponsor:
University
University of Sydney
NHMRC Clinical Trials Centre
Level 6, Medical Foundation Bld (K25)
92-94 Parramatta Rd
Camperdown NSW 2050
Australia
Secondary Sponsor:
Other Collaborative groups
PrECOG, LLC.
1818 Market Street
Suite 3000
Philadelphia, PA 19103
United States of America
Other Collaborator:
Other Collaborative groups
Thoracic Oncology Group of Australasia (TOGA)
Level 6, 1 Chifley Square, Sydney, NSW 2000
Australia
Commercial sector/Industry
AstraZeneca Pty Ltd
66 Talavera Rd
Macquarie Park, NSW 2113
Australia
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