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Trial registered on ANZCTR


Registration number
ACTRN12620001199909
Ethics application status
Approved
Date submitted
8/09/2020
Date registered
11/11/2020
Date last updated
7/04/2021
Date data sharing statement initially provided
11/11/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
DREAM3R: A phase 3 trial of durvalumab with chemotherapy as first line treatment in mesothelioma
Scientific title
DREAM3R: DuRvalumab (MEDI4736) With chEmotherapy as First Line treAtment in Advanced Pleural Mesothelioma - A Phase 3 Randomised Trial investigating overall survival
Secondary ID [1] 302198 0
NCT04334759
Secondary ID [2] 302199 0
CTC 0231 / PrE0506
Universal Trial Number (UTN)
Trial acronym
DREAM3R
Linked study record
DREAM (ACTRN12616001170415)
PrE0505 (NCT02899195)

Health condition
Health condition(s) or problem(s) studied:
Advanced Malignant Pleural Mesothelioma (MPM) 318886 0
Condition category
Condition code
Cancer 316872 316872 0 0
Lung - Mesothelioma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
All study treatment will be given intravenously (IV) by experienced medical oncologists and their teams within a hospital based treatment facility.

Arm A (Experimental Group):
Durvalumab 1500 mg IV every 3 weeks + Standard Chemotherapy (Cisplatin 75 mg/m² IV every 3 weeks + Pemetrexed 500 mg/m² IV every 3 weeks) for up to 6 cycles, followed by maintenance with Durvalumab 1500 mg IV every 4 weeks.

Arm B (Control Group):
Cisplatin 75 mg/m² IV every 3 weeks + Pemetrexed 500 mg/m² IV every 3 weeks for up to 6 cycles, followed by close observation per standard of care.

In both groups, participants will receive study treatment until progressive disease or unacceptable toxicity.
Intervention code [1] 318494 0
Treatment: Drugs
Comparator / control treatment
Arm B (Standard Chemotherapy):
Cisplatin 75 mg/m² IV every 3 weeks + Pemetrexed 500 mg/m² IV every 3 weeks for up to 6 cycles, followed by Observation until end of study (up to approximately 5 years).
Control group
Active

Outcomes
Primary outcome [1] 324976 0
Overall Survival
Timepoint [1] 324976 0
Defined as the time from randomisation to the date of death due to any cause. Minimum follow-up is 24 months after randomisation.
Secondary outcome [1] 386398 0
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.
Timepoint [1] 386398 0
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 24 months after randomisation).
Secondary outcome [2] 386399 0
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.
Timepoint [2] 386399 0
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 24 months after randomisation).
Secondary outcome [3] 386400 0
Frequency and severity of adverse events as assessed by CTCAE V5.0.
Timepoint [3] 386400 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.
Secondary outcome [4] 386401 0
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).
Timepoint [4] 386401 0
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 24 months after randomisation).
Secondary outcome [5] 386404 0
Healthcare Resource use (Australian sites only), assessed using hospitalisation data and collection of Medicare Benefits Schedule (MBS) and Pharmaceutical Benefits Schedule (PBS) information.
Timepoint [5] 386404 0
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 24 months after randomisation.
Secondary outcome [6] 386406 0
Incremental cost effectiveness, assessed using hospitalisation data (all recruiting sites) and MBS/PBS data (Australian sites only).
Timepoint [6] 386406 0
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 24 months after randomisation.

Eligibility
Key inclusion criteria
1. Adults (18 years or over) with a histological diagnosis of malignant pleural mesothelioma
that is not amenable to curative surgical resection.
2. Measurable disease as per modified RECIST 1.1 (mRECIST 1.1) criteria for assessment of
response in malignant pleural mesothelioma, without prior radiotherapy to these sites.
3. Body weight greater than 30kg.
4. ECOG performance status of 0 or 1.
5. Tumour tissue (FFPE) available from diagnostic biopsy for PD-L1 testing and other correlative biomarker testing at a central laboratory.
6. Life expectancy of at least 12 weeks.
7. Adequate blood tests (done within 14 days prior to registration) and with values within
the ranges specified below. Blood transfusions are permissible if completed at least 7 days
prior to treatment start.
*Haemoglobin greater than or equal to 9.0 g/L
*Absolute neutrophil count greater than or equal to 1.5 x 109/L
*Platelets greater than or equal to 100 x 109/L
*Total bilirubin less than or equal to 1.5 x upper limit of normal (ULN) (except participants with Gilbert’s Syndrome, who are eligible with bilirubin less than or equal to 2.5 ULN)
*Alanine transaminase less than or equal to 2.5 x ULN, unless liver metastases or invasion are present, in which case it must be less than or equal to 5 x ULN
*Aspartate aminotransferase less than or equal to 2.5 x ULN, unless liver metastases or invasion are present, in which case it must be less than or equal to 5 x ULN
*Creatinine clearance (CrCl) greater than or equal to 60 mL/min (use Cockcroft-Gault formula)
6. Patient consent must be appropriately obtained in accordance with applicable local and
regulatory requirements. Each patient must sign a consent form prior to enrolment in the trial to document their willingness to participate.
7. Willing and able to comply with all study requirements, including treatment, timing and/or
nature of required assessments.
8. Women of childbearing potential must use a reliable means of contraception during
treatment and for at least 90 days thereafter. Breastfeeding is not permissible during or for
at least 90 days after the final study treatment. Men must have been surgically sterilised or
use a (double if required) barrier method of contraception if they are sexually active with a
woman of child bearing potential.
9. Evidence of post-menopausal status or negative serum pregnancy test for female premenopausal patients. Women will be considered post-menopausal if they have been
amenorrheic for 12 months without an alternative medical cause.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Prior chemotherapy or other systemic anti-cancer or immunotherapy for MPM.
2. Diagnosis on cytology or fine needle aspiration biopsy only.
3. Active or prior documented autoimmune or inflammatory disorders (including inflammatory
bowel disease [e.g. colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this criterion:
a. Patients with vitiligo or alopecia
b. Patients with hypothyroidism (e.g. following Hashimoto syndrome) stable on hormone replacement
c. Any chronic skin condition that does not require systemic therapy
d. Patients without active disease in the last 5 years may be included
e. Patients with celiac disease controlled by diet alone
4. Any condition requiring systemic treatment with either corticosteroids (greater than 10 mg daily prednisone or equivalent dose of an alternative corticosteroid) or other immunosuppressive medications within 28 days of durvalumab administration. Intranasal, inhaled or topical steroids or local steroid injections (e.g. intra-articular injection) are permitted in the absence of active autoimmune disease. Standard steroid premedication given prior to chemotherapy or as prophylaxis for imaging contrast allergy should not be counted for this criterion.
5. Participants with symptomatic or uncontrolled brain metastases or leptomeningeal disease
are excluded.
6. Prior therapy with an anti-PD-1, anti-PD-L1 (including durvalumab), anti-PD-L2, anti-CTLA-
4 antibody, or any other antibody or drug specifically targeting T cell co-stimulation or
immune checkpoint pathways.
7. Current treatment or treatment within the last 12 months with any investigational anticancer
products.
8. Concurrent enrolment in another clinical study, unless it is an observational(noninterventional) clinical study or during the follow-up period of an interventional study.
9. Mean QT interval corrected for heart rate using Fridericia’s formula (QTcF) greater than or equal to 470 msec in screening ECG measured using standard institutional method or history of familial long QT syndrome.
10. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first
dose of study treatment. Note: Local surgery of isolated lesions for palliative intent is acceptable.
No other malignancy that requires active treatment. Participants with a past history of
adequately treated carcinoma in situ, non-melanoma skin cancer or lentigo maligna without
evidence of disease or superficial transitional cell carcinoma of the bladder are eligible.
11. Hearing loss or peripheral neuropathy considered by the investigators to contraindicate
cisplatin administration.
12. History of allergy or hypersensitivity to investigational product, cisplatin, pemetrexed or any
excipient.
13. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection,
symptomatic congestive cardiac failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, active peptic ulcer disease or gastritis, serious chronic gastrointestinal conditions associated with diarrhoea, active bleeding diatheses.
14. Hepatitis B, hepatitis C or human immunodeficiency virus (HIV). Exceptions include past or
resolved Hepatitis B (defined as the presence of hepatitis B core antibody [anti-HBc] and
absence of HBsAg) and patients positive for hepatitis C (HCV) antibody if polymerase chain
reaction is negative for HCV RNA. HIV testing is not required in absence of clinical
suspicion of HIV.
15. Known history of primary immunodeficiency, allogeneic organ transplant, pneumonitis or
active tuberculosis.
16. Receipt of live attenuated vaccination within 30 days prior to enrolment or within 30 days of
receiving durvalumab.
17. Specific comorbidities or conditions or concomitant medications which may interact with the
investigational product(s).
18. Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results.
19. Serious medical or psychiatric conditions or social situation that might limit compliance with
study requirements, substantially increase risk of incurring adverse events or compromise the ability of the patient to give written informed consent.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central randomisation by computer.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomisation stratified for:
1. Age (18-70 years vs older than 70)
2. Gender (male vs female)
3. Histology (epithelioid vs non-epithelioid)
4. Region (Australia/New Zealand vs USA vs other)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
480 patients (320 durvalumab, 160 control) will be recruited over 27 months and followed for another 24 months to provide over 85% power if the true hazard ratio for overall survival was 0.70 with 2-sided alpha of 0.05, assuming a median survival of 15 months in the control group, 21.4 months in the experimental group, and 6% use of immunotherapy in the control group after progression. A single interim analysis will be conducted (at least 6 months after the completion of recruitment and 50% of the events are observed) with alpha spending according to the O’Brien-Fleming boundary.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 17383 0
The Canberra Hospital - Garran
Recruitment hospital [2] 17384 0
Westmead Hospital - Westmead
Recruitment hospital [3] 17385 0
The Chris O’Brien Lifehouse - Camperdown
Recruitment hospital [4] 17386 0
Liverpool Hospital - Liverpool
Recruitment hospital [5] 17388 0
Coffs Harbour Base Hospital - Coffs Harbour
Recruitment hospital [6] 17389 0
Gosford Hospital - Gosford
Recruitment hospital [7] 17390 0
Calvary Mater Newcastle - Waratah
Recruitment hospital [8] 17391 0
Blacktown Hospital - Blacktown
Recruitment hospital [9] 17392 0
Nepean Hospital - Kingswood
Recruitment hospital [10] 17393 0
Orange Health Service - Orange
Recruitment hospital [11] 17394 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [12] 17395 0
Epworth Richmond - Richmond
Recruitment hospital [13] 17396 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [14] 17397 0
Goulburn Valley Health - Shepparton campus - Shepparton
Recruitment hospital [15] 17398 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [16] 17399 0
Border Medical Oncology - Albury
Recruitment hospital [17] 17403 0
Sunshine Hospital - St Albans
Recruitment hospital [18] 17404 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [19] 17405 0
The Townsville Hospital - Douglas
Recruitment hospital [20] 17406 0
The Prince Charles Hospital - Chermside
Recruitment hospital [21] 17407 0
Icon Cancer Care Chermside - Chermside
Recruitment hospital [22] 17408 0
Icon Cancer Care South Brisbane - South Brisbane
Recruitment hospital [23] 17409 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [24] 17410 0
Sunshine Coast University Hospital - Birtinya
Recruitment hospital [25] 17411 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [26] 17413 0
The Queen Elizabeth Hospital - Woodville
Recruitment hospital [27] 17414 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [28] 17415 0
Royal Hobart Hospital - Hobart
Recruitment hospital [29] 17417 0
Launceston General Hospital - Launceston
Recruitment hospital [30] 17420 0
Icon Cancer Care Wesley - Auchenflower
Recruitment hospital [31] 17814 0
Northern Cancer Institute- St Leonards - St Leonards
Recruitment hospital [32] 17815 0
Frankston Private Hospital - Frankston
Recruitment postcode(s) [1] 31112 0
2605 - Garran
Recruitment postcode(s) [2] 31113 0
2145 - Westmead
Recruitment postcode(s) [3] 31114 0
2050 - Camperdown
Recruitment postcode(s) [4] 31115 0
2170 - Liverpool
Recruitment postcode(s) [5] 31117 0
2450 - Coffs Harbour
Recruitment postcode(s) [6] 31118 0
2250 - Gosford
Recruitment postcode(s) [7] 31119 0
2298 - Waratah
Recruitment postcode(s) [8] 31120 0
2148 - Blacktown
Recruitment postcode(s) [9] 31121 0
2747 - Kingswood
Recruitment postcode(s) [10] 31122 0
2800 - Orange
Recruitment postcode(s) [11] 31123 0
3000 - Melbourne
Recruitment postcode(s) [12] 31124 0
3121 - Richmond
Recruitment postcode(s) [13] 31125 0
3084 - Heidelberg
Recruitment postcode(s) [14] 31126 0
3630 - Shepparton
Recruitment postcode(s) [15] 31127 0
3168 - Clayton
Recruitment postcode(s) [16] 31128 0
2640 - Albury
Recruitment postcode(s) [17] 31131 0
3021 - St Albans
Recruitment postcode(s) [18] 31132 0
4102 - Woolloongabba
Recruitment postcode(s) [19] 31133 0
4814 - Douglas
Recruitment postcode(s) [20] 31134 0
4032 - Chermside
Recruitment postcode(s) [21] 31135 0
4101 - South Brisbane
Recruitment postcode(s) [22] 31136 0
3050 - Parkville
Recruitment postcode(s) [23] 31137 0
4575 - Birtinya
Recruitment postcode(s) [24] 31138 0
5042 - Bedford Park
Recruitment postcode(s) [25] 31140 0
5011 - Woodville
Recruitment postcode(s) [26] 31141 0
6009 - Nedlands
Recruitment postcode(s) [27] 31142 0
7000 - Hobart
Recruitment postcode(s) [28] 31144 0
7250 - Launceston
Recruitment postcode(s) [29] 31147 0
4066 - Auchenflower
Recruitment outside Australia
Country [1] 22909 0
United States of America
State/province [1] 22909 0
Country [2] 22910 0
New Zealand
State/province [2] 22910 0
Auckland

Funding & Sponsors
Funding source category [1] 306622 0
Commercial sector/Industry
Name [1] 306622 0
AstraZeneca Pty Ltd
Address [1] 306622 0
66 Talavera Rd
Macquarie Park, NSW 2113
Country [1] 306622 0
Australia
Primary sponsor type
University
Name
University of Sydney
Address
NHMRC Clinical Trials Centre
Level 6, Medical Foundation Bld (K25)
92-94 Parramatta Rd
Camperdown NSW 2050
Country
Australia
Secondary sponsor category [1] 307151 0
Other Collaborative groups
Name [1] 307151 0
PrECOG, LLC.
Address [1] 307151 0
1818 Market Street
Suite 3000
Philadelphia, PA 19103
Country [1] 307151 0
United States of America

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306803 0
Sydney Local Health District Ethics Review Committee - RPAH Zone
Ethics committee address [1] 306803 0
Suite 210A
RPA Medical Centre
Cnr Missenden Road and Carillon Avenue
Newtown, NSW 2042
Ethics committee country [1] 306803 0
Australia
Date submitted for ethics approval [1] 306803 0
18/11/2019
Approval date [1] 306803 0
17/02/2020
Ethics approval number [1] 306803 0
X19-0462 and 2019/ETH13618
Ethics committee name [2] 306813 0
HDEC (Northern A/B)
Ethics committee address [2] 306813 0
Ministry of Health, 650 Great South Road, Penrose, Auckland 1051
Ethics committee country [2] 306813 0
New Zealand
Date submitted for ethics approval [2] 306813 0
09/09/2020
Approval date [2] 306813 0
Ethics approval number [2] 306813 0

Summary
Brief summary
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 malignant pleural mesothelioma (MPM).

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 MPM that cannot be surgically removed.

Study details:
The study involves allocating participants to receive treatment with standard chemotherapy given with durvalumab, or chemotherapy alone. These treatments are allocated by chance. Treatment will be given by infusion until your disease worsens or you experience unmanageable side effects.

Study treatment:
Chemotherapy and durvalumab group (2 out of every 3 study participants):
This group will receive standard chemotherapy for mesothelioma (cisplatin 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.

Chemotherapy alone group (1 out of every 3 study participants):
This group will receive standard chemotherapy for mesothelioma (cisplatin and pemetrexed) every 3 weeks (one cycle) for a maximum of 6 cycles (about 18 weeks).

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 2 months 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 the treatment of advanced mesothelioma. Durvalumab is approved for locally advanced lung cancer and advanced bladder cancer in Australia and the 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.
Trial website
Trial related presentations / publications
Public notes
University of Sydney are the trial sponsor in Australia/New Zealand.
PrECOG LLC are the trial sponsor in the USA.

Contacts
Principal investigator
Name 105078 0
Prof Anna Nowak
Address 105078 0
Sir Charles Gairdner Hospital
c/o Medical Oncology
Hospital Ave
Nedlands WA 6009
Country 105078 0
Australia
Phone 105078 0
+61 8 6457 3333
Fax 105078 0
Email 105078 0
dream3r@ctc.usyd.edu.au
Contact person for public queries
Name 105079 0
Ms Ailsa Langford
Address 105079 0
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown NSW 1450
Country 105079 0
Australia
Phone 105079 0
+61 9562 5000
Fax 105079 0
Email 105079 0
dream3r@ctc.usyd.edu.au
Contact person for scientific queries
Name 105080 0
Ms Ailsa Langford
Address 105080 0
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown NSW 1450
Country 105080 0
Australia
Phone 105080 0
+61 9562 5000
Fax 105080 0
Email 105080 0
dream3r@ctc.usyd.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Participant trial data will be entered directly into a web based CRF held by the NHMRC Clinical Trials Centre, University of Sydney. Access will only be granted to the research staff directly involved with the trial. Individual participant data will not be made publicly available. Only grouped data which does not identify individual participants will be published.
What supporting documents are/will be available?
No other documents available
Summary results
No Results