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Trial registered on ANZCTR


Trial ID
ACTRN12616001170415
Ethics application status
Approved
Date submitted
22/08/2016
Date registered
26/08/2016
Date last updated
9/01/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
A phase 2 trial of durvalumab with first line chemotherapy in mesothelioma with a safety run in.
Scientific title
A phase 2 trial of durvalumab with first line chemotherapy in mesothelioma with a safety run in.

Secondary ID [1] 289567 0
CTC 0142/ALTG 15/003
Universal Trial Number (UTN)
Trial acronym
DREAM
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malignant Pleural Mesothelioma (MPM). 299297 0
Condition category
Condition code
Cancer 299292 299292 0 0
Lung - Mesothelioma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A safety run-in phase will be conducted to confirm the tolerability of the standard dose of durvalumab. The safety run-in of the study will be done at a limited number of study sites, once the durvalumab dose is confirmed recruitment will be expanded to all sites for the remainder of the trial.

Durvalumab 1125mg (dose to be confirmed by safety run in) AND chemotherapy (cisplatin 75mg/m2 and pemetrexed 500 mg/m2) are all given intravenously (IV) on day 1, repeated every 3 weeks for a maximum of 6 cycles. If there is no progression, continue durvalumab 1125mg IV on day 1 every 3 weeks for a maximum of an additional 12 cycles (18 cycles in total).

The study intervention will be delivered by experienced medical oncologists and their teams within a hospital based treatment facility.
Intervention code [1] 295164 0
Treatment: Drugs
Comparator / control treatment
No control group.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 298784 0
Progression free survival at 6 months (PFS6) according to mRECIST for MPM.
Timepoint [1] 298784 0
6 months PFS measured from the date of trial entry until the date that disease progression is first observed, or the date of death from any cause, whichever occurs first.
Secondary outcome [1] 325190 0
The objective tumour response rate is defined as the proportion (percentage) of participants with a confirmed response of either Complete Response (CR) or Partial Response (PR) assessed by the investigator according to modified RECIST criteria for assessment of response in malignant pleural mesothelioma and according to modified immune-related response criteria (modified irRC).
Timepoint [1] 325190 0
For each participant, objective response will be based on evaluable response assessments performed up until progression or commencement of non-protocol anti-cancer therapy, whichever occurs first.
Secondary outcome [2] 326610 0
Frequency and severity of adverse events (as per CTCAE v4.03).
Timepoint [2] 326610 0
Adverse Events will be recorded from the first dose of study treatment until 90 days after cessation of study treatment.
Secondary outcome [3] 326611 0
Progression free survival (PFS) according to mRECIST for MPM and mirRC.
Timepoint [3] 326611 0
PFS is measured from the date of registration until the date that disease progression is first observed, or the date of death from any cause, whichever occurs first. The date of first disease progression based on imaging is that of the first positive scan, even if this is determined in retrospect.
Secondary outcome [4] 326612 0
Overall survival (OS).
Timepoint [4] 326612 0
OS is defined as the interval from the date of registration to the date of death from any cause.

Eligibility
Key inclusion criteria
1. Adults (18 years or over) with a histological or cytological diagnosis of malignant pleural mesothelioma that is not amendable to curative surgical resection
2. Measurable disease as per modified RECIST criteria for assessment of response in malignant pleural mesothelioma
3. ECOG performance status of 0 or 1
4. Tumour tissue (FFPE) available for PD-L1 testing at a central laboratory
5. Must have measurable disease without prior radiotherapy to these sites
6. Adequate bone marrow function (done within 28 days prior to registration and with values within the ranges specified below). Blood transfusions are permissible.
* Haemoglobin greater than or equal to 90 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
7. Adequate liver function (done within 28 days prior to registration and with values within the ranges specified below):
* Alanine transaminase less than or equal to 3 x upper limit of normal (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 3 x ULN, unless liver metastases or invasion are present, in which case it must be less than or equal to 5 x ULN
* Total bilirubin less than or equal to 1.5 x ULN (except participants with Gilbert’s Syndrome, who are eligible with bilirubin less than or equal to 2.5 ULN)
8. Adequate renal function (done within 28 days prior to registration and with values within the ranges specified below):
* Serum creatinine less than or equal to 1.5 x ULN
or
* Creatinine clearance (CrCl) greater than or equal to 60 mL/min (use Cockroft-Gault formula)
9. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments
10. Signed, written informed consent
11. Women must be post-menopausal, infertile, or use a reliable means of contraception. Women of childbearing potential must have a negative serum pregnancy test done within 24 hours prior to enrolment. 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.
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. Active, known or suspected autoimmune disease. Participants are not excluded if they have vitiligo, type 1 diabetes mellitus, Grave’s disease, residual hypothyroidism due to an autoimmune condition requiring only hormone replacement, or psoriasis not requiring systemic treatment within the past 2 years.
3. Any condition requiring systemic treatment with either corticosteroids (>10mg daily prednisone or equivalent dose of an alternative corticosteroid) or other immunosuppressive medications within 28 days of durvalumab administration. Intranasal, inhaled or topical steroids are permitted in the absence of active autoimmune disease.
4. Participants with symptomatic or uncontrolled brain metastases or leptomeningeal disease are excluded. Controlled brain metastases are those which have been treated and are radiologically and/or clinically stable, and the patient is asymptomatic and does not require corticosteroids.
5. 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
6. Current treatment or treatment within the last 12 months with any investigational products
7. Life expectancy of less than 24 weeks
8. History of another malignancy within 5 years prior to enrolment. Participants with a past history of adequately treated carcinoma-in-situ, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or superficial transitional cell carcinoma of the bladder are eligible. Participants with a history of other malignancies are eligible if they have been continuously disease free for at least 5 years after definitive primary treatment.
9. Mean QT interval corrected for heart rate (QTc) greater than or equal to 470 ms calculated from 3 electrocardiograms using Fridericia’s Correction (QTc equal to QT/RR1/3)
10. Hearing loss or peripheral neuropathy considered by the investigators to contraindicate cisplatin administration
11. History of hypersensitivity to investigational product, cisplatin/pemetrexed or any excipient
12. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive cardiac failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses, hepatitis B, hepatitis C or human immunodeficiency virus
13. Known history of interstitial lung disease from any cause
14. Known history of primary immunodeficiency, allogeneic organ transplant, inflammatory bowel disease (e.g. Crohn’s disease or ulcerative colitis), pneumonitis or active tuberculosis
15. Receipt of live attenuated vaccination within 30 days prior to enrolment or within 30 days of receiving durvalumab
16. Specific comorbidities or conditions or concomitant medications which may interact with the investigational product(s)
17. Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results
18. Serious medical or psychiatric conditions that might limit the ability of the patient to comply with the protocol.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Not applicable
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not applicable
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
The study will begin with an initial safety run-in using a 3+3 design and an expected accrual of 6 participants. These participants will be included in the total sample size of 54 evaluable participants, consisting of 31 recruited in stage 1, and another 23 recruited in stage 2. The null hypothesis is that the true PFS6 rate is 45%, which is in keeping with standard therapy and would be considered not worthy of further evaluation. With a one-sided type I error rate of 5%, the two-stage design provides greater than 90% power if the true PFS6 rate is 65% (alternate hypothesis).

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
Current
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA,VIC
Recruitment hospital [1] 6450 0
Northern Cancer Institute - St Leonards
Recruitment hospital [2] 6451 0
The Chris O’Brien Lifehouse - Camperdown
Recruitment hospital [3] 6452 0
Coffs Harbour Base Hospital - Coffs Harbour
Recruitment hospital [4] 6453 0
Nepean Hospital - Kingswood
Recruitment hospital [5] 6454 0
Albury Wodonga Health - Albury campus - Albury
Recruitment hospital [6] 6455 0
The Prince Charles Hospital - Chermside
Recruitment hospital [7] 6456 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [8] 6457 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [9] 6458 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [10] 6459 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [11] 6460 0
Border Medical Oncology - Wodonga
Recruitment hospital [12] 6461 0
Murray Valley Private Hospital - Wodonga
Recruitment hospital [13] 6462 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment postcode(s) [1] 14004 0
2050 - Camperdown
Recruitment postcode(s) [2] 14005 0
2450 - Coffs Harbour
Recruitment postcode(s) [3] 14006 0
2747 - Kingswood
Recruitment postcode(s) [4] 14007 0
2640 - Albury
Recruitment postcode(s) [5] 14008 0
4032 - Chermside
Recruitment postcode(s) [6] 14009 0
4102 - Woolloongabba
Recruitment postcode(s) [7] 14010 0
5042 - Bedford Park
Recruitment postcode(s) [8] 14011 0
3000 - Melbourne
Recruitment postcode(s) [9] 14012 0
3084 - Heidelberg
Recruitment postcode(s) [10] 14013 0
3690 - Wodonga
Recruitment postcode(s) [11] 14015 0
6009 - Nedlands
Recruitment postcode(s) [12] 14095 0
2065 - St Leonards
Recruitment outside Australia
Country [1] 8090 0
New Zealand
State/province [1] 8090 0
Auckland and Christchurch Hospitals

Funding & Sponsors
Funding source category [1] 294273 0
Commercial sector/Industry
Name [1] 294273 0
AstraZeneca Pty Ltd
Address [1] 294273 0
66 Talavera Rd
Macquarie Park
NSW 2113

Country [1] 294273 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] 293109 0
None
Name [1] 293109 0
N/A
Address [1] 293109 0
N/A
Country [1] 293109 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295705 0
SLHD Ethics Committee (RPAH zone)
Ethics committee address [1] 295705 0
Suite 210A
RPA Medical Centre
Cnr Missenden Road and Carillon Avenue
NEWTOWN NSW 2042
Ethics committee country [1] 295705 0
Australia
Date submitted for ethics approval [1] 295705 0
06/06/2016
Approval date [1] 295705 0
09/08/2016
Ethics approval number [1] 295705 0
X-16-0234 and HREC/16/RPAH/287

Summary
Brief summary
This study will investigate the effectiveness of durvalumab in combination with standard chemotherapy for mesothelioma.

Who is it for?
You may be eligible to join this study if you are aged 18 years or above, have had a diagnosis of malignant pleural mesothelioma that is not amenable to curative surgical resection.

Study details
All participants in the study will receive standard first-line chemotherapy for mesothelioma and the new treatment, durvalumab, intravenously on day 1 of each 3 week cycle for a maximum number of 18 cycles.

Participants will be followed-up for a minimum of 12 months to determine progression free survival and tumour response rate.

Durvalumab is an antibody (a type of human protein) that works by blocking a body substance called PD-L1. Blocking PD-L1 helps the body’s immune system to attack cancer cells. Research has shown that durvalumab can slow tumour growth and shrink tumours in some people with cancer. We plan to enrol 54 participants in this study from hospitals and clinics throughout Australia. Durvalumab is currently an experimental treatment. This means that it is not yet approved for the treatment of mesothelioma, or any other condition, in Australia, or in other countries.
Trial website
http://www.ctc.usyd.edu.au/our-research/clinical-trials/oncology/lung-cancer/active-trials.aspx
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 67014 0
Prof Anna Nowak
Address 67014 0
Sir Charles Gairdner Hospital
c/o Medical Oncology
Hospital Ave
Nedlands
WA 6009
Country 67014 0
Australia
Phone 67014 0
+61 8 6151 1078
Fax 67014 0
Email 67014 0
tracey.hayward@uwa.edu.au
Contact person for public queries
Name 67015 0
Ms Hannora Jurkovic
Address 67015 0
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown
NSW 1450
Country 67015 0
Australia
Phone 67015 0
+61 2 9562 5000
Fax 67015 0
Email 67015 0
dream@ctc.usyd.edu.au
Contact person for scientific queries
Name 67016 0
Prof Anna Nowak
Address 67016 0
Sir Charles Gairdner Hospital
c/o Medical Oncology
Hospital Ave
Nedlands
WA 6009
Country 67016 0
Australia
Phone 67016 0
+61 8 6151 1078
Fax 67016 0
Email 67016 0
tracey.hayward@uwa.edu.au