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Trial registered on ANZCTR


Registration number
ACTRN12617001000392
Ethics application status
Approved
Date submitted
4/07/2017
Date registered
11/07/2017
Date last updated
8/02/2019
Date data sharing statement initially provided
8/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Cancer Molecular Screening and Therapeutics (MoST) Program Substudy Addendum 3 substudies 6 - 8: olaparib plus durvalumab
Scientific title
Single arm, open label, signal seeking, phase IIa trial of the activity of Olaparib in combination with Durvalumab in patients with tumours with homologous recombination repair defects
Secondary ID [1] 292359 0
Nil
Universal Trial Number (UTN)
U1111-1182-6652
Trial acronym
MoST Addendum 3
Linked study record
ACTRN12616000908437

Health condition
Health condition(s) or problem(s) studied:
Cancer 303906 0
Condition category
Condition code
Cancer 303270 303270 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Olaparib will be administered orally twice daily at 300 mgs (2 tablets). Olaparib will be administered for 28 days before starting durvalumab on day 1 of cycle 2. Patients will receive a fixed dose of 1500 mg durvalumab via IV infusion every 4 weeks for up to 13 cycles (28 day cycles). Patients will be treated until they are no longer deriving benefit in the opinion of the treating clinician or the patient. Treatment will stop short of the 13 cycles if there is disease progression, intolerable toxicity or patient withdrawal for another reason.

Retreatment with durvalumab is allowed (once only) for patients meeting the retreatment criteria below. The same treatment guidelines followed during the initial 13-cycle treatment period will be followed during the retreatment period, including the same dose and frequency of treatments and the same Schedule of Assessments.

Patients who complete 13 cycles of treatment and achieve disease control (ie, CR, PR, or SD) through to the end of this treatment period may restart treatment with durvalumab upon evidence of progression, with or without confirmation according to RECIST 1.1.

Before restarting treatment with durvalumab, the Investigator must ensure that the patient:

a) Does not have any significant, unacceptable, or irreversible toxicities that indicate treatment will not further benefit the patient

b) Still fulfils the eligibility criteria for treatment, including consenting to restart durvalumab

c) Has not received an intervening systemic anticancer therapy after their assigned treatment discontinuation.

d) Has had a baseline tumor assessment within 28 days of restarting durvalumab. All further scans will take place 8 weekly from the date of first treatment.

Treatment through progression is at the Investigator’s discretion, and the Investigator must ensure that patients do not have any significant, unacceptable, or irreversible toxicities that indicate that continuing treatment will not further benefit the patient.

Patients who the Investigator determines may not continue treatment will enter follow-up.

Total treatment on this study will be approximately two years with further treatment to be discussed with the treating clinician.

Participating institutions will maintain a record of drug dispensed for each patient and record any unused drug returned to the pharmacy.
Intervention code [1] 298533 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 302648 0
The primary end point is disease control defined as a composite of:
1. Objective tumour response (OTR), based on complete and partial responses using cancer specific response criteria; and/or
2. Time to progressive disease exceeds the documented time to progressive disease on the last treatment prior to substudy entry by at least 1.3 times (TTP2/TTP1 greater than 1.3).
* Or exceeds 6 months if TTP1 is not evaluable.

CT scans for disease evaluation will take place every 8 weeks until progression.
Where disease evaluation is not based on CT scans alternative validated guidelines, such as
Gynecologic Cancer Intergroup (GCIG) and Prostate Cancer Working Group 2 (PCWG2) criteria will be employed.
Where radiological progression cannot be assessed, evidence for clinical progression will be documented. These data will be collected from patient questionnaires, such as quality of life per the QLQ-C30 version 3 or Brief Pain Inventory, if applicable or clinical reports to supplement the primary
outcome.
Timepoint [1] 302648 0
Tumour progression will be monitored by CT scans (or other imaging as appropriate) and GCIG and PCWG2 criteria every 8 weeks until disease progression.
Quality of life or pain scores, if applicable will be collected every 4 weeks.
Secondary outcome [1] 336644 0
Overall survival (OS) (death from any cause)
Timepoint [1] 336644 0
For the duration of the study estimated at 2 years
Secondary outcome [2] 336652 0
Safety and tolerability of treatment (rates of adverse events) assessed according to CTC AE version 4.03.

Some, but not all, common expected adverse events for the combination with olaparib and durvalumab single treatment include: diarrhoea, tiredness, decreased kidney function, dizziness

The patient information sheet will contain this information.
Timepoint [2] 336652 0
Until 30 days after the last treatment
Secondary outcome [3] 336653 0
Health related quality of life during treatment will be assessed using the EORTC QLQ-C30 tool.
Timepoint [3] 336653 0
For the duration of the study at baseline (before treatment) and then every 4 weeks until progression

Eligibility
Key inclusion criteria
1. Male or female patients, aged 18 years and older, with pathologically confirmed advanced and/or metastatic solid cancer of any histologic type or an earlier diagnosis of a poor prognosis cancer;
2. Patients with tumours carrying the following:
Germline or somatic deleterious germline or somatic mutations/deletions in BRCA1 or BRCA 2
OR
Germline or somatic mutations/deletions in non-BRCA1/2 HR pathway genes including ATM, PALB2, RAD51C, RAD51D, CHEK1, CHEK2, ATR, CDK12, BAP1, BARD1, BRIP1 and FANC genes.
3. Sufficient and accessible tissue for PDL-1 testing and for exploratory objectives;
4. Received and failed all standard anticancer therapy (where standard therapy exists) or have documented unsuitability for any further standard anticancer therapy – with the exception of current therapy patient is receiving. It is the intention to screen patients whilst they are receiving the last line of planned standard therapy.
5. ECOG performance status 0 or 1;
6. Willing and potentially able to comply with study requirements, including treatment, timing and/or nature of required assessments;
7. Adequate organ function
These are some of the inclusion criteria. You will be assessed for all criteria when joining the study.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Suitable for standard therapy or accepted standard care, if the patient has not been previously treated
2. Specific comorbidities or conditions (e.g. psychiatric) or concomitant medications which may contraindicate participation and/or interact with the investigational product(s);
3. Other comorbidities or conditions that may compromise assessment of key outcomes or in the opinion of the clinician, limit the ability of the patient to comply with the protocol;
4. For non central nervous system (CNS) cancers, patients with symptomatic CNS involvement of his/her cancer, unless the subject has stable neurological function without evidence of CNS progression within 12 weeks prior to study entry and does not require treatment with enzyme-inducing anticonvulsants or steroids (within 4 weeks prior to substudy inclusion and during substudy participation);
5. Administration of any non-oncologic investigational treatment within 30 days or 5 half-lives (whichever is longer) prior to receiving the first dose of study treatment;
6. History of another malignancy within 2 years prior to registration. Patients 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;
7. Pregnancy, lactation, or inadequate contraception. Women must be post-menopausal, infertile, or use a reliable means of contraception. Women of childbearing potential must have a negative pregnancy test done within 7 days prior to registration. Men must have been surgically sterilised or use a barrier
method of contraception (double barrier, if required).
8. Patients with BRCA1 or BRCA2 mutant breast, ovarian or prostate cancer
9. Patients who are eligible for other clinical studies involving durvalumab and/or olaparib
10. Blood transfusions within 28 days prior to registration
11. Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab and/or a PARPi, including olaparib
12. Mean QT interval corrected for heart rate (QTc) greater than or equal to 470 ms calculated from 3 electrocardiograms (ECGs) using Fredericia’s Correction

13. Current or prior use of immunosuppressive medication within 7 days before the registration, including corticosteroids (greater than 10 mg/day of intranasal and inhaled prednisolone or equivalent systemic corticosteroids at physiological doses)
14. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn's disease], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). Subjects without active disease in the last 5 years may be included at discretion of the Investigator. Subjects with the following conditions are eligible: vitiligo, alopecia, hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement, any chronic skin condition that does not require systemic therapy, celiac disease controlled by diet alone.
15. Current or prior use of immunosuppressive medication within 7 days before the registration, including corticosteroids (greater than 10 mg/day of intranasal and inhaled prednisolone or equivalent systemic corticosteroids at physiological doses)
16. History of primary immunodeficiency or allogeneic organ transplantation
17. History of leptomeningeal carcinomatosis

18. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn's disease], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). Subjects without active disease in the last 5 years may be included at discretion of the Investigator. Subjects with the following conditions are eligible: vitiligo, alopecia, hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement, any chronic skin condition that does not require systemic therapy, celiac disease controlled by diet alone.
13. Receipt of live attenuated vaccination and influenza vaccine within 14 days prior to registration
These are some of the exclusion criteria. You will be assessed for all criteria when joining the study.


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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
A group of 48 patients will be treated with olaparib in combination with durvalumab. Patients will be allocated to 3 sub-groups of 16 patients each, based on the type of HR repair defect. HR pathway defects are classified into three different categories, as follows:
Group 1: Germline or somatic deleterious mutations/deletions in BRCA1 or BRCA2; OR
Group 2 and 3: Germline or somatic mutations/deletions in non-BRCA1/2 HR pathway genes (including ATM, PALB2, RAD51C, RAD51D, CHEK1, CHEK2, ATR, CDK12, BAP1, BARD1, BRIP1 and FANC genes).

For group 2 and 3, HRD scores determined post-hoc will be used to divide non-BRCA1/2 HR defects into the 2 groups below at the end of the study. The median score will be used as an arbitrary cut-off to divide patients into two equal groups of 16 patients:
Group 2: HRD high Group 3: HRD low
Each group will be considered a substudy for the purpose of the MoST program.

As described in the framework protocol (ACTRN12616000908437), substudies with greater than or equal to 3 out of 16 responding patients, will in general be sufficiently interesting to investigate further. As a general rule, substudies with less than 3 out of 16 responses will be considered to not support the molecular hypothesis behind the substudy.

If some activity is recognised in a 16 patient substudy cohort but further information is needed to inform development of phase II testing, iterative substudies may be opened to enrich for patients that harbour a specific common biomarker or histologic cancer subtype.

Each such iteration would constitute a new substudy for the purposes of this framework.

The sample size and guiding definitions of what constitutes an interesting signal are determined empirically as the investigators considered these numbers of patients as sufficient for signal-seeking purpose.

The PD-L1 and TIL expression levels will be determined post hoc and will not guide treatment.

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)
NSW
Recruitment hospital [1] 8480 0
St Vincent's Private Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [2] 8481 0
The Chris O’Brien Lifehouse - Camperdown
Recruitment hospital [3] 8482 0
St George Hospital - Kogarah
Recruitment postcode(s) [1] 16563 0
2010 - Darlinghurst
Recruitment postcode(s) [2] 16564 0
2050 - Camperdown
Recruitment postcode(s) [3] 16565 0
2217 - Kogarah

Funding & Sponsors
Funding source category [1] 296912 0
Government body
Name [1] 296912 0
Office for Health and Medical Research
Address [1] 296912 0
Locked Bag 961
North Sydney NSW 2059
Country [1] 296912 0
Australia
Primary sponsor type
University
Name
University of Sydney
Address
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown NSW 1450
Country
Australia
Secondary sponsor category [1] 295920 0
None
Name [1] 295920 0
Address [1] 295920 0
Country [1] 295920 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298122 0
St Vincent's Hospital Ethics Committee
Ethics committee address [1] 298122 0
Translational Research Centre
97-105 Boundary Street
Darlinghurst NSW 2010
Ethics committee country [1] 298122 0
Australia
Date submitted for ethics approval [1] 298122 0
01/05/2017
Approval date [1] 298122 0
23/06/2017
Ethics approval number [1] 298122 0

Summary
Brief summary
This is a substudy of the Cancer Molecular Screening and Therapeutics (MoST) Program, which is registered on ANZCTR with ID ACTRN12616000908437. This substudy will evaluate the activity of olaparib treatment in combination with durvalumab in patients with advanced cancers and tumours.
Who is it for? All participants in this study must have completed screening as part of the Cancer Molecular Screening and Therapeutics (MoST) Program (ACTRN12616000908437), and been identified as having one of the following molecular targets: Germline or somatic deleterious mutations/deletions in BRCA1 or BRCA2; OR germline or somatic mutations/deletions in non-BRCA1/2 HR pathway genes (including ATM, PALB2, RAD51C, RAD51D, CHEK1, CHEK2, ATR, CDK12, BAP1, BARD1, BRIP1 and FANC genes).

Study details: All participants in this study will take the oral drug olaparib for 28 days alone and then add the intravenous drug durvalumab once every 28 days. Treatment with durvalumab will be administered once every 28 days until 13 cycles are complete. Olaparib treatment will continue until progression, unacceptable toxicity or withdrawal. Retreatment with durvalumab after 13 cycles will be discussed with you by your doctor.

All participants will undergo assessments at 8 weekly intervals or as clinically indicated in order to evaluate tumour response, safety and tolerability of treatment, health related quality of life during treatment, and overall survival.

We cannot guarantee that patients will receive any benefits from this study. This study is being carried out to improve the way we treat cancer patients who may have limited treatment options available to them. It is hoped that treatment will be well tolerated and will improve outcomes for future patients, however, there may be no clear benefit from participation in this study.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 76070 0
A/Prof Anthony Joshua
Address 76070 0
Garvan Institute of Medical Research
The Kinghorn Cancer Centre, 370 Victoria Street
Darlinghurst NSW 2010
Country 76070 0
Australia
Phone 76070 0
+ 61 (0)2 9355 5632
Fax 76070 0
+61 (0)2 9355 5602
Email 76070 0
Anthony.Joshua@svha.org.au
Contact person for public queries
Name 76071 0
Dr Lucille Sebastian
Address 76071 0
NHMRC Clinical Trials Centre
Level 6, Chris O'Brien Lifehouse
119-143 Missenden Road, Camperdown NSW 2050
Country 76071 0
Australia
Phone 76071 0
+61295625000
Fax 76071 0
Email 76071 0
most@ctc.usyd.edu.au
Contact person for scientific queries
Name 76072 0
A/Prof Anthony Joshua
Address 76072 0
Garvan Institute of Medical Research
The Kinghorn Cancer Centre, 370 Victoria Street
Darlinghurst NSW 2010
Country 76072 0
Australia
Phone 76072 0
+6129355 5632
Fax 76072 0
Email 76072 0
Anthony.Joshua@svha.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
Summary results
Not applicable