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Trial registered on ANZCTR


Registration number
ACTRN12616001019493
Ethics application status
Approved
Date submitted
11/07/2016
Date registered
2/08/2016
Date last updated
6/03/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Cancer Molecular Screening and Therapeutics (MoST) Program Substudy Addendum: durvalumab plus tremelimumab
Scientific title
Single arm, open label, signal seeking, phase IIa trial of the activity of Durvalumab (MEDI4736) in combination with Tremelimumab in patients with advanced rare or neglected cancers.
Secondary ID [1] 289648 0
CTC0141 Addendum 2
Universal Trial Number (UTN)
U1111-1182-6652
Trial acronym
MoST addendum 2
Linked study record
ACTRN12616000908437

Health condition
Health condition(s) or problem(s) studied:
Cancer 299447 0
Condition category
Condition code
Cancer 299427 299427 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients weighing 30 kg or more will receive a combination of a fixed dose of 1500 mg durvalumab via intravenous infusion followed by a 75 mg tremelimumab intravenous infusion every 4 weeks (28 days) for up to 4 doses/cycles. After this, treatment will continue with 1500 mg durvalumab every four weeks (28 days) starting on Week 16 for up to 9 doses.

Retreatment is allowed (once only) for patients meeting the retreatment criteria below:

1. Patients who achieve and maintain disease control (ie, CR, PR, or SD) through to the end of the 12-month treatment period may restart treatment with the combination upon evidence of PD, with or without confirmation according to RECIST 1.1, during follow-up.

2. Patients who complete the 4 dosing cycles of the combination of durvalumab and tremelimumab portion of the regimen (with clinical benefit per Investigator judgment), but subsequently have evidence of PD during the durvalumab monotherapy portion of the combination regimen, with or without confirmation according to RECIST 1.1, may restart treatment with the combination.

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.
Intervention code [1] 295270 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 298895 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 > 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] 298895 0
Tumour progression will be monitored by CT scans (or other imaging as appropriate) and GCIG and PCWG2 criteria every 8 weeks.

Quality of life or pain scores, if applicable will be collected every 4 weeks.
Secondary outcome [1] 325555 0
Overall survival (OS) (death from any cause)
Timepoint [1] 325555 0
For the duration of the study estimated at 2 years
Secondary outcome [2] 325556 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 and durvalumab single treatment include: diarrhoea, tiredness, effects on the function of the pancreas, iItchiness, rash, inflammation of large intestine

The patient information sheet will contain this information.
Timepoint [2] 325556 0
Until 30 days after the last treatment
Secondary outcome [3] 325557 0
Health related quality of life during treatment will be assessed using the EORTC QLQ-C30 tool.
Timepoint [3] 325557 0
For the duration of the study at baseline (before treatment) and then every 4 weeks until progression.

Eligibility
Key inclusion criteria
To be eligible for treatment in a substudy, patients must continue to meet all of the inclusion criteria and none of the exclusion criteria specified for entry into molecular screening at the time of registration to a treatment substudy. In addition, they must meet all the inclusion criteria and none of the exclusion criteria in the substudy addendum at the time of registration.

1. Confirmation of molecular eligibility by the molecular tumour board;
2. Received and failed all standard anticancer therapy or have documented unsuitability for any further standard therapy, if standard therapy exists;
3. Clinical or radiological progression on or following last anticancer therapy;
4. Adequate organ system function per addendum definitions
5. Meet any additional inclusion criteria specified in the relevant substudy addendum;
6. Signed, written informed consent to participation in the specific treatment substudy.

Inclusion criteria specific to this sub-study:
1. ECOG performance status of 0 or 1
2. Sufficient and accessible tumor tissue for PD-L1 testing and exploratory objectives
3. Adequate liver function. See protocol definition.
4. Serum creatinine CL greater than 40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance.

Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria will include those relevant for screening but also include:
1. Contraindications to investigational product, as listed in the substudy addendum and outlined in the Investigator Brochure appended to each substudy module;
2. Known history of hypersensitivity to active or inactive components of investigational product;
3. Previous treatment with the same agent or same class of agent;
4. Treatment with any of the following anti-cancer therapies prior to the first dose of study treatment:
o Radiation therapy, surgery or tumour embolization within 14 days prior to the first dose of study treatment. Palliative radiotherapy (for analgesia) is acceptable only if the irradiated field does not include target lesions;
o Immunotherapy within 28 days prior to the first dose of study treatment;
o Chemotherapy, biologic therapy, investigation therapy or hormonal therapy within 30 days or 5 half-lives of a drug (whichever is longer), prior to the first dose of study treatment;
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. Any additional exclusion criteria specified in the relevant substudy addendum.

Exclusion Criteria specific to the sub-study:
1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
2. Patients with cutaneous melanoma, non-small cell lung cancer, squamous cell carcinoma of the head and neck, breast cancer, bladder cancer, thymoma, thymic carcinoma or pancreatic cancer
3. Patients who are eligible for other clinical studies involving durvalumab and/or tremelimumab
4. Eligible for participation in another MoST substudy based on identification of an actionable mutation. Patients who have previously participated in another MoST substudy may subsequently participate in this study, all other inclusion and exclusion criteria being satisfied
5. Participation in another clinical study with an investigational product during the last 4 weeks prior to study enrolment
6. Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab or an anti- CTLA-4, including tremelimumab
7. Any unresolved toxicity (greater than CTCAE grade 2) from previous anti-cancer therapy. Subjects with irreversible toxicity that is not reasonably expected to be exacerbated by the investigational product may be included (e.g., hearing loss, peripherally neuropathy)
8. Mean QT interval corrected for heart rate (QTc) greater than 470 ms calculated from 3 electrocardiograms (ECGs) using Fredericia’s Correction
9. Current or prior use of immunosuppressive medication within 28 days before the first dose of durvalumab or tremelimumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid
10. Any prior Grade 3 or greater immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE greater Grade 1
11. Active or prior documented autoimmune disease within the past 2 years NOTE: Subjects with vitiligo, Grave’s disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded.
12. Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis)
13. History of primary immunodeficiency
14. History of allogeneic organ transplant
15. History of hypersensitivity to durvalumab or tremelimumab or any excipient
16. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent
17. Known history of active tuberculosis
18. History of leptomeningeal carcinomatosis
19. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab or tremelimumab

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 64 patients will be analyzed, divided into 4 sub-groups of 16 subjects each based on PD-L1 and TIL expression levels. Median expression levels will be used as an arbitrary cutoff to assign patients to sub-groups of high and low expressors
(PD-L1 high TIL high, PD-L1 high TIL low, PD-L1 low TIL high, PD-L1 low TIL low).
Each sub-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
Active, not 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] 6148 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [2] 6149 0
The Chris O’Brien Lifehouse - Camperdown
Recruitment hospital [3] 10265 0
St George Hospital - Kogarah
Recruitment postcode(s) [1] 13588 0
2010 - Darlinghurst
Recruitment postcode(s) [2] 13589 0
2050 - Camperdown
Recruitment postcode(s) [3] 21932 0
2217 - Kogarah

Funding & Sponsors
Funding source category [1] 294031 0
Government body
Name [1] 294031 0
Office for Health and Medical Research
Address [1] 294031 0
Locked Bag 961
North Sydney NSW 2059
Country [1] 294031 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] 292852 0
None
Name [1] 292852 0
Address [1] 292852 0
Country [1] 292852 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295445 0
St Vincent's Hospital Ethics Committee
Ethics committee address [1] 295445 0
Translational Research Centre
97-105 Boundary Street
Darlinghurst NSW 2010
Ethics committee country [1] 295445 0
Australia
Date submitted for ethics approval [1] 295445 0
04/07/2016
Approval date [1] 295445 0
16/08/2016
Ethics approval number [1] 295445 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 tremelimumab treatment in combination with durvalumab followed by single durvalumab treatment 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 having no actionable molecular targets.
Study details All participants in this study will take the intravenous drugs tremelimumab plus durvalumab once every 28 day cycle. From week 16 of treatment durvalumab will be administered alone once every 28 days. Treatment will continue until progression, unacceptable toxicity or withdrawal. Retreatment 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 palbociclib 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 67326 0
Prof David Thomas
Address 67326 0
Garvan Institute of Medical Research
The Kinghorn Cancer Centre, 370 Victoria Street
Darlinghurst NSW 2010
Country 67326 0
Australia
Phone 67326 0
+61293555770
Fax 67326 0
+612 9355 5872
Email 67326 0
d.thomas@garvan.org.au
Contact person for public queries
Name 67327 0
Dr Lucille Sebastian
Address 67327 0
NHMRC Clinical Trials Centre
Level 6, Chris O'Brien Lifehouse
119-143 Missenden Road, Camperdown NSW 2050
Country 67327 0
Australia
Phone 67327 0
+61295625000
Fax 67327 0
Email 67327 0
most@ctc.usyd.edu.au
Contact person for scientific queries
Name 67328 0
Prof David Thomas
Address 67328 0
Garvan Institute of Medical Research
The Kinghorn Cancer Centre, 370 Victoria Street
Darlinghurst NSW 2010
Country 67328 0
Australia
Phone 67328 0
+61293555770
Fax 67328 0
+612 9355 5872
Email 67328 0
d.thomas@garvan.org.au

No data has been provided for results reporting
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary