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Trial registered on ANZCTR


Registration number
ACTRN12620000918921
Ethics application status
Approved
Date submitted
18/08/2020
Date registered
17/09/2020
Date last updated
17/09/2020
Date data sharing statement initially provided
17/09/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Cancer Molecular Screening and Therapeutics (MoST) Program Substudy Addendum 7: Tremelimumab
Scientific title
Single arm, open label, signal seeking, phase IIa trial of the activity of Tremelimumab in patients with advanced rare or neglected cancers
Secondary ID [1] 300091 0
CTC0141 Addendum 7
Universal Trial Number (UTN)
U1111-1182-6652
Trial acronym
MoST addendum 7
Linked study record
This record is an addendum to the MoST framework (ACTRN12616000908437). The MoST framework protocol consists of 1/molecular screening (genomic analysis to determine whether participants are suitable for a sub-study) and 2/ sub-study design structure (study treatment for specific genomic expression/participant population). Additionally, the sub-study shares the same study objectives and outcomes as the framework. Hence, this is a substudy that linked to ACTRN12616000908437.

Health condition
Health condition(s) or problem(s) studied:
cancer 315616 0
Condition category
Condition code
Cancer 313909 313909 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A group of 48 patients will be treated with tremelimumab. A post-hoc analysis will be performed to allocate patients to 3 sub-groups of 16 patients each, on the basis ordinally ranked TMB score, as follows:
Group 1: High TMB
Group 2 and 3: Medium TMB
Groups 2 and 3 will be ordinally ranked by TMB score.
Each group will be considered a substudy for the purpose of the MoST program.

Patients will be treated with a fixed dose of 10 mg/kg tremelimumab via intravenous infusion every 4 weeks for 6 cycles.
Participants will be followed up for at least 90 days after end of treatment for new adverse events and to follow up any adverse events which are ongoing at the end-of-treatment visit.
Patients will be followed up for overall survival or subsequent anticancer treatments at 12 weekly intervals post progression.

A patient who has been receiving the study treatment - tremelimumab and is deemed to be clinically benefiting despite unconfirmed progression (iUPD per iRECIST) in the event of suspected pseudoprogression may continue tremelimumab at the discretion of the treating investigator. In this case, a confirmatory follow-up scan no later than the next imaging visit (no less than 8 weeks) is warranted per iRECIST.

No dose reductions and/or dose escalations of tremelimumab are permitted.
The management of immune and non-immune related adverse events will be managed by the site and MoST team.
Intervention code [1] 316364 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 322299 0
The primary end point is the progression-free survival at 6 months (PFS). PFS is defined as the interval from date of registration to the date of first evidence of disease progression or death from any cause, whichever occurs first. Participants who did not progress or die will be censored on the date of their last clinical assessment or tumour assessment.
Disease progression is defined according to RECIST v1.1, RANO guidelines or clinical progression. Clinical progression is defined as the development of symptoms attributable to cancer progression or initiation of other anticancer treatment for cancer. Participants who started any subsequent anti-cancer therapy without a prior reported progression will be considered to have progressed at the time of commencement of subsequent therapy.
Timepoint [1] 322299 0
Tumour progression will be monitored by CT scans (or other imaging as appropriate) and GCIG and PCWG2 criteria every 12 weeks.
Secondary outcome [1] 378007 0
Best overall objective response as per RECIST v1.1 or RANO guidelines.
Timepoint [1] 378007 0
CT, MRI or PET scan timing should be undertaken at 4 weekly intervals from commencement of treatment. Once treatment has completed, scans will continue on 12 weekly intervals until disease progression, death of patient or end of MoST sub-study 7, whichever comes first.
Secondary outcome [2] 378009 0
Overall survival (OS) (death from any cause)
Timepoint [2] 378009 0
For the duration of the study estimated at 2 years
Secondary outcome [3] 378010 0
The ratio of time to progression (TTP) on study treatment (TTP2) to TTP in the period prior to this substudy (TTP1) (TTP2/TTP1))
Timepoint [3] 378010 0
The study will compare the time to progression using therapy selected by MoST molecular profiling of a patient’s tumour (period 2) with the time to progression on the most recent therapy on which the patient had just experienced progression (period 1). If the ratio of TTP of period 2 over TTP of period 1 (TTP2/TTP1) is greater than or equal to 1.3, then the study therapy will be defined as having benefit for the patient, as durable stable disease is achieved. This efficacy assessment is based on key elements shared with the WINTHER trial conducted by the WIN consortium (NCT01856296). For patients where time to progression prior to trial therapy (TTP1) cannot be evaluated, TTP2 exceeding 6 months (i.e. stable disease on study maintained for > 6 month) would meet the criteria of benefit.
Secondary outcome [4] 378011 0
Safety and tolerability of treatment (rates of adverse events) assessed according to CTC AE version 5.0.
Some, but not all, common expected adverse events for tremelimumab include: diarrhoea, effects on the function of the pancreas, iItchiness, rash, inflammation of large intestine.
The patient information sheet will contain this information.
Timepoint [4] 378011 0
Until 30 days after the last treatment
Secondary outcome [5] 378012 0
Health related quality of life during treatment will be assessed using the EORTC QLQ-C30 tool.
Timepoint [5] 378012 0
For the duration of the study at baseline (before treatment) then every 4 weeks for 7 months and then every 12 weeks until progression.

Eligibility
Key inclusion criteria
To be eligible for treatment in this substudy, patients must meet all of the inclusion criteria below:

1. Adults, aged 18 years and older, with pathologically confirmed advanced or metastatic solid cancer of any histologic type or an earlier diagnosis of a poor prognosis cancer;
2. Measurable disease by iRECIST and RECIST or RANO
3. Confirmation of molecular eligibility by the molecular tumour board;
4. ECOG performance status 0, 1, 2;
5. Received and failed all standard anticancer therapy or have documented unsuitability for any further standard therapy, if standard therapy exists;
6. Clinical or radiological progression on or following last anticancer therapy unless such anticancer therapy stopped due to toxicity / treatment intolerance;
7. Adequate organ system function as assessed by the following minimal laboratory requirements (within 7 days prior to first administration of study drug):
a. bone marrow function; platelets greater than or equal to 100 x 109/L, ANC greather than or equal to 1.5 x 109/L, and haemoglobin greater than or equal to 9g/dL (5.6mmol/L);
b. liver function; ALT/AST less than or equal to 3 x ULN (in the absence of liver metastases, less than or equal to 5 x ULN for patients with liver involvement) and total bilirubin less than or equal to 1.5xULN. Bilirubin requirements will not apply to participants with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician.
c. renal function; serum creatinine less than or equal to 1.5xULN;
8. Tumour tissue sample available;
9. Sufficient and accessible tumour tissue for CTLA-4 testing and other correlative objectives;
10. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments
11. Signed, written informed consent to participation in the specific treatment substudy.
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. Specific comorbidities or conditions (e.g. psychiatric) or concomitant medications which may interact with the investigational product(s);
5. Co-morbidities 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;
6. Treatment with any of the following anti-cancer therapies prior to the first dose of study treatment:
a. 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;
b. Immunotherapy within 28 days prior to the first dose of study treatment;
c. Chemotherapy, biologic therapy, or hormonal therapy within 14 days or 5 half-lives of a drug prior to the first dose of study treatment or until recovery from previous therapy (whichever is longer);
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, peripheral neuropathy);
8. Administration of any investigational treatment within 30 days or 5 half-lives (whichever is longer) prior to receiving the first dose of study treatment;
9. For non-central nervous system (CNS) cancers, patients with symptomatic CNS involvement of his/her cancer are excluded. Subjects with stable neurological function, on stable doses of steroids/anti-epileptics over 4 weeks, and with no evidence of CNS progression within 12 weeks prior to screening are eligible;
10. History of another malignancy within 2 years prior to molecular screening registration are excluded unless adequately treated and determined free of progressive and metastatic disease for at least 6 months. 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 can be included;
11. 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 (double if required) barrier method of contraception;
12. Patients with pancreatic cancer;
13. Eligible for participation in another MoST substudy based on identification of an actionable mutation. However, patients who have previously participated in another MoST substudy may subsequently participate in this study, only if all other inclusion and exclusion criteria are satisfied;
14. Participation in another clinical study with an investigational product during the last 4 weeks prior to study enrolment;
15. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study;
16. Any previous treatment with a PD-1 or PD-L1 inhibitor, including durvalumab or an anti- CTLA-4, including tremelimumab;
17. Mean QT interval corrected for heart rate (QTc) greater an or equal to 470 ms calculated from 3 electrocardiograms (ECGs) using Fredericia’s Correction;
18. Any prior Grade greater than or equal to 3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE greather than Grade 1;
19. Prolonged use of moderate to high doses of immunosuppressive medication before the first dose of tremelimumab. Exceptions include intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses (eg. less than 10 mg/day of prednisone; use of dexamethasone up to 4mg /day within 14 days of initial treatment for patients with brain tumours);
20. Active autoimmune disease or prior documented autoimmune disease requiring systemic treatment within the past 2 years NOTE: Participants with vitiligo, alopecia or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded;
21. Active or prior documented inflammatory bowel disease requiring systemic treatment within the past 2 years (e.g., Crohn’s disease, ulcerative colitis);
22. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of tremelimumab. Note: Local surgery of isolated lesions for palliative intent is acceptable.
23. History of primary immunodeficiency;
24. History of allogeneic organ transplant;
25. 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 participants 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 participants to give written informed consent;
26. Known history of active tuberculosis;
27. History of leptomeningeal carcinomatosis;
28. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving 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 48 patients will be analyzed, divided into 3 sub-groups of 16 participants each based on TMB score. 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.

Recruitment
Recruitment status
Not yet 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,NT,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 15516 0
The Canberra Hospital - Garran
Recruitment hospital [2] 15517 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [3] 15518 0
St George Hospital - Kogarah
Recruitment hospital [4] 15520 0
Royal Darwin Hospital - Tiwi
Recruitment hospital [5] 15521 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [6] 15522 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [7] 15523 0
Royal Hobart Hospital - Hobart
Recruitment hospital [8] 15524 0
Linear Clinical Research - Nedlands
Recruitment hospital [9] 15525 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment postcode(s) [1] 28880 0
2605 - Garran
Recruitment postcode(s) [2] 28881 0
2010 - Darlinghurst
Recruitment postcode(s) [3] 28882 0
2217 - Kogarah
Recruitment postcode(s) [4] 28884 0
0810 - Tiwi
Recruitment postcode(s) [5] 28885 0
4102 - Woolloongabba
Recruitment postcode(s) [6] 28886 0
5000 - Adelaide
Recruitment postcode(s) [7] 28887 0
7000 - Hobart
Recruitment postcode(s) [8] 28888 0
6009 - Nedlands
Recruitment postcode(s) [9] 28889 0
3000 - Melbourne

Funding & Sponsors
Funding source category [1] 304537 0
Government body
Name [1] 304537 0
Office for Health and Medical Research
Address [1] 304537 0
Locked Bag 961
North Sydney NSW 2059
Country [1] 304537 0
Australia
Funding source category [2] 304556 0
Other Collaborative groups
Name [2] 304556 0
Outsmarting Cancer Together - OMICO
Address [2] 304556 0
Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst NSW 2010
Country [2] 304556 0
Australia
Primary sponsor type
University
Name
The University of Sydney
Address
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown NSW 1450
Country
Australia
Secondary sponsor category [1] 304834 0
None
Name [1] 304834 0
Address [1] 304834 0
Country [1] 304834 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304966 0
St Vincent's Hospital Human Research Ethics Committee
Ethics committee address [1] 304966 0
Translational Research Centre
97-105 Boundary Street
Darlinghurst NSW 2010
Ethics committee country [1] 304966 0
Australia
Date submitted for ethics approval [1] 304966 0
27/01/2020
Approval date [1] 304966 0
14/08/2020
Ethics approval number [1] 304966 0
2020/ETH01274

Summary
Brief summary
This study will determine if an immunotherapy drug (called tremelimumab) has an effect on progression-free survival in patients with rare or neglected cancers. This is a substudy of the Cancer Molecular Screening and Therapeutics (MoST) Program, which is registered on ANZCTR with ID ACTRN12616000908437.

Who is it for?
You may be eligible for this study if you are an adult with and advanced and/or metastatic solid cancer.

Study details
Participants will receive the study drug (Tremelimumab) via intravenous infusion every 4 weeks for 6 cycles.

Participants will complete imaging, clinical and safety assessments throughout the study.

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 tremelimumab 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 98794 0
Prof David Thomas
Address 98794 0
Garvan Institute of Medical Research
The Kinghorn Cancer Centre, 370 Victoria St Darlinghurst NSW 2010
Country 98794 0
Australia
Phone 98794 0
+61 293555770
Fax 98794 0
+61 293555872
Email 98794 0
d.thomas@garvan.org.au
Contact person for public queries
Name 98795 0
Dr Lucille Sebastian
Address 98795 0
NHMRC Clinical Trials Centre, Medical Foundation Building Levels 4-6, 92-94 Parramatta Road, Camperdown NSW 2050
Country 98795 0
Australia
Phone 98795 0
+61 295625000
Fax 98795 0
Email 98795 0
most@ctc.usyd.edu.au
Contact person for scientific queries
Name 98796 0
Prof David Thomas
Address 98796 0
Garvan Institute of Medical Research
The Kinghorn Cancer Centre, 370 Victoria St Darlinghurst NSW 2010
Country 98796 0
Australia
Phone 98796 0
+61 293555770
Fax 98796 0
+61 293555872
Email 98796 0
d.thomas@garvan.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
There are no plans for this to occur at this time and participant consent is required for data sharing.
What supporting documents are/will be available?
No other documents available
Summary results
No Results