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Trial registered on ANZCTR


Registration number
ACTRN12620000984998
Ethics application status
Approved
Date submitted
3/07/2020
Date registered
30/09/2020
Date last updated
30/09/2020
Date data sharing statement initially provided
30/09/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Cancer Molecular Screening and Therapeutics (MoST) Program Substudy Addendum 11 substudy 25-26: Tildrakizumab
Scientific title
Single arm, open label signal seeking, phase II trial to study the clinical activity of Tildrakizumab in patients with advanced osteosarcoma and soft tissue sarcomas
Secondary ID [1] 301688 0
CTC0141-addendum 11
Universal Trial Number (UTN)
U1111-1182-6652
Trial acronym
MoST Addendum 11
Linked study record
This record is an addendum to the MoST framework protocol (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 is linked to ACTRN12616000908437

Health condition
Health condition(s) or problem(s) studied:
Cancer 318136 0
Advanced Osteosarcoma 318460 0
Soft Tissue Sarcoma 318461 0
Condition category
Condition code
Cancer 316161 316161 0 0
Any cancer
Cancer 316466 316466 0 0
Sarcoma (also see 'Bone') - soft tissue
Cancer 316467 316467 0 0
Other cancer types

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Tildrakizumab is the study intervention in this trial and is registered with the TGA for plaque psoriasis.

Tildrakizumab will be administered by the Study Coordinator/Research Nurse via subcutaneous injection as a flat dose of 200 mg every 4 weeks and will be administered continuously until disease progression is documented or when the participant experiences intolerable toxicity or withdraws for another reason. No dose reductions will be allowed.

Participant medication compliance will be determined at each clinic visit by standard compliance assessments to determine the actual dose taken. Participants will be asked to return unused drug and empty drug containers at each return visit. The Pharmacy Department at participating institutions will maintain a record of drugs dispensed for each participant.
Intervention code [1] 317998 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 324343 0
The primary outcome is to test the clinical activity of Tildrakizumab as measured by objective tumour response using FDG-PET/CT scans or the ratio of time-to-progression on study over the preceding period.
Timepoint [1] 324343 0
FDG-PET/CT scans to measure objective tumour response will take place at:
Primary timepoint: Screening (within 14 days prior to registration)
Secondary Timepoints: During treatment, scans will be performed 8-weekly (every 2 cycles from start of treatment). During follow-up, scans will be performed every 8 weeks until progression.

Secondary outcome [1] 384391 0
Overall survival (OS) (death from any cause);
Timepoint [1] 384391 0
Patients will be followed up for overall survival at 8 weekly intervals until progression and at 12 weekly intervals post progression until the date of death from any cause (or the date of last known vital status during follow up within 12 months from registration).
Secondary outcome [2] 384397 0
Safety and tolerability of treatment (rates of adverse events). Adverse events that may occur whilst on treatment include:
-Cold-like symptoms (runny nose, sneezing) and/or sinusitus
-Injection site pain
-Diarrhoea
-Nausea
-Fatigue and tiredness
-Back pain, muscle ache, and pain in extremity

These events will be assessed as per the Common Terminology Criteria for Adverse Events (CTCAE).
Timepoint [2] 384397 0
Adverse events will be recorded from the first dose of study treatment until 30 days after cessation of study treatment.
Secondary outcome [3] 384398 0
Health related quality of life during treatment will be assessed using the EORTC QLQ-C30 form.
Timepoint [3] 384398 0
During the on-treatment stage, health related quality of life will be assessed every cycle before treatment (up to 3 days prior), starting from the first treatment cycle. During follow-up, quality of life will be assessed every 8 weeks until disease progression is noted.
Secondary outcome [4] 385333 0
Overall survival at 12 months
Timepoint [4] 385333 0
At 12 months from participant registration to date of death from any cause (or the date of last known vital status during follow up within 12 months from registration).
Secondary outcome [5] 385334 0
Progression free survival. 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, guidelines.
Timepoint [5] 385334 0
FDG-PET/CT scans to measure objective tumour response will take place during the treatment phase at 8-weekly intervals (every 2 cycles from start of treatment). During follow-up, scans will be performed every 8 weeks until disease progression is noted.
Secondary outcome [6] 385335 0
Progression free survival at 6 months. This is defined as the proportion of participants on study who are alive and progression free at 6 months as measured by FDG-PET/CT scans of tumour response.
Timepoint [6] 385335 0
At 6 months post participant registration.

Eligibility
Key inclusion criteria
Inclusion Criteria – molecular screening:
1. Male or female patients, aged 18 years and older, with pathologically confirmed advanced and/or metastatic cancer of any histologic type, including haematological cancers, or an earlier diagnosis of a poor prognosis cancer;
2. Sufficient and accessible tissue for molecular screening;
3. Patients receiving their last line of standard treatment or who have received and failed all standard anticancer therapy (where standard therapy exists) or have documented unsuitability for any further standard anticancer therapy. Poor prognosis cancers or cancers with low expected response rate to standard treatment (in the opinion of the investigator and based on available evidence) may be screened on an earlier line of treatment.
a. Failure is defined as either progression of disease (clinical or radiological) or intolerance to standard therapy resulting in the discontinuation of the therapy.
b. Documented unsuitability for further standard therapy includes known hypersensitivity, organ dysfunction or other patient factors that would make therapy unsuitable in the judgement of the responsible investigator;
4. Eastern Cooperative Oncology Group (ECOG) Performance Status performance status 0, 1 or 2;
5. Willing and potentially able to comply with study requirements, including treatment, timing and/or nature of required assessments; It is the intention to screen patients who are in principle wishing to take part in a MoST substudy if they are found to have an appropriate tumour biomarker and are still eligible for enrolment at the time of the treatment phase;

It is the intention to screen patients who are in principle wishing to take part in a MoST substudy if they are found to have an appropriate tumour biomarker and are still eligible for enrolment at the time of the treatment phase (substudy).

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.

Inclusion Criteria – substudy:
1. Adults, aged 18 years and older, with pathologically confirmed advanced osteosarcoma or soft-tissue sarcoma;
2. Has measurable disease as defined by RECIST 1.1;
3. Confirmation of molecular eligibility by the molecular tumour board;
4. ECOG 0-2;
5. Sufficient and accessible tumour tissue for exploratory objectives
6. Received and failed all standard anticancer therapy or have documented unsuitability for any further standard therapy, if standard therapy exists;
7. Clinical or radiological progression on or following last anticancer therapy unless such anticancer therapy stopped due to toxicity / treatment intolerance;
8. 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 greater 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;
c. renal function; serum creatinine less than or equal to 1.5xULN;
9. Archival tissue sample available
10. Willing and able to comply with all study requirements, including treatment, timing, and on-treatment biopsy.
11. Signed, written informed consent to participation in the specific treatment substudy.
12. The patient is considered to be eligible according to the following tuberculosis (TB) screening criteria, defined as:
a. No history of untreated latent or active TB prior to screening.
b. Has no signs or symptoms suggestive of active TB upon medical history and/or physical examination.
c. Has had no recent close contact with a person with active TB OR, if there has been such contact, to be referred to a respiratory physician at least 4 weeks prior to the first administration of study medication.
d. Has a negative diagnostic TB test results, defined as a negative intradermal tuberculin skin test (TST) or a negative QuantiFERON-TB Gold test (QFTG) within 4 weeks prior to first administration of study medication.
e. A subject who has a positive contact history, or a positive TST or QFTG test, or has signs or symptoms suggestive of active TB upon medical history and physical examination, must have a negative chest X-ray (both posterior-anterior and lateral views) or chest computed tomography (CT) scan taken within 4 weeks prior to first administration of study medication to exclude current active TB or old inactive TB, read by a qualified radiologist.
f. Patient with LTBI, defined as a positive TST and QFTG but no clinical and radiological evidence of active TB infection, may be included if they receive prophylactic treatment, or have previously completed an adequate course of prophylactic treatment according to local guidelines or regulations without subsequent new exposure to active TB. Prophylactic treatment for LTBI must be initiated at least 4 weeks prior to first administration of study medication, as per local guidelines.
g. Referral to a respiratory specialist physician is strongly encouraged to assess the need for repeat of prophylactic therapy if there is a history of new exposure to active TB subsequent to completion of prior treatment for LTBI or if prior treatment of LTBI was completed more than 3 months prior to screening.
13. Female subject must be:
a. Postmenopausal status as determined by:
i. greater than or equal to 45 years of age with more than 1 year since last menses, more than or equal to 2 years after completion of last dose cytotoxic chemotherapy, OR
ii. If a subject is less than 45 years of age, follicle-stimulating hormone (FSH) level must be documented as elevated into the postmenopausal range at screening.
b. Pre-menopausal female and agrees to abstain from heterosexual activity, OR use a medically accepted and appropriate effective method of contraception.
14. Patient must have negative human immunodeficiency virus (HIV) test result, hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) test results.
15. For women of childbearing potential, a negative serum pregnancy test at screening and a negative urine pregnancy test within 24 hours prior to the first dose of study medication.
16. Patient must have a satisfactory physical examination within normal limits or clinically acceptable limits to the investigator prior to the first dose of study medication.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusions criteria - molecular screening
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;
3. Other 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;
4. 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;
5. 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;
6. Pregnancy, lactation or inadequate contraception.

Exclusion criteria - substudy
1. Contraindications to investigational product;
2. Known history of hypersensitivity to active or inactive components of investigational product or latex;
3. Previous treatment with tildrakizumab (MK-3222) or other IL-23/Th-17 pathway inhibitors, including p40, p19, and IL-17 antagonists.
4. Specific co-morbidities or conditions (e.g. psychiatric) or concomitant medications which may interact with the investigational product(s);
5. Presence of any infection or history of recurrent infection requiring treatment with systemic antibiotics within 2 weeks prior to screening, or severe infection (e.g., pneumonia, cellulitis, bone, or joint infections) requiring hospitalization or treatment with intravenous antibiotics within 8 weeks prior to screening.
6. 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;
7. 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);
8. 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);
9. Any significant organ dysfunction or clinically significant laboratory abnormalities that place the subject at unacceptable risk for participation in a trial of an immunomodulatory therapy in the judgment of the investigator, within 6 months prior to screening.
10. Hospitalization due to an acute cardiovascular event, cardiovascular illness, or cardiovascular surgery within 6 months of screening.
11. Uncontrolled hypertension (systolic blood pressure of greater than or equal to 160 mm Hg and/or diastolic blood pressure of greater than or equal to 100 mm Hg at screening) or uncontrolled diabetes at screening
12. Administration of any investigational treatment within the indicated washout period prior to receiving the first dose of study treatment:
a. Live viral or bacterial vaccination within 28 days.
b. Injectable or oral corticosteroids (greater or equal to daily dose of 20 mg equivalent of prednisone) within 28 days
c. Received another biological agent (e.g., monoclonal antibodies), including immune checkpoint blockades, within 28 days
d. Concurrent participation in an interventional trial with another pharmacologic agent (Observational studies are permitted).
e. Participated in an interventional clinical trial within 4 weeks or 5 half-lives of a drug (whichever is longer)
f. Radiation therapy, surgery or tumour embolization within 14 days. Palliative radiotherapy (for analgesia) is acceptable only if the irradiated field does not include target lesions
g. Chemotherapy, biologic therapy, or hormonal anticancer therapy within 14 days or 5 half-lives of a drug or until recovery from previous therapy (whichever is longer)
13. Symptomatic CNS metastasis or leptomeningeal disease from underlying sarcoma, unless the participant has a 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;
14. Concurrent or a past history of another malignancy prior to molecular screening with a less favourable prognosis than the index malignancy are permitted to participate, except for:
a. adequately treated skin cancers (including basal cell carcinoma, squamous cell carcinoma squamous cell carcinoma), superficial transitional cell carcinoma of the bladder, or carcinoma of cervix uteri, or;
b. other solid or haematological malignancies determined to be free of progressive and metastatic disease at the time of screening.
15. 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

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
Other design features
Phase
Phase 2
Type of endpoint(s)
Statistical methods / analysis
A group of 32 patients will be recruited for 2 substudies containing 16 subjects each. Subjects in group 1 will have advanced osteosarcoma and subjects in group 2 will have other advanced soft tissue sarcomas..

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

Funding & Sponsors
Funding source category [1] 306125 0
Government body
Name [1] 306125 0
Office for Health and Medical Research
Address [1] 306125 0
Locked Bag 961 North Sydney NSW 2059
Country [1] 306125 0
Australia
Funding source category [2] 306126 0
Other Collaborative groups
Name [2] 306126 0
Australian Genomic Cancer Medicine Centre (AGCMC)
Address [2] 306126 0
Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst NSW 2010
Country [2] 306126 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] 306593 0
None
Name [1] 306593 0
Address [1] 306593 0
Country [1] 306593 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306342 0
St Vincent's Hospital Human Research Ethics Committee
Ethics committee address [1] 306342 0
Translational Research Centre, 97-105 Boundary Street, Darlinghurst NSW 2010
Ethics committee country [1] 306342 0
Australia
Date submitted for ethics approval [1] 306342 0
29/05/2020
Approval date [1] 306342 0
14/08/2020
Ethics approval number [1] 306342 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 Tildrakizumab in patients 18 years or older, with pathologically confirmed advanced osteosarcoma or soft-tissue sarcomas.

Who is it for:
You may be eligible to join the study if you are aged 18 years and older, with pathologically confirmed advanced and/or metastatic cancer of any histologic type, including haematological cancers, or an earlier diagnosis of a poor prognosis cancer and have confirmed molecular markers. Molecular profiling will be performed and assessed by the Molecular Tumour Board who will confirm if you have the right molecular markers for this study .

Study details:
Eligible participants will receive Tildrakizumab at a dose of 200mg every 28 days continuously via subcutaneous injection as long as they and their doctor agree there is a benefit from treatment. Tildrakizumab works by targeting a protein called IL-23, and recent research conducted at Garvan Institute has shown that IL-23 may be involved in growth of sarcomas and osteosarcomas. Tildrakizumab is approved in Australia and is used to treat psoriasis. However, tildrakizumab is not approved to treat bone or soft tissue sarcoma and is therefore an investigational treatment for these advanced and rare cancer types.

Clinical and safety assessments are scheduled prior to registration and then every 4 weeks during treatment. Clinical assessments will continue until treatment is stopped.

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 Tildrakizumab 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 103554 0
Prof David Thomas
Address 103554 0
Garvan Institute of Medical Research The Kinghorn Cancer Centre 370 Victoria St Darlinghurst NSW 2010
Country 103554 0
Australia
Phone 103554 0
+61 2 9355 5770
Fax 103554 0
+61 2 9355 5872
Email 103554 0
d.thomas@garvan.org.au
Contact person for public queries
Name 103555 0
Dr Lucille Sebastian
Address 103555 0
NHMRC Clinical Trials Centre, Medical Foundation Building Levels 4-6, 92-94 Parramatta Road, Camperdown NSW 2050
Country 103555 0
Australia
Phone 103555 0
+61 2 9562 5000
Fax 103555 0
Email 103555 0
most@ctc.usyd.edu.au
Contact person for scientific queries
Name 103556 0
Prof David Thomas
Address 103556 0
Garvan Institute of Medical Research The Kinghorn Cancer Centre 370 Victoria St Darlinghurst NSW 2010
Country 103556 0
Australia
Phone 103556 0
+61 2 9355 5770
Fax 103556 0
+61 2 9355 5872
Email 103556 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