Please be advised that due to the high volume of submissions, the ANZCTR is currently experiencing delays in processing submissions from those outside of Australia and New Zealand. As the ANZCTR is funded by Australia and New Zealand, we must prioritise submissions from these countries first. International submissions should allow additional time for registration. Apologies for any inconvenience caused.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12618000281291
Ethics application status
Approved
Date submitted
15/02/2018
Date registered
22/02/2018
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 4 substudy 9: vismodegib
Scientific title
Single arm, open label, signal seeking, phase IIa trial of the activity of vismodegib in patients with tumours harbouring PTCH1 or SMO mutations
Secondary ID [1] 293871 0
CTC0141-addendum 4
Universal Trial Number (UTN)
U1111-1182-6652
Trial acronym
MoST Addendum 4
Linked study record
ACTRN12616000908437

Health condition
Health condition(s) or problem(s) studied:
Cancer 306335 0
Condition category
Condition code
Cancer 305422 305422 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Vismodegib will be taken orally by the participant, at home, at a dose of 150 mg/day (1 capsule), Vismodegib will be taken continuously until disease progression is documented, the patient experiences intolerable toxicity or withdraws for another reason. 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 patient.
Intervention code [1] 300139 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 304665 0
The primary end point is disease control defined as:
1. Objective tumour response, based on complete and partial responses using cancer specific response criteria 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.

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 The Brief Pain Inventory, or clinical reports to supplement the primary outcome.
Timepoint [1] 304665 0
CT, MRI or PET scans for disease evaluation will take place every 8 weeks until disease progression or completion of the treatment schedule.
Secondary outcome [1] 342720 0
Overall survival (OS) (death from any cause).
Timepoint [1] 342720 0
For the duration of the study.
Secondary outcome [2] 342721 0
Safety and tolerability of treatment (rates of adverse events)
Timepoint [2] 342721 0
Adverse events will be recorded from the first dose of study treatment until 30 days after cessation of study treatment.
Secondary outcome [3] 342722 0
Health related quality of life during treatment will be assessed using the EORTC QLQ-C30 and The Brief Pain Inventory Forms
Timepoint [3] 342722 0
Every 4 weeks during the study and follow-up until disease progression

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 solid cancer of any histologic type 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. ECOG 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.

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. 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 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 10^9/L, ANC greater than or equal to 1.5 x 10^9/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;
5. Subjects with tumours with germline, or somatic Hedgehog pathway mutations in PTCH1 or SMO, excluding mutations in SMO known to affect vismodegib binding (ie. SMO G497W, SMO D473Y).
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion 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(s);
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. 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 study entry are eligible.
5. History of another malignancy within 2 years prior to registration 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 are eligible;
6. 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).

Exclusion Criteria – treatment substudy
7. Contraindications to investigational product, as listed in the substudy addendum and outlined in the Investigator Brochure appended to each substudy module;
8. Known history of hypersensitivity to active or inactive components of investigational product;
9. Previous treatment with the same agent or same class of agent;
10. Treatment with any of the following anti-cancer therapies prior to the first dose of study treatment:
-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;
-Immunotherapy within 28 days prior to the first dose of study treatment;
-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);
11. Administration of any investigational treatment within 30 days or 5 half-lives (whichever is longer) prior to receiving the first dose of study treatment;
12. Subjects with BCC or melanoma
13. Tumours with SUFU mutations
14. Patients with one of the following rare hereditary conditions: galactose intolerance, primary hypolactasia, or glucose-galactose malabsorption
15. Participants unable or unwilling to swallow capsules
16. Prior treatment with a Hedgehog pathway inhibitor
17. Treatment with CYP and P-gp inhibitors or CYP inducers within 7 days of registration
18. 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 use a barrier method of contraception (double barrier, if required), even after vasectomy during sexual intercourse with women while being treated with vismodegib.

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
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
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] 9937 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [2] 9938 0
The Chris O’Brien Lifehouse - Camperdown
Recruitment hospital [3] 9939 0
St George Hospital - Kogarah
Recruitment hospital [4] 13074 0
Linear Clinical Research - Nedlands
Recruitment postcode(s) [1] 18749 0
2010 - Darlinghurst
Recruitment postcode(s) [2] 18750 0
2050 - Camperdown
Recruitment postcode(s) [3] 18751 0
2217 - Kogarah
Recruitment postcode(s) [4] 25582 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 298489 0
Government body
Name [1] 298489 0
Office for Health and Medical Research
Address [1] 298489 0
Locked Bag 961
North Sydney NSW 2059
Country [1] 298489 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] 297632 0
None
Name [1] 297632 0
Address [1] 297632 0
Country [1] 297632 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299476 0
St Vincent's Hospital Ethics Committee
Ethics committee address [1] 299476 0
Translational Research Centre
97-105 Boundary Street
Darlinghurst NSW 2010
Ethics committee country [1] 299476 0
Australia
Date submitted for ethics approval [1] 299476 0
27/11/2017
Approval date [1] 299476 0
07/02/2018
Ethics approval number [1] 299476 0
SVH file number 17/258

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 vismodegib in patients with advanced cancers and tumours.

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 solid cancer of any cell type or an earlier diagnosis of a poor prognosis cancer and have received all standard anticancer therapy. Participants will have tumours with mutations in PTCH1 or SMO.

Study details
Participants will continue to consume one 150mg capsule of vismodegib for as long as they and their doctor agree there is a benefit from treatment. Participants will undergo imaging assessments at 8 weekly intervals or as clinically indicated in order to evaluate tumour response. Safety and tolerability of treatment and health related quality of life during treatment will be assessed at 4 weekly intervals.

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 vismodegib 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 80538 0
Dr Subotheni Thavaneswaran
Address 80538 0
Garvan Institute of Medical Research
The Kinghorn Cancer Centre
370 Victoria St Darlinghurst NSW 2010
Country 80538 0
Australia
Phone 80538 0
+ 61 (0)2 9355 5655
Fax 80538 0
+61 (0)2 9355 5602
Email 80538 0
s.thavaneswaran@garvan.org.au
Contact person for public queries
Name 80539 0
Dr Lucille Sebastian
Address 80539 0
NHMRC Clinical Trials Centre Level 6
Chris O'Brien Lifehouse
119–143 Missenden Road
Camperdown NSW 2050
Country 80539 0
Australia
Phone 80539 0
+61 (0)2 9562 5000
Fax 80539 0
Email 80539 0
most@ctc.usyd.edu.au
Contact person for scientific queries
Name 80540 0
Dr Subotheni Thavaneswaran
Address 80540 0
Garvan Institute of Medical Research
The Kinghorn Cancer Centre
370 Victoria St Darlinghurst NSW 2010
Country 80540 0
Australia
Phone 80540 0
+ 61 (0)2 9355 5655
Fax 80540 0
+61 (0)2 9355 5602
Email 80540 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.
What supporting documents are/will be available?
No other documents available
Summary results
No Results