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Trial registered on ANZCTR


Registration number
ACTRN12618000281291
Ethics application status
Approved
Date submitted
15/02/2018
Date registered
22/02/2018
Date last updated
6/07/2024
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 Objective tumour response, based on complete and partial responses using cancer specific response criteria. 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
Secondary outcome [4] 434926 0
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).
Timepoint [4] 434926 0
Secondary outcome [5] 434927 0
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).
Timepoint [5] 434927 0
The study will compare the time to progression using therapy selected by MoST molecular screening 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. 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.

Eligibility
Key inclusion criteria
1. Adults, 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, identified through the MoST molecular screening program.
2. 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).
3. Confirmation of molecular eligibility by the molecular tumour board.
4. ECOG performance status 0, 1 or 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. Measurable disease as assessed by RECIST 1.1 or RANO.
8. Adequate organ system function as assessed by the following minimal laboratory requirements:
a. bone marrow function; platelets equal or greater than 100 x 10^9/L, ANC equal or greater than 1.5 x 10^9/L, and haemoglobin equal or greater than 9g/dL (5.6mmol/L);
b. liver function; ALT/AST equal or less than 3 x ULN (in the absence of liver metastases, equal or less than 5 x ULN for patients with liver involvement) and total bilirubin equal or less than 1.5xULN;
c. renal function; serum creatinine equal or less than 1.5xULN;
9. Willing and able to comply with all study requirements, including treatment (including ability to swallow whole capsules intact, without chewing, crushing, or opening the capsules), timing and/or nature of required assessments
10. Signed, written informed consent to participation in the specific treatment substudy.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Contraindications to investigational product.
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 per the vismodegib IB. 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 even after vasectomy during sexual intercourse with women while being treated with vismodegib
12. Subjects with Basal Cell Carcinoma (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. Prior treatment with a Hedgehog pathway inhibitor
16. Treatment with CYP and P-gp inhibitors or CYP inducers within 7 days of registration

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
Completed
Date of first participant enrolment
Anticipated
1/09/2018
Actual
7/12/2018
Date of last participant enrolment
Anticipated
1/06/2023
Actual
12/12/2022
Date of last data collection
Anticipated
1/06/2024
Actual
3/05/2024
Sample size
Target
16
Accrual to date
Final
16
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 hospital [5] 19460 0
The Canberra Hospital - Garran
Recruitment hospital [6] 19461 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [7] 19462 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [8] 19463 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [9] 19464 0
Royal Hobart Hospital - Hobart
Recruitment hospital [10] 19465 0
Royal Darwin Hospital - Tiwi
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
Recruitment postcode(s) [5] 34052 0
2605 - Garran
Recruitment postcode(s) [6] 34053 0
5000 - Adelaide
Recruitment postcode(s) [7] 34054 0
3000 - Melbourne
Recruitment postcode(s) [8] 34055 0
4102 - Woolloongabba
Recruitment postcode(s) [9] 34056 0
7000 - Hobart
Recruitment postcode(s) [10] 34057 0
0810 - Tiwi

Funding & Sponsors
Funding source category [1] 298489 0
Government body
Name [1] 298489 0
Office for Health and Medical Research
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
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
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
[email protected]
Contact person for public queries
Name 80539 0
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
[email protected]
Contact person for scientific queries
Name 80540 0
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
[email protected]

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 Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.