Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623001216606
Ethics application status
Approved
Date submitted
23/10/2023
Date registered
27/11/2023
Date last updated
28/05/2024
Date data sharing statement initially provided
27/11/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Single-institution, single-arm, open-label phase II basket study of mutation and/or elevated hedgehog (Hh) expression-directed smoothened inhibitor sonidegib in patients with advanced solid malignancies
Scientific title
Single-institution, single-arm, open-label phase II basket study investigating the effect of mutation and/or elevated hedgehog (Hh) expression-directed smoothened inhibitor sonidegib in patients with advanced solid malignancies
Secondary ID [1] 310782 0
CT-2023-CTN-04330-1
Universal Trial Number (UTN)
Trial acronym
MEHDSAM
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cancer 331749 0
Condition category
Condition code
Cancer 328501 328501 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Part I (biomarker screening): Screening and eligibility review will be conducted by the study Principal Investigator (PI), Associate Investigator (AI) and sub-Investigators (sub-Is). Patients must meet eligibility for treatment with sonidegib, which involves molecular screening on archival tumour tissue and 1 blood sample with an anticipated turnaround time of 2-4 weeks. Biomarker positive patients will be invited to participate in part II of the study and receive sonidegib. As per protocol, treatment must start within 28 days of confirmation of biomarker positivity. Patients will be accepted for part II who are known to be biomarker positive from a prior commercially available molecular screen, provided other eligibility criteria are met.

Part II (treatment with sonidegib): Odomzo (sonidegib) 200mg oral tablet once daily (may be escalated to 800mg daily at investigators discretion), until disease progression or unacceptable toxicity for a period of 12 months. Clinical review will take place every 4 weeks. Adherence will be monitored via patient diaries and pharmacy pill counts.
Intervention code [1] 327190 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 336334 0
Evaluate the activity of mutation and/or elevated Hh expression-directed Sonidegib
Timepoint [1] 336334 0
Baseline and every 8 weeks for 12 months post-first dose until progression or unacceptable toxicity
Secondary outcome [1] 427873 0
Disease control rate (Stable Disease (SD) + Partial Response (PR) + Complete Response (CR) – investigator assessed as a composite assessment)
Timepoint [1] 427873 0
Baseline and every 8 weeks for 12 months post-first dose until progression or unacceptable toxicity
Secondary outcome [2] 427874 0
Progression-free survival (PFS)
Timepoint [2] 427874 0
Baseline and every 8 weeks for 12 months post-first dose until progression or unacceptable toxicity
Secondary outcome [3] 427917 0
Toxicity/Tolerability
Timepoint [3] 427917 0
ongoing from baseline, assessed every 4 weeks in clinical follow-up or patient reported post-first dose through to 30-day post-trial safety visit
Secondary outcome [4] 427918 0
Medication compliance
Timepoint [4] 427918 0
From first dose to last dose/end of treatment
Secondary outcome [5] 427919 0
Local incidence of SMO/PTCH1 mutations and elevated Hh expression in patients with advanced solid malignancies at a typical tertiary institution
Timepoint [5] 427919 0
Part 1 (screening), within 14 days of enrolment

Eligibility
Key inclusion criteria
Part 1 - Biomarker Screening:
• Advanced solid organ malignancy, with the exception of basal cell carcinoma
• Equal to or more than 18 years old
• ECOG 2 or less
• At least 1 line of prior systemic therapy (on active treatment allowed)
• RECIST v1.1 measurable disease
• Archival tissue (FFPE, core biopsy or unstained slides) for NGS and Hh expression testing
• Signed consent to screen for NGS and elevated Hh expression (blood and tissue)

Part 2 - Interventional Study (following fulfilment of criteria specified for part 1, further inclusion criteria for treatment with Sonidegib):
• Presence of tumour SMO/PTCH1 mutation, or elevated tissue or serum Hh expression found through screening, or pre-identified on prior commercial NGS panel
• At least one line of prior systemic therapy (where standard of care systemic therapy exists)
• Radiologic confirmed measurable disease as per RECIST Version 1.1 (confirmed equal to or more than 28 days prior to enrollment)
• Prior palliative radiotherapy is permissible if completed equal to or more than 14 days prior to Sonidegib treatment to areas which are not included in response assessment
• Adequate bone marrow function (e.g. platelets more than 100 x 109/L, ANC equal to or more than 1.5 x 109/L, Hb equal to or more than 90)
• Adequate renal function (e.g. creatinine clearance equal to or more than 50 ml/min, serum creatinine less than or equal to 1.5 x ULN)
• Adequate liver function (e.g. ALT/AST equal or less than 3 x ULN or equal to or less than 5 x ULN if liver metastases are present, bilirubin equal to or less than 2 x ULN)
• Adequate cardiac function (e.g ECG and echocardiogram if clinically indicated)
• Study treatment both planned and able to start within 28 days of confirmation of SMO or PTCH1 mutation, or elevated hedgehog expression
• Signed, written informed consent (for trial inclusion and tissue collection)
• Prior, part 2, screen failure patients are eligible for re-screening for Part 2
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria for Part 2 - Interventional Study:
• Prior Sonidegib therapy
• SMO mutation detected via NGS with known resistance to sonidegib (see supplementary materials)
• No prior systemic anticancer therapy
• Life expectancy less than or equal to 3 months
• Untreated or non-clinically stable CNS disease [patients with asymptomatic, treated and clinically stable CNS disease, including leptomeningeal disease will be eligible]
• Patients with neuromuscular disorders associated with elevated CK (i.e. inflammatory myopathy)
• Concomitant therapy with drugs that are recognised to cause rhabdomyolysis
• Concomitant therapy with drugs that are strong CYP3A4/5 inducers or inhibitors, that are deemed medically necessary
• Significant uncontrolled infection including hepatitis B, hepatitis C and HIV (patients with treated and stable viral hepatitis may be eligible)
• Concurrent illness which may jeopardize the ability of the patient to undergo the procedures outlined in this protocol with reasonable safety
• Comorbid malabsorption syndrome which may impact absorption of study drug
• Serious medical or psychiatric comorbidity which may limit the ability of a patient to comply with the protocol
• Prior history of another malignancy in the 2-year period preceding registration. Patients with adequately treated carcinoma-in-situ, basal cell carcinoma or squamous cell carcinoma of the skin, superficial transitional cell carcinoma of the bladder or curatively treated cervical carcinoma in situ will be eligible.
• Pregnancy, lactation, or inadequate contraception. Women must be post-menopausal, or use adequate means of contraception (e.g. barrier method, oral contraceptive pill, intra-uterine device (IUD), or implant). Women of childbearing age must have a negative pregnancy test done within 7 days prior to starting treatment, if eligible for part 2 of this study. Men must have been surgically sterilised or use a barrier method of contraception.
• An inability to travel to the enrolled site to participate in the trial and all required visits.

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
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
4/12/2023
Actual
12/12/2023
Date of last participant enrolment
Anticipated
2/10/2025
Actual
Date of last data collection
Anticipated
2/10/2028
Actual
Sample size
Target
20
Accrual to date
1
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 25742 0
Royal North Shore Hospital - St Leonards
Recruitment postcode(s) [1] 41566 0
2065 - St Leonards

Funding & Sponsors
Funding source category [1] 315015 0
Hospital
Name [1] 315015 0
RNSH Clinical Trials Unit
Country [1] 315015 0
Australia
Funding source category [2] 315041 0
Commercial sector/Industry
Name [2] 315041 0
Sun Pharmaceutical Industries LTD
Country [2] 315041 0
India
Primary sponsor type
Hospital
Name
Northern Sydney Local Health District
Address
Royal North Shore Hospital, Reserve Road, St Leonards, NSW 2065
Country
Australia
Secondary sponsor category [1] 317064 0
None
Name [1] 317064 0
Address [1] 317064 0
Country [1] 317064 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313984 0
Northern Sydney Local Health District Research Office
Ethics committee address [1] 313984 0
Level 13 Kolling Building, Royal North Shore Hospital. Reserve Road, St Leonards, NSW 2065
Ethics committee country [1] 313984 0
Australia
Date submitted for ethics approval [1] 313984 0
21/07/2022
Approval date [1] 313984 0
22/08/2022
Ethics approval number [1] 313984 0

Summary
Brief summary
The purpose of the study is to investigate whether Sonidegib (an anti-cancer drug) is effective and safe to use in patients with advanced solid organ cancers that have a specific SMO/PTCH1 gene mutation or elevated Hedgehog protein levels.

Who is it for?
This study will involve an initial screening phase followed by an intervention/treatment phase. You may be eligible for the screening study if you are aged 18 years or older, you have been diagnosed with advanced solid organ cancer apart from advanced basal cell carcinoma and you have received at least one prior cancer treatment. Treatment naïve Individuals with a solid organ cancer that has no standard treatment may be eligible to screen.
If the screening study identifies that your particular cancer expresses an SMO/PTCH1 gene mutation or an elevated Hedgehog protein level, you may be eligible to participate in the treatment phase. Additional health assessments to check your liver, kidney and heart function will be undertaken to determine eligibility for the treatment study.

Study details
All participants who chose to enrol in this study will firstly undergo an initial screening phase. This screening phase will involve providing a blood sample for testing, as well as allowing the study investigators to access previously collected tissue samples of your cancer for testing. Participants who meet the eligibility criteria for the treatment phase will be enrolled and asked to take an oral tablet, containing the study drug, Sonidegib, each day for a minimum of 8 weeks. Any participants who experience severe side effects while taking the study drug will be asked to stop taking the drug. Participants who do not experience severe side effects will be asked to continue taking the drug for a maximum of 12 months, unless they experience any spread of their cancer or later develop severe side effects to the drug. Participants will be asked to undergo CT scans once every 8 weeks while taking the study drug.

It is hoped this research will determine whether a new anti-cancer treatment, Sonidegib, is safe to use in people with advanced solid cancers. If the drug is safe and is shown to reduce the size or activity of cancer cells in these patients, a larger randomised trial to assess the effect of Sonidegib may be undertaken.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 130022 0
A/Prof Alexander Guminski
Address 130022 0
Medical Oncology Clinical Trials Unit, Royal North Shore Hospital, Reserve Road, St Leonards, NSW 2065
Country 130022 0
Australia
Phone 130022 0
+61 2 9463 1199
Fax 130022 0
Email 130022 0
alexander.guminski@sydney.edu.au
Contact person for public queries
Name 130023 0
Ms Sally McCowatt
Address 130023 0
Clinical Trials Unit Manager, Royal North Shore Hospital, Reserve Road, St Leonards, NSW 2065
Country 130023 0
Australia
Phone 130023 0
+61 2 9463 1199
Fax 130023 0
Email 130023 0
Sally.McCowatt@health.nsw.gov.au
Contact person for scientific queries
Name 130024 0
Dr Madhawa De Silva
Address 130024 0
Medical Oncology Clinical Trials Unit, Royal North Shore Hospital, Reserve Road, St Leonards, NSW 2065
Country 130024 0
Australia
Phone 130024 0
+61 2 9463 1199
Fax 130024 0
Email 130024 0
Madhawa.DeSilva@health.nsw.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


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.