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

Phase 2

Recruiting

• Conditions: Cancer; Cancer - Any cancer

• Registration Number: ACTRN12623001216606
• Lead Sponsor: orthern Sydney Local Health District

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2023-11-27
• Last Update Posted: 3 June 2024

Recruitment & Eligibility

• Status: Recruiting
• Sex: All
• Target Recruitment: 20

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

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

• Study Type: Interventional
• Study Design: Not specified