MoST addendum 4 and substudy 9: Single arm, open label, signal seeking, phase IIa trial of the activity of vismodegib in patients with tumours harbouring PTCH1 or SMO mutations.

Trial Summary:

Abnormal signalling within the Hedgehog pathway was first characterised in studies of basal cell nevus syndrome (BCNS), a condition caused by a germline deletion of one copy of patched 1 (PTCH1). This defect conferred a notably high risk of advanced basal cell carcinoma (BCC) and medulloblastomas. These findings were reinforced by the demonstration of mutations in PTCH1, SMO and SUFU in a significant proportion of spontaneous BCCs and medulloblastomas (1). Subsequent reports of Hedgehog pathway hyperactivation in many solid tumours, with a preponderance for cancers with high mortality (2), support its importance in carcinogenesis and provide rationale for targeting it as a therapeutic strategy.

Mutations in the Hedgehog pathway and resultant hyperactivation in tumours is a target for treatment by inhibitors such as vismodegib. SMO inhibition should reduce activity of this pathway and suppress tumour growth.

The aim of this MoST substudy is to assess the clinical activity of the Hedgehog pathway inhibitor vismodegib in patients with advanced solid cancers harbouring mutations in PTCH1 or SMO, including deactivating PTCH1 mutations or activating SMO mutations. 

To be eligible for this substudy, participants must continue to meet all of the inclusion criteria and none of the exclusion criteria specified in the MoST framework protocol (sections 5.3-5.8) and, in addition, meet all the inclusion criteria and none of the exclusion criteria at the time of registration.

Supported By:

OHMR, CGMP, Rare Cancers Australia, Roche


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).

Registration ID:





In follow-up

Activation Date:



Subotheni Thavaneswaran