Phase Ib/IIa, single arm dose escalation trial of mistletoe plant extract (AVF2) in patients with Ta G1/G2 or T1 G1/G2 non-muscle invasive bladder cancer who had a marker lesion left in bladder after TURBT. A weekly instillation of AVF2 was started 2 weeks after TURBT. Instillations were performed weekly for 6 weeks and then patients assessed for a response 6 weeks after completion of therapy (14 weeks from TURBT).
Pre-clinical work demonstrated that mistletoe extracts have an antiproliferative effect on bladder cancer cell lines and anti-tumor activity in rodent bladder tumor models. This trial sought to establish safety with intravesical administration of mistletoe plant extracts specifically using AVF2 in the setting of a marker lesion. The primary endpoint was safety with dose escalation and the secondary endpoint was tumor remission rate of the marker lesion.
AVF2 was well-tolerated and may have activity against intermediate risk papillary tumors (12 patients had T1 G1/G2 and 9 patients had Ta G2 disease). This study did not use the revised 2004 WHO Pathologic staging criteria and so it is unclear what the true pathology is for the T1G1 patients. This trial excluded CIS patients and so appropriately a marker lesion design was performed which more accurately assesses response of papillary tumors to treatment alone. However, 3 months and 12 months are not sufficient durations of follow-up to clearly establish efficacy of AVF2. Furthermore, it is unclear whether patients would have done equally well if they had been given perioperative mitomycin C.
No grade III toxicity attributable to AVF2 was noted and so dose safely increased to 45 ampules (675 mg AVF2 extract). 30 patients available for assessment of marker lesion and 20 (~67%) had no visible lesion and a negative biopsy at 14 weeks from TURBT. Only 19 of the original patients had follow-up at 1 year and 14 of these patients (73.7%) remained tumor-free.