62P - Phase I/II study of pazopanib and temozolomide in patients with newly diagnosed glioblastoma multiforme: PAZOGLIO trial

Background

Pazopanib (PZB), an anti-angiogenic tyrosine kinase inhibitor, has shown activity in pre-treated advanced glioblastomas (GBM). Biological and clinical data support the evaluation of PZB activity in earlier stage of the disease. The objective of PAZOGLIO trial (NCT02331498) is to evaluate the safety (phase I) and efficacy (phase II) of PZB combined with Temozolomide (TMZ) during the maintenance phase as defined by the “Stupp protocol” in GBM patients after complete or partial resection surgery. Here, we report the updated results of the phase I.

Methods

PAZOGLIO trial is a prospective dose escalation phase I (3+3 design) clinical trial conducted between 2015 and 2022 in 3 French centers. Four doses levels of PZB were predefined (200 mg, 400 mg, 600 mg and 800 mg). The dose-limiting toxicity (DLT) was assessed during the first two cycles. The maximum tolerated dose (MTD) was defined as the dose at which a pre-determined number of patients (2/3 or 2/6) experienced DLT. At this dose, dose escalation was discontinued. The recommended dose for phase II (RP2D) was defined as the lower level dose of the MTD.

Results

A total 20 patients were enrolled. Median age was 54 years (25 to 69), 14/20 (70%) were women, 15/20 (75%) had a complete resection. The 1-year OS and PFS were 71% [52-96] and 42% [25-72] respectively. In addition, the median OS and PFS were 22 months (95%CI [16.7-NA]) and 9.5 months (95%CI [6.4-NA]), respectively. Three-hundred and twenty-eight treatment-related AEs were observed, including 203 grade 1 (62%), 102 grade 2 (31%), and 23 grade 3 (7%). Neither severe hemorrhage or healing issues, nor treatment-related deaths were observed. Three of the 20 patients (15%) presented DLT, 1/6 patient (12.5%) at dose level of 600 mg (grade 2 thrombopenia) and 2/6 patients (33.5%) at dose level of 800 mg (grade 3 thrombopenia and hypertension). Finally, a statistically significant increase in terms of AUC_0-24h (p=0.005), AUC_0-8h (p=0.013) and C_max (p=0.008) between Cycle 1 and Cycle 2 was observed.

Conclusions

The addition of PZB to TMZ in “Stupp protocol” is feasible in resected GBM patients. The RP2D is daily 600 mg PZB in combination with TMZ during the maintenance phase of the Stupp protocol. The phase II part is currently enrolling.

Clinical trial identification

NCT 02331498.

Editorial acknowledgement

Legal entity responsible for the study

Centre Antoine Lacassagne, Nice, France.

Funding

Novartis.

Disclosure

All authors have declared no conflicts of interest.