5G-PEARL: Paxalisib in Malignant Brain Tumours
brief summary
The purpose of this clinical trial is to evaluate the safety and tolerability of paxalisib in combination with temozolomide and to determine the preliminary antitumour activity of the combination therapy. In the Phase 1b of this study parallel biomarker defined arms will be opened in the front-line unmethylated MGMT setting, enrolling 10 patients onto each arm. These patients will be treated with paxalisib in combination with temozolomide (TMZ). The starting dose of paxalisib will be 45mg once a day (OD) with the option of increasing to 60 mg (30 mg BD) in Cycle 2. TMZ will be administered once daily by mouth on days 1 to 5 in a 28-day cycle, with a starting dose of 150mg/m2 during cycles 1 and 2, and subsequent dose escalation to 200mg/m2 at the start of cycle 3 if cycles 1 and 2 have been well tolerated with no significant toxicity.
detailed description
The clinical trial will be divided into two parts: Phase 1b (proof of concept of hypothesis-driven biomarker-guided therapies) and Phase 2 (preliminary efficacy testing).
This is a study within 5G: A Next Generation AGile Genomically Guided Glioma Modular Platform for proof-of-concept molecular hypothesis testing in patients with high grade malignant brain tumours.
5G-PEARL is a Bayesian multi-centre, multi-arm, open-label, adaptive, seamless Phase 1/2 trial of paxalisib in combination with temozolomide, for patients with malignant brain tumours.
5G-PEARL will recruit patients with glioblastoma (GBM) into two molecularly-defined biomarker arms of patients who have tumours that harbour:
* Hyperactivating PI3K pathogenic mutations in either PIK3CA (p100) or PIK3R1 (p85) as defined by COSMIC. * PTEN loss as defined by 'two hits' (including either biallelic loss of PTEN, or PTEN LOH + loss of function mutation) NB: Patients with both co-occurring pathogenic PI3K mutation and PTEN loss will be defaulted to the PTEN arm.
Each biomarker arm, within Phase 1, will have robust GO/ADAPT decision points, reviewed by the Safety Review Committee (SRC) to allow for both agility and clear direction for next steps. A 2-stage Bayesian adaptive design will be performed to assess preliminary efficacy.
In the Phase 1b of this study parallel biomarker defined arms will be opened, initially in the front-line unmethylated MGMT setting setting, enrolling 10 patients onto each arm. These patients will be treated with paxalisib in combination with temozolomide. The starting dose of paxalisib will be 45mg once a day (OD) with the option of increasing to 60 mg (30 mg BD) in Cycle 2. TMZ will be administered once daily by mouth on days 1 to 5 in a 28-day cycle, with a starting dose of 150mg/m2 during cycles 1 and 2, and subsequent dose escalation to 200mg/m2 at the start of cycle 3 if cycles 1 and 2 have been well tolerated with no significant toxicity.
Assuming all 'GO' decisions are met, each biomarker arm will recruit a maximum of 32 patients across Phase 1b/2.
official title
5G-PEARL: Paxalisib in Combination With Temozolomide in Patients With High Grade Malignant Brain Tumours Within the 5G Platform