Malignant Primary Gliomas, Glioblastoma Multiforme (GBM)
Conditions
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.
Interventions
DRUGPaxalisib
Supplied as 15 mg capsules (35 capsules per bottle).
Temozolomide will be supplied as 5, 20, 100, 140, 180 or 250 mg hard capsules.
Sponsors
Institute of Cancer Research, United Kingdom
Minderoo Foundation
Kazia Therapeutics Limited
Royal Marsden NHS Foundation Trust
Cambridge University Hospitals NHS Foundation Trust
Cancer Research UK
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
HEALTH_SERVICES_RESEARCH
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Phase 1b front line mrd cohort: 1. Patients with histologically confirmed advanced WHO Stage IV glioblastoma (per fourth edition 2016). Per the new 2021 fifth edition of WHO Classification of Tumours of the Central Nervous System, this will include: • Glioblastoma, IDH-wildtype Grade 4 2. Patients for Phase 1b will need to have consented to the Minderoo Precision Brain Tumour Programme and have whole genome, and transcriptome data available. Patients who have had NHS funded whole genome sequencing and have available frozen tissue stored can be recruited to the study in parallel to consenting to the Minderoo Precision Brain Tumour Programme to have transcriptome analysis done. 3. Patients for the minimal residual disease (mrd) cohort will be eligible following completion of optimal surgery and Stupp based adjuvant chemoradiotherapy as long as they meet all other inclusion/
Exclusion criteria
. Patients will need to commence Cycle 1 Day 1 of the study no later than 6 weeks from the completion of chemoradiotherapy. Patients who are radiologically progressing following chemo-radiotherapy will not be eligible. 4. 16 years or over. 5. Life expectancy of at least 12 weeks. 6. World Health Organisation (WHO) performance status of 0-1. 7. Neurologically stable (eg without a progression of neurological symptoms or requiring escalating doses of systemic steroid therapy within one week prior to cycle 1, day 1. 8. Written (signed or dated) informed consent and be capable of co-operating with treatment and follow up. 9. Haematological and biochemical indices within the ranges shown below. These measurements must be performed within one week prior to the first dose of either IMP. Haemoglobin (Hb): ≥ 9.0 g/dL Absolute neutrophil count: ≥1.5 x 10\^9/L Platelet count: ≥100 x 10\^9/L Coagulation: INR \< 1.5 and APTT \<1.5x if not anticoagulated INR stable \> 7 days within intended therapeutic range if anticoagulated Bilirubin: ≤1.5 x ULN; participants with Gilbert's syndrome can enrol if conjugated bilirubin is within normal ranges. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST): \<3 x ULN Albumin: ≥ 28 g/L Creatinine: \<1.5 x ULN Sodium: ≥130 mmol/L Potassium, Calcium, Magnesium, phosphate: Within institution normal ranges (replacement is permitted) HbA1C (%): \<8.0 Urinary protein: \< 1+ on dipstick 10. Female patients with reproductive potential must have a negative serum pregnancy test within 14 days prior to start of trial. 11. Men and women of childbearing potential must agree to comply with the use of a highly effective method of contraception so as to avoid impregnating a partner or becoming pregnant, respectively, during the study, and for at least 180 days after the last dose of either investigational drug. Please, refer to section 4.1 of the Clinical Trials Facilitation and Coordination Group (CTCG) guidance for further details.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b - Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) in patients with malignant brain tumours | 12 months | To identify the incidence, nature and severity of adverse events and laboratory abnormalities, with severity determined according to NCI CTCAE v5.0 |
| Phase 1b - To determine the preliminary antitumour activity of the investigational agent administered at the RP2D in patients with molecularly defined malignant brain tumours | 12 months | Antitumour activity will be defined on the basis of the following outcomes. If any of the following occur, patients will be considered to have clinically benefitted: For front line unmethylated GBM (MRD): • Progression-free survival (PFS) |
| Phase 2 - To determine the antitumour activity of investigational agent administered at the RP2D in patients with molecularly defined malignant brain tumours | 24 months | Antitumour activity will be defined on the basis of the following outcome: • Progression-free survival (PFS), defined as the time from enrolment to the first occurrence of disease progression or death from any cause (whichever occurs first), as determined by the investigator according to RANO |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b - To identify genetic biomarkers of response in patients with molecularly selected brain tumours | 12 months | Determine co-occurring genetic biomarkers predicting response. |
| Phase 2 - To identify genetic biomarkers of response in patients with molecularly selected brain tumours. | 24 months | Determine co-occurring genetic biomarkers predicting response. |
| Phase 2 - To assess changes in Quality of Life over time | 12 months | OS12, defined as the percentage of patients who remained free of death at 12 months from study enrolment |
| Phase 2 - Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) of combination with TMZ when given as standard of care maintenance therapy | 24 months | To identify the incidence, nature and severity of adverse events and laboratory abnormalities, with severity determined according to NCI CTCAE v5.0 |
Countries
United Kingdom
Contacts
CONTACT5G Team
STUDY_DIRECTORJuanita Lopez, MD, PhD
National Health Service, United Kingdom
Outcome results
None listed