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Malignant Primary GliomasPhase 1/25G-PEARLNCT07391215

5G-PEARL: Paxalisib in Malignant Brain Tumours

A Phase 1/2 study testing Paxalisib and Temozolomide capsule in people with Malignant Primary Gliomas and Glioblastoma Multiforme (GBM), run by Institute of Cancer Research, United Kingdom at 1 site in United Kingdom.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 16 years and older
What is being tested?
Paxalisib and Temozolomide capsule
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
64 participants
Where
1 siteUnited Kingdom
Study dates
19 Jan 2026to 30 Jun 2029
Phase
Phase 1/2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 16 years and older
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Who may be able to join

  • Phase 1b front line mrd cohort:
  • 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
  • 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.
  • 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.
  • 16 years or over.
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  • Life expectancy of at least 12 weeks.
  • World Health Organisation (WHO) performance status of 0-1.
  • 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.
  • Written (signed or dated) informed consent and be capable of co-operating with treatment and follow up.
  • 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
  • Female patients with reproductive potential must have a negative serum pregnancy test within 14 days prior to start of trial.
  • 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.
  • This will be broadened following an assessment of the safety and tolerability seen in the Phase 1 to be more inclusive and reflective of the real-world population.
  • Patients with any other CNS tumours will only be eligible for defined Phase 2 biomarker arms once a Phase 1b GO decision has been met. Specific eligibility criteria for these tumours will be defined following an amendment.

Who cannot join

  • Phase 1b frontline mrd cohort:
  • Receipt of treatment before the first dose of study drug (Cycle 1 Day 1) within an interval shorter than the following, as applicable:
  • Bevacizumab during the prior 6 weeks
  • Any investigational medicinal product since diagnosis.
  • Tumour treating fields during the prior 6 weeks
  • Prior immune checkpoint inhibitor therapy or vaccine therapy is not permitted. Prior use of any other immune-modulatory investigational agent must be discussed with sponsor team and CI.
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  • Ongoing Grade 2 or greater toxicities from pre-existing conditions or from previous treatments.
  • Patients with carcinomatous meningitis, leptomeningeal spread of tumour, spread of tumour to the brain stem or spinal cord.
  • Has evidence of recent intratumoural or peritumoural haemorrhage on baseline MRI. Patients with radiological findings that are stable on at least 2 consecutive MRI scans at least 3 weeks apart will be eligible.
  • History of clinical relevant bleeding disorders, including significant GI bleeding within last 6 months.
  • History of arterial thromboembolism.
  • Recent (within 3 months) deep vein thrombosis or pulmonary embolism or other significant thromboembolism. Venous port of catheter thrombosis or superficial thrombosis are not considered significant. Patients with prior thrombosis (> 3 months ago) on stable anticoagulation are permitted to be enrolled.
  • History of clinically significant cardiac disorders:
  • Myocardial infarction, or New York Heart Association Class II to IV congestive heart failure, within 6 months of the first dose of study drug.
  • Concurrent and clinically significant abnormalities on electrocardiogram (ECG) at Screening, including a corrected QT interval (QTcF >480ms).
  • History of malabsorption syndrome or other conditions that may interfere with enteral absorption. Patients with a history of or active inflammatory bowel disease (eg Crohn's disease or ulcerative colitis). History of gastrointestinal perforation or fistulae.
  • History of uncontrolled diabetes. Patients with controlled diabetes on therapy with HbA1C <8% will be eligible.
  • Has urine protein > 1g/24 hours. Participants with >1+ on urine dipstick testing will undergo 24-hour urine collection for quantitative assessment of proteinuria.
  • Has significant lung disease including pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis, cystic fibrosis, active tuberculosis, or history of opportunistic infections (including PCP or CMV pneumonia).
  • Known to be serologically positive for hepatitis B, hepatitis C or human immunodeficiency virus (HIV).
  • Steroid requirement for neurological symptom control of >3mg Dexamethasone per day (patients will allowed to enrol if they have been on a stable dose of steroids of equivalent or less than 3mg Dexamethasone for at least 5 days prior to Day 1 of Cycle 1).
  • Has received a live vaccine within 30 days of planned start of study therapy. Note: inactive vaccines including COVID vaccines are allowed prior to 1 week of Day 1 of Cycle 1).
  • Current active concurrent malignancy. Cancer survivors who have undergone potentially curative therapy for a prior malignancy, have no evidence of that disease recurrence for three years or more and are deemed at negligible risk of recurrence will be eligible.
  • Is a participant or plans to participate on another interventional clinical trial while taking part in this Phase 1 study. Participation in an observational trial would be acceptable.
  • Any other condition which in the investigator's opinion would not make the patient a good candidate for the clinical trial.
  • Exposure to medications (with or without prescriptions), supplements, herbal remedies, or foods with potential for drug-drug interactions with study interventions within 14 days prior to the first dose of study intervention and during the course of therapy, including strong CYP3A4 inhibitors or inducers, due to potential drug-drug interactions with both paxalisib and temozolomide.
  • Major surgery within 4 weeks (excluding placement of vascular access), minor surgery within 2 weeks.
  • Live and attenuated vaccines are not permitted during or within 4 weeks prior to initiation of study treatment.

Trial locations and contacts

1 site in 1 country. Contact the study team or a site near you to ask about taking part.

5G Team contact

0203 437 6003

5G-enquiries@icr.ac.uk

United Kingdom1 site, 1 recruiting

  • Royal Marden NHS Foundation Trust

    Sutton, SM2 5PT

    Juanita Lopez, MD, PhD, +44 (0)20 86613539, juanita.lopez@icr.ac.uk

    Recruiting

Other trials in United Kingdom

About this study

Official title: 5G-PEARL: Paxalisib in Combination With Temozolomide in Patients With High Grade Malignant Brain Tumours Within the 5G Platform

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.

Read the 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.

Being tested
Paxalisib, Temozolomide capsule
Medical subject headings
Glioblastoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • PaxalisibDrug

    Also called GDC-0084

    Supplied as 15 mg capsules (35 capsules per bottle).

  • Temozolomide capsuleDrug

    Also called Temodal

    Temozolomide will be supplied as 5, 20, 100, 140, 180 or 250 mg hard capsules.

Study groups in NCT07391215
Study groupRoleWhat they receive
Phase 1bExperimentalThe Phase 1b will evaluate the safety and tolerability of paxalisib in combination with temozolomide and determine their preliminary antitumour activity in patients with molecularly defined malignant brain tumours.
Receives: Drug: Paxalisib; Drug: Temozolomide capsule
Phase 2ExperimentalThe Phase 2 part of the study will determine the antitumour activity of investigational agents administered at the RP2D in patients with molecularly defined malignant brain tumours.
Receives: Drug: Paxalisib; Drug: Temozolomide capsule

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Phase 1b - Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) in patients with malignant brain tumours

    To identify the incidence, nature and severity of adverse events and laboratory abnormalities, with severity determined according to NCI CTCAE v5.0

    Measured: 12 months

  2. Phase 1b - To determine the preliminary antitumour activity of the investigational agent administered at the RP2D in patients with molecularly defined malignant brain tumours

    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)

    Measured: 12 months

  3. Phase 2 - To determine the antitumour activity of investigational agent administered at the RP2D in patients with molecularly defined malignant brain tumours

    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

    Measured: 24 months

  4. Phase 2 - To determine the antitumour activity of investigational agent administered at the RP2D in patients with molecularly defined malignant brain tumours

    Antitumour activity will be defined on the basis of the following outcome:

    Overall survival (OS), defined as the time from enrolment to death from any cause

    Measured: 24 months

Secondary outcomes (7)

  1. Phase 1b - To identify genetic biomarkers of response in patients with molecularly selected brain tumours

    Determine co-occurring genetic biomarkers predicting response.

    Measured: 12 months

  2. Phase 2 - To identify genetic biomarkers of response in patients with molecularly selected brain tumours.

    Determine co-occurring genetic biomarkers predicting response.

    Measured: 24 months

  3. Phase 2 - To assess changes in Quality of Life over time

    OS12, defined as the percentage of patients who remained free of death at 12 months from study enrolment

    Measured: 12 months

  4. Phase 2 - To assess changes in Quality of Life over time

    PFS6, defined as the percentage of patients who remained free of disease progression 6 months from study enrolment

    Measured: 6 months

  5. Phase 2 - Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) of combination with TMZ when given as standard of care maintenance therapy

    To identify the incidence, nature and severity of adverse events and laboratory abnormalities, with severity determined according to NCI CTCAE v5.0

    Measured: 24 months

  6. Phase 2 - To assess changes in Quality of Life over time

    Global changes over time in health-related quality of life (HRQOL) as assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ C30) (Baseline, end of C1, C3D1).

    Measured: 24 months

  7. Phase 2 - To assess changes in Quality of Life over time

    Global changes over time in health-related quality of life (HRQOL) as assessed by the 20-item European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Brain Neoplasm module (EORTC QLQ-BN20) (Baseline, end of C1, C3D1)

    Measured: 24 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted5 Feb 2026
  2. Study start19 Jan 2026 (estimated)
  3. Primary completion19 Jan 2029 (estimated)
  4. Study completion30 Jun 2029 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Health services research
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
64 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT07391215
Sponsor's protocol ID
CCR5814
Acronym
5G-PEARL
Status last verified
Jan 2026
First submitted
5 Oct 2023
Last updated
5 Feb 2026
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Paxalisib and Temozolomide capsule in people with Malignant Primary Gliomas and Glioblastoma Multiforme (GBM), run by Institute of Cancer Research, United Kingdom at 1 site in United Kingdom.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 17 inclusion and 28 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 5 Feb 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact 5G Team (0203 437 6003, 5G-enquiries@icr.ac.uk), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Phase 1b - Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) in patients with malignant brain tumours (time frame: 12 months). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT07391215.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Feb 2026.

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