Safety, Pharmacokinetics and Efficacy of Paxalisib (GDC-0084) in Newly-diagnosed Glioblastoma

NCT03522298 | Completed Phase 2 Results FDA Drug

• 1 other identifier: NVGN-0084-201
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 6

Brief Summary

This protocol has a 2-part design: This phase 2 study is an open-label, multicenter, dose-escalation and expansion study to assess the safety, tolerability, recommended phase 2 dose (RP2D), pharmacokinetics (PK) and clinical activity of paxalisib in patients with newly-diagnosed glioblastoma (GBM) with unmethylated MGMT promoter status as adjuvant therapy following surgical resection and initial chemoradiation with temozolomide (TMZ).

Conditions

Glioblastoma, Adult

Keywords

newly diagnosed; unmethylated O6 methylguanine-methyltransferase (MGMT) promoter status

Outcome Measures

Primary Outcomes (1)

• Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs)

  A DLT was defined as a Grade 3 or 4 toxicity occurring within the DLT assessment window and assessed to be probably or possibly related to paxalisib. DLTs were graded using the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. CTCAE Grade 3 is a severe adverse event (AE) and Grade 4 is a life-threatening or disabling AE. DLTs were collected to determine the maximum tolerated dose (MTD), which was defined as the dose level below the dose at which less than 33% of participants experienced a DLT.

  Cycle 1, Days 1-28

Secondary Outcomes (7)

• Incidence of Treatment-emergent Adverse Events (TEAEs)

  24 months

• Incidence of Serious Adverse Events (SAEs)

  24 months

• Incidence of Treatment-emergent Grade 3/4 Treatment Emergent Adverse Events

  24 months

• Number of Participants Who Experienced a Change in Electrocardiogram (ECG) Parameter QTc

  24 months

• Number of Participants Who Experienced a Change Left Ventricular Ejection Fraction

  24 months

Other Outcomes (6)

• Pharmacokinetics of Paxalisib as Area Under the Curve From Time 0 to Last Measurable Time Point (AUC0-last) and/or Area Under the Curve From Time 0 to Infinity (AUC0-inf).

  24 hours

• Maximum Observed Plasma Concentration of Paxalisib (Cmax)

  24 hours

• Pharmacokinetics of Paxalisib as Time to Reach Cmax (Tmax).

  24 hours

Study Arms (1)

Dose Escalation and Expansion Cohorts

EXPERIMENTAL

This is an open-label study. Patients in Stage 1 will be enrolled and sequentially assigned to a dose cohort. The initial cohort will receive an oral dose of 60 mg paxalisib QD (4 x 15 mg capsules). Patients of future dose cohorts will receive paxalisib at increasing levels with 15 mg steps until a dose-limiting toxicity occurs (DLT) occurs. The dose level where \<1/3 of the patients exhibit a DLT will be determined the Maximum Tolerated Dose (MTD). In stage 1, dose escalation will occur for QD dosing. In stage 2, the expansion phase, patients will receive doses of oral paxalisib at the MTD in stage 1, until disease progression or an unacceptable toxicity, whichever occurs first. Patients will be randomized in a 1:1 ratio to fed or fasted schedules.

Drug: Paxalisib (GDC-0084)

Interventions

Paxalisib (GDC-0084) DRUG

Patients will be dosed orally with paxalisib (GDC-0084) capsules (15-mg each) at the dose and schedule to which they are assigned.

Dose Escalation and Expansion Cohorts

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 18 years;
• Life expectancy \> 12 weeks;
• Present with histologically confirmed intracranial (supratentorial) unmethylated MGMT promotor status GBM (WHO Grade lV astrocytoma) with a MGMT status that has been confirmed by validated PCR or validated alternate genomic analysis;
• Have undergone maximal surgical resection of their tumor and within 6 weeks of surgery received initial treatment with XRT/TMZ which consisted of XRT by external beam to a partial brain field in daily fractions of 2.0 Gray (Gy), to a planned total dose to the tumor of 60.0 Gy, in conjunction with TMZ oral QD 75 mg/m2 in accordance with the Stupp regimen;
• KPS ≥ 70;
• Cranial magnetic resonance imaging (MRI) must have been performed within 7 days prior to or on the day of the Randomization/Week 1 Visit;
• Stable or decreasing corticosteroid dose within 7 days prior to the first dose;
• Adequate bone marrow/hematological function within 7 days prior to Day 1;
• Adequate liver and renal function within 14 days prior to Day 1;
• International normalized ratio (INR) or prothrombin time (PT) (secs) and activated partial thromboplastin time (aPTT) within 7 days prior to randomization:
• Patients must be willing to forego other drug therapy against the tumor while enrolled in the study.

You may not qualify if:

• Previous radiotherapy to the brain or cytotoxic drug therapy (including Gliadel® wafers) in addition to the required postoperative radiation plus TMZ, non-cytotoxic drug therapy, or experimental drug therapy directed against the brain tumor prior to this regimen, will be excluded. Patients may have received or be receiving corticosteroids, analgesics, and other drugs to treat symptoms or prevent complications but the dose must be stable at treatment start. NOTE: 5 aminolevulinic acid-mediated photodynamic therapy administered prior to surgery to aid in optimal surgical resection is not considered a chemotherapy agent;
• Any prior or anticipated concomitant treatment involving a medical device (such as Optune®) applying tumor treating fields (TTF);
• QT interval time of ≥ 470 msec;
• Undetermined/indeterminate MGMT status;
• Diabetic patients; prediabetic patients treated with metformin;
• Use of any CYP3A4 inducing or inhibiting agents;
• Significant medical illnesses;
• Women who are pregnant or who are lactating;
• Diagnosed with infratentorial GBM, a tumor outside of brain or gliomatosis cerebri;
• Evidence of recent hemorrhage on postoperative MRI of the brain;
• Any previous malignancy; except for adequately controlled limited basal cell carcinoma of the skin, squamous carcinoma of the skin or carcinoma in situ of the cervix, or one which has been absent for ≥3 years;

Sponsors & Collaborators

• Kazia Therapeutics Limited: lead

Study Sites (6)

University of California Los Angeles - Jonsson Comprehensive Cancer Center

Los Angeles, California, 90095, United States

Location

University of Colorado Cancer Center

Aurora, Colorado, 80045, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

John Theurer Cancer Center at Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

Location

University of Oklahoma Health Sciences Center (Stephenson Cancer Center)

Oklahoma City, Oklahoma, 73104, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

MeSH Terms

Conditions

Glioblastoma

Interventions

GDC-0084

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Results Point of Contact

• Title: Jeremy Simpson
• Organization: Kazia

jeremy.simpson@kaziatherapeutics.com

+61 400 410 974

Study Officials

• James Garner, MD

  Kazia Therapeutics Limited

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: This phase 2 study comprises an open-label, multicenter, dose-escalation and expansion study to assess the safety, tolerability, RP2D, PK and clinical activity of paxalisib in patients with newly-diagnosed GBM with unmethylated MGMT promoter status as adjuvant therapy following surgical resection and initial chemoradiation with TMZ.

Study Record Dates

• First Submitted: March 20, 2018
• First Posted: May 11, 2018
• Study Start: May 15, 2018
• Primary Completion: March 30, 2023
• Study Completion: March 30, 2023
• Last Updated: March 24, 2025
• Results First Posted: March 24, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (6)