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

A Phase 2 Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of the PI3K/mTOR Inhibitor Paxalisib (GDC-0084) Administered to Patients With Glioblastoma Characterized by Unmethylated O6-methylguanine-methyltransferase Promoter Status Following Surgical Resection and Standard Concomitant Chemoradiation Therapy With Temozolomide

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).

Study Overview

• Status: Completed
• Conditions: Glioblastoma, Adult
• Intervention / Treatment: Drug: Paxalisib (GDC-0084)

Detailed Description

Stage 1 Dose-Escalation and Maximum Tolerated Dose The dose-escalation portion of the study (Stage 1) will use a standard "3 + 3" design to determine the MTD for QD dosing.

Approximately 6 - 12 patients with newly diagnosed GBM will be enrolled in Stage 1.

The MTD for QD dosing will be determined. The initial dose level for QD dosing will be 60 mg (Dose Level 0). This dose is based on the phase 1 findings outlined in the rationale in the protocol, adding 1 dose level to test for a potential MTD increase.

Dose-escalation will occur in Stage 1:

• The initial dose (Dose Level 0) for QD MTD determination in Step 1 will be 60 mg. Dose levels will increase in 15 mg steps;
• The dose-escalation portion of the study (Stage 1) will use a standard "3 + 3" design to assess the safety, tolerability, and PK of paxalisib administered orally in 28-day cycles;

Decisions regarding dose-escalation and selection will be made by a Cohort Review Committee (CRC).

All AEs, including DLTs, will be reported, with severity assessed according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03.

After determination of the MTD, patients continue to receive their protocol-assigned dose levels of paxalisib until progression of their disease or an unacceptable toxicity, whichever occurs first.

Stage 2 Expansion stage (2) of the study will be a two-arm, randomized, open-label expansion study to further characterize the safety, tolerability and PK of paxalisib as well as to provide a preliminary assessment of single-agent activity of paxalisib in patients with GBM. Approximately 20 patients will be enrolled in the expansion cohort in 2 treatment arms (10 per am) to examine the PK of paxalisib in fed and fasted-conditions, according to the defined study eligibility criteria.

Stage 2 of the study will be initiated with recruitment of new patients as soon as the MTD has been determined.

Patients enrolled in Stage 2 may continue the study at the dose allocated until disease progression or unacceptable toxicity.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • University of California Los Angeles - Jonsson Comprehensive Cancer Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana Farber Cancer Institute
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • John Theurer Cancer Center at Hackensack University Medical Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center (Stephenson Cancer Center)
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Patients must meet all the following inclusion criteria to be eligible for enrollment into the study:

1. Age ≥ 18 years;
2. Life expectancy > 12 weeks;
3. 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;
4. 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;
5. Must have measurable disease, according to RANO criteria for inclusion in the expansion cohort. Patients with non-measurable disease can be included in the dose-escalation cohorts;
6. KPS ≥ 70;
7. Cranial magnetic resonance imaging (MRI) must have been performed within 7 days prior to or on the day of the Randomization/Week 1 Visit;
8. Stable or decreasing corticosteroid dose within 7 days prior to the first dose;
9. Adequate bone marrow/hematological function within 7 days prior to Day 1;
10. Adequate liver and renal function within 14 days prior to Day 1;
11. International normalized ratio (INR) or prothrombin time (PT) (secs) and activated partial thromboplastin time (aPTT) within 7 days prior to randomization:
12. Patients must be willing to forego other drug therapy against the tumor while enrolled in the study.

Exclusion Criteria:

1. 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;
2. Any prior or anticipated concomitant treatment involving a medical device (such as Optune®) applying tumor treating fields (TTF);
3. QT interval time of ≥ 470 msec;
4. Undetermined/indeterminate MGMT status;
5. Diabetic patients; prediabetic patients treated with metformin;
6. Use of any CYP3A4 inducing or inhibiting agents;
7. Significant medical illnesses;
8. Women who are pregnant or who are lactating;
9. Diagnosed with infratentorial GBM, a tumor outside of brain or gliomatosis cerebri;
10. Evidence of recent hemorrhage on postoperative MRI of the brain;
11. 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;

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Dose Escalation and Expansion Cohorts; 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); Patients will be dosed orally with paxalisib (GDC-0084) capsules (15-mg each) at the dose and schedule to which they are assigned.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Treatment-emergent Adverse Events (TEAEs)	The toxicity assessments were made according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. A TEAE is any AE occurring or worsening on/after the first study drug dose and within 28 days after the last dose date. The number of participants with Grade 1 to 5 TEAEs are reported here. Specific Adverse Event terms are provided in the Adverse Event module	24 months
Incidence of Serious Adverse Events (SAEs)	An SAE is any AE that meets one or more of the following: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; requires intervention to prevent permanent impairment or damage. Specific AE terms are provided in the Adverse Event module	24 months
Incidence of Treatment-emergent Grade 3/4 Treatment Emergent Adverse Events	Treatment emergent Adverse Events 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. Participants are counted at the highest grade TEAE that they experienced.	24 months
Number of Participants Who Experienced a Change in Electrocardiogram (ECG) Parameter QTc	A change in ECG parameter QTc was defined as an increase of QTc to a value ≥ 500 msec or a change from baseline of at least 60 msec.	24 months
Number of Participants Who Experienced a Change Left Ventricular Ejection Fraction	A change in left ventricular ejection fraction (LVEF) was defined as a reduction in LVEF to a value of ≤ 45% from baseline.	24 months
Progression-free Survival Interval Using Using mRANO Criteria/Investigator Review.	Progression-free survival is defined as the duration of time from start of treatment to time of progression or death, whichever comes first.	24 months
Overall Survival Using RANO Criteria.	Overall survival is defined as the duration of time from the first day of study treatment until the date of death.	24 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	Blood samples were obtained and plasma concentrations were determined using a validated high-pressure liquid chromatography method. Samples were obtained: prior to the initial dose on Cycle 1 Day 1 and then at 30 minutes, and at 1, 2, 3, 4, 6 8 and 24 hours post dose.	24 hours
Maximum Observed Plasma Concentration of Paxalisib (Cmax)	Blood samples were obtained and plasma concentrations were determined using a validated high-pressure liquid chromatography method. Samples were obtained: prior to the initial dose on Cycle 1 Day 1 and then at 30 minutes, and at 1, 2, 3, 4, 6 8 and 24 hours post dose.	24 hours
Pharmacokinetics of Paxalisib as Time to Reach Cmax (Tmax).	Blood samples were obtained and plasma concentrations were determined using a validated high-pressure liquid chromatography method. Samples were obtained: prior to the initial dose on Cycle 1 Day 1 and then at 30 minutes, and at 1, 2, 3, 4, 6 8 and 24 hours post dose.	24 hours
Change in FDG-PET Uptake in Response to Paxalisib in Patients With Measurable Disease.	FDG-PET imaging was obtained using a stand-alone PET or combined PET/computed tomography (CT) scanner, or hybrid PET/MRI systems and the and mean FDG-PET standard uptake value quantified	Cycle 1, Day 3
Change in FDG-PET Uptake in Response to Paxalisib in Patients With Measurable Disease	FDG-PET imaging was obtained using a stand-alone PET or combined PET/computed tomography (CT) scanner, or hybrid PET/MRI systems and the and mean FDG-PET standard uptake value quantified	Cycle 1, Day 7
Disease Control Rate.	Response to treatment was assessed by MRI using the response assessment in neuro-oncology (RANO) criteria based on the assessment of the MRI scan and clinical features. The DCR is defined as the proportion of patients achieving a confirmed best overall response of complete response (CR; disappearance of all enhancing disease, clinically stable/improved), partial response (PR; 50% or more decrease in measurable enhancing lesions, clinically stable/improved), or stable disease (SD, does not qualify for CR or PR, does not qualify for disease progression, clinically stable). To be assigned a status of CR, PR or SD patients need to have two consecutive assessments of CR, PR or SD. To be assigned a best overall response of SD patients must have a minimum duration of SD of at least 6 weeks.	24 months

Collaborators and Investigators

• Sponsor: Kazia Therapeutics Limited
• Investigators: Study Director: James Garner, MD, Kazia Therapeutics Limited

Study record dates

Study Major Dates

• Study Start (Actual): May 15, 2018
• Primary Completion (Actual): March 30, 2023
• Study Completion (Actual): March 30, 2023

Study Registration Dates

• First Submitted: March 20, 2018
• First Submitted That Met QC Criteria: May 9, 2018
• First Posted (Actual): May 11, 2018

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 5, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: newly diagnosed; unmethylated O6 methylguanine-methyltransferase (MGMT) promoter status
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; GDC-0084
• Other Study ID Numbers: NVGN-0084-201

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No