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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).
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:
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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. |
|
| 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 |
| 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 |
| 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. |
Inclusion Criteria:
Patients must meet all the following inclusion criteria to be eligible for enrollment into the study:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| James Garner, MD | Kazia Therapeutics Limited | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of California Los Angeles - Jonsson Comprehensive Cancer Center | Los Angeles | California | 90095 | United States | ||
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Each stage started with a screening period (Days -28 to -1), followed by treatment and follow-up periods
Open-label, multicenter dose-escalation study with expansion. This study comprised 2 stages, Stage 1 (dose escalation) and Stage 2 (dose expansion and fed/fasted investigation)
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| ID | Title | Description |
|---|---|---|
| FG000 | Dose-escalating Cohort 1: Paxalisib 60mg | Stage 1, Cohort 1 Participants were administered 60 mg paxalisib (4 ×15 mg capsules) orally once per day in 28-day cycles. Participants fasted for 10 hours pre-dose and for 4 hours post-dose on days when they underwent PK assessments (Cycle 1 Day 1 and Cycle 2 Day 1). On all other days doses were administered at least 1 hour before or 2 hours after food to ensure the study medication was taken on an empty stomach |
| FG001 | Dose-escalating Cohort 2: Paxalisib 75 mg | Participants were administered 75 mg paxalisib (5 ×15 mg capsules) orally once per day in 28-day cycles. Participants fasted for 10 hours pre-dose and for 4 hours post-dose on days when they underwent PK assessments (Cycle 1 Day 1 and Cycle 2 Day 1). On all other days doses were administered at least 1 hour before or 2 hours after food to ensure the study medication was taken on an empty stomach. |
| FG002 | Expansion Cohort: Paxalisib 60mg (Fed) | Participants were administered 60 mg paxalisib (4 ×15 mg capsules) orally once per day in 28-day cycles. Participants consumed a high-fat, high-calorie meal approximately 30 minutes prior to dosing, and fasted thereafter for at least 4 hours on days when they underwent PK assessments (Cycle 1 Day 1 and Cycle 2 Day 1). On all other days doses were administered at least 1 hour before or 2 hours after food to ensure the study medication was taken on an empty stomach. |
| FG003 | Expansion Cohort: Paxalisib 60mg (Fasted) | Stage 2, Fasted Participants were administered 60 mg paxalisib (4 ×15 mg capsules) orally once per day in 28-day cycles. Participants fasted for 10 hours pre-dose and for 4 hours post-dose on days when they underwent PK assessments (Cycle 1 Day 1 and Cycle 2 Day 1). On all other days doses were administered at least 1 hour before or 2 hours after food to ensure the study medication was taken on an empty stomach. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
ITT population The intent-to-treat (ITT) population consisted of all patients who were enrolled in the study, whether in Stage 1 or Stage 2.
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| ID | Title | Description |
|---|---|---|
| BG000 | Dose-escalating Cohort 1: Paxalisib 60mg | Stage 1, Cohort 1 Participants were administered 60 mg paxalisib (4 ×15 mg capsules) orally once per day in 28-day cycles. Participants fasted for 10 hours pre-dose and for 4 hours post-dose on days when they underwent PK assessments (Cycle 1 Day 1 and Cycle 2 Day 1). On all other days doses were administered at least 1 hour before or 2 hours after food to ensure the study medication was taken on an empty stomach |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | All participants in Stage 1 (dose-escalating cohorts 1 and 2) who received at least one dose of paxalisib | Posted | Count of Participants | Participants | Cycle 1, Days 1-28 |
|
24 months
Adverse events may have been volunteered spontaneously by the patient, discovered as a result of general questioning by the study staff, or determined by physical examination. Adverse events were followed until they resolved, were stable, or until the patient's last study visit or were lost to follow-up.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Dose-escalating Cohort 1: Paxalisib 60mg | Stage 1, Cohort 1 Participants were administered 60 mg paxalisib (4 ×15 mg capsules) orally once per day in 28-day cycles. Participants fasted for 10 hours pre-dose and for 4 hours post-dose on days when they underwent PK assessments (Cycle 1 Day 1 and Cycle 2 Day 1). On all other days doses were administered at least 1 hour before or 2 hours after food to ensure the study medication was taken on an empty stomach |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Fatigue | General disorders | MedDRA (19.1) | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Fatigue | General disorders | MedDRA (19.1) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Jeremy Simpson | Kazia | +61 400 410 974 | jeremy.simpson@kaziatherapeutics.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Mar 31, 2020 | Dec 2, 2024 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D005909 | Glioblastoma |
| ID | Term |
|---|---|
| D001254 | Astrocytoma |
| D005910 | Glioma |
| D018302 | Neoplasms, Neuroepithelial |
| D017599 | Neuroectodermal Tumors |
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| ID | Term |
|---|---|
| C000630586 | GDC-0084 |
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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.
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| 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 |
| 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 |
| University of Colorado Cancer Center |
| Aurora |
| Colorado |
| 80045 |
| United States |
| Dana Farber Cancer Institute | Boston | Massachusetts | 02115 | United States |
| John Theurer Cancer Center at Hackensack University Medical Center | Hackensack | New Jersey | 07601 | United States |
| University of Oklahoma Health Sciences Center (Stephenson Cancer Center) | Oklahoma City | Oklahoma | 73104 | United States |
| MD Anderson Cancer Center | Houston | Texas | 77030 | United States |
| Death |
|
| Patient decision |
|
| BG001 | Dose-escalating Cohort 2: Paxalisib 75 mg | Participants were administered 75 mg paxalisib (5 ×15 mg capsules) orally once per day in 28-day cycles. Participants fasted for 10 hours pre-dose and for 4 hours post-dose on days when they underwent PK assessments (Cycle 1 Day 1 and Cycle 2 Day 1). On all other days doses were administered at least 1 hour before or 2 hours after food to ensure the study medication was taken on an empty stomach. |
| BG002 | Expansion Cohort: Paxalisib 60mg (Fed) | Participants were administered 60 mg paxalisib (4 ×15 mg capsules) orally once per day in 28-day cycles. Participants consumed a high-fat, high-calorie meal approximately 30 minutes prior to dosing, and fasted thereafter for at least 4 hours on days when they underwent PK assessments (Cycle 1 Day 1 and Cycle 2 Day 1). On all other days doses were administered at least 1 hour before or 2 hours after food to ensure the study medication was taken on an empty stomach. |
| BG003 | Expansion Cohort: Paxalisib 60mg (Fasted) | Stage 2, Fasted Participants were administered 60 mg paxalisib (4 ×15 mg capsules) orally once per day in 28-day cycles. Participants fasted for 10 hours pre-dose and for 4 hours post-dose on days when they underwent PK assessments (Cycle 1 Day 1 and Cycle 2 Day 1). On all other days doses were administered at least 1 hour before or 2 hours after food to ensure the study medication was taken on an empty stomach. |
| BG004 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Time since diagnosis | Mean | Standard Deviation | months |
|
| Type of surgery | Count of Participants | Participants |
|
| Histological diagnosis | Count of Participants | Participants |
|
| Karnofsky Performance Status | 100: Normal no complaints; no evidence of disease 90: Able to carry on normal activity; minor signs or symptoms of disease 80: Normal activity with effort; some signs or symptoms of disease 70: Cares for self; unable to carry on normal activity or to do active work 60: Requires occasional assistance, but is able to care for most of his personal needs 50: Requires considerable assistance and frequent medical care 40 or less: Unable to care for self; requires equivalent of institutional or hospital care; disease may be progressing rapidly. | Count of Participants | Participants |
|
| OG001 | Dose-escalating Cohort 2: Paxalisib 75 mg | Stage 1, Cohort 2 Participants were administered 75 mg paxalisib (5 ×15 mg capsules) orally once per day in 28-day cycles. Participants fasted for 10 hours pre-dose and for 4 hours post-dose on days when they underwent PK assessments (Cycle 1 Day 1 and Cycle 2 Day 1). On all other days doses were administered at least 1 hour before or 2 hours after food to ensure the study medication was taken on an empty stomach. |
|
|
| Secondary | 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 | Safety population: All participants who received at least 1 dose of paxalisib | Posted | Count of Participants | Participants | 24 months |
|
|
|
| Secondary | 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 | Safety population: All participants who received at least 1 dose of paxalisib | Posted | Count of Participants | Participants | 24 months |
|
|
|
| Secondary | 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. | Safety population: All participants who received at least 1 dose of paxalisib | Posted | Count of Participants | Participants | 24 months |
|
|
|
| Secondary | 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. | Safety population: All participants who received at least 1 dose of paxalisib | Posted | Count of Participants | Participants | 24 months |
|
|
|
| Secondary | 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. | Safety population: All participants who received at least 1 dose of paxalisib | Posted | Count of Participants | Participants | 24 months |
|
|
|
| Secondary | 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. | Intention to treat: All patients who were enrolled in the study, whether in Stage 1 or Stage 2. | Posted | Median | 95% Confidence Interval | Months | 24 months |
|
|
|
| Secondary | 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. | Intention to treat: All patients who were enrolled in the study, whether in Stage 1 or Stage 2. | Posted | Median | 95% Confidence Interval | Months | 24 months |
|
|
|
| Other Pre-specified | 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. | Safety population: All participants who received at least 1 dose of paxalisib | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL*h | 24 hours |
|
|
|
| Other Pre-specified | 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. | Safety population: All participants who received at least 1 dose of paxalisib | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | 24 hours |
|
|
|
| Other Pre-specified | 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. | Safety population: All participants who received at least 1 dose of paxalisib | Posted | Median | Full Range | Hours | 24 hours |
|
|
|
| Other Pre-specified | 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 | All participants in Stage 2 (dose-expansion cohorts) who received at least one dose of paxalisib and had measurable disease | Posted | Mean | Standard Deviation | standardized uptake value | Cycle 1, Day 3 |
|
|
|
| Other Pre-specified | 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 | All participants in Stage 2 (dose-expansion cohorts) who received at least one dose of paxalisib and had measurable disease | Posted | Mean | Standard Deviation | standardized uptake value | Cycle 1, Day 7 |
|
|
|
| Other Pre-specified | 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. | Safety population: All participants who received at least 1 dose of paxalisib | Posted | Count of Participants | Participants | 24 months |
|
|
|
| 2 |
| 3 |
| 2 |
| 3 |
| 3 |
| 3 |
| EG001 | Dose-escalating Cohort 2: Paxalisib 75 mg | Participants were administered 75 mg paxalisib (5 ×15 mg capsules) orally once per day in 28-day cycles. Participants fasted for 10 hours pre-dose and for 4 hours post-dose on days when they underwent PK assessments (Cycle 1 Day 1 and Cycle 2 Day 1). On all other days doses were administered at least 1 hour before or 2 hours after food to ensure the study medication was taken on an empty stomach. | 4 | 6 | 5 | 6 | 6 | 6 |
| EG002 | Expansion Cohort: Paxalisib 60mg (Fed) | Participants were administered 60 mg paxalisib (4 ×15 mg capsules) orally once per day in 28-day cycles. Participants consumed a high-fat, high-calorie meal approximately 30 minutes prior to dosing, and fasted thereafter for at least 4 hours on days when they underwent PK assessments (Cycle 1 Day 1 and Cycle 2 Day 1). On all other days doses were administered at least 1 hour before or 2 hours after food to ensure the study medication was taken on an empty stomach. | 8 | 10 | 6 | 10 | 10 | 10 |
| EG003 | Expansion Cohort: Paxalisib 60mg (Fasted) | Stage 2, Fasted Participants were administered 60 mg paxalisib (4 ×15 mg capsules) orally once per day in 28-day cycles. Participants fasted for 10 hours pre-dose and for 4 hours post-dose on days when they underwent PK assessments (Cycle 1 Day 1 and Cycle 2 Day 1). On all other days doses were administered at least 1 hour before or 2 hours after food to ensure the study medication was taken on an empty stomach. | 8 | 11 | 5 | 11 | 11 | 11 |
| Dehydration | Metabolism and nutrition disorders | MedDRA (19.1) | Systematic Assessment |
|
| Hyperglycaemia | Metabolism and nutrition disorders | MedDRA (19.1) | Systematic Assessment |
|
| Stomatitis | Gastrointestinal disorders | MedDRA (19.1) | Systematic Assessment |
|
| confusional state | Psychiatric disorders | MedDRA (19.1) | Systematic Assessment |
|
| Pneumonia | Infections and infestations | MedDRA (19.1) | Systematic Assessment |
|
| Status epilepticus | Nervous system disorders | MedDRA (19.1) | Systematic Assessment |
|
| Drug reaction with eosinophilia and systemic symptoms | Skin and subcutaneous tissue disorders | MedDRA (19.1) | Systematic Assessment |
|
| Meningitis | Infections and infestations | MedDRA (19.1) | Systematic Assessment |
|
| Encephalopathy | Nervous system disorders | MedDRA (19.1) | Systematic Assessment |
|
| Acute kidney injury | Renal and urinary disorders | MedDRA (19.1) | Systematic Assessment |
|
| Dermatitis exfoliative | Skin and subcutaneous tissue disorders | MedDRA (19.1) | Systematic Assessment |
|
| Posterior reversible encephalopathy syndrome | Nervous system disorders | MedDRA (19.1) | Systematic Assessment |
|
| Central nervous system haemorrhage | Nervous system disorders | MedDRA (19.1) | Systematic Assessment |
|
| Cerebral ischaemia | Nervous system disorders | MedDRA (19.1) | Systematic Assessment |
|
| Reversible cerebral vasoconstriction syndrome | Nervous system disorders | MedDRA (19.1) | Systematic Assessment |
|
| Wound infection | Infections and infestations | MedDRA (19.1) | Systematic Assessment |
|
| Gait disturbance | General disorders | MedDRA (19.1) | Systematic Assessment |
|
| Embolism | Vascular disorders | MedDRA (19.1) | Systematic Assessment |
|
| Vasogenic cerebral oedema | Nervous system disorders | MedDRA (19.1) | Systematic Assessment |
|
| Mental status changes | Psychiatric disorders | MedDRA (19.1) | Systematic Assessment |
|
| Hydrocephalus | Nervous system disorders | MedDRA (19.1) | Systematic Assessment |
|
| Wound dehiscence | Injury, poisoning and procedural complications | MedDRA (19.1) | Systematic Assessment |
|
| Fall | Injury, poisoning and procedural complications | MedDRA (19.1) | Systematic Assessment |
|
| Embolic stroke | Nervous system disorders | MedDRA (19.1) | Systematic Assessment |
|
| Urinary tract infection | Infections and infestations | MedDRA (19.1) | Systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA (19.1) | Systematic Assessment |
|
| Chills | General disorders | MedDRA (19.1) | Systematic Assessment |
|
| Gait disturbance | General disorders | MedDRA (19.1) | Systematic Assessment |
|
| Pyrexia | General disorders | MedDRA (19.1) | Systematic Assessment |
|
| Malaise | General disorders | MedDRA (19.1) | Systematic Assessment |
|
| Stomatitis | Gastrointestinal disorders | MedDRA (19.1) | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA (19.1) | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA (19.1) | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA (19.1) | Systematic Assessment |
|
| Dysphagia | Gastrointestinal disorders | MedDRA (19.1) | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | MedDRA (19.1) | Systematic Assessment |
|
| Decreased appetite | Metabolism and nutrition disorders | MedDRA (19.1) | Systematic Assessment |
|
| Hyperglycaemia | Metabolism and nutrition disorders | MedDRA (19.1) | Systematic Assessment |
|
| Dehydration | Metabolism and nutrition disorders | MedDRA (19.1) | Systematic Assessment |
|
| Hypokalaemia | Metabolism and nutrition disorders | MedDRA (19.1) | Systematic Assessment |
|
| Hypertrigliceridaemia | Metabolism and nutrition disorders | MedDRA (19.1) | Systematic Assessment |
|
| Rash maculo-papular | Skin and subcutaneous tissue disorders | MedDRA (19.1) | Systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | MedDRA (19.1) | Systematic Assessment |
|
| Pruritus | Skin and subcutaneous tissue disorders | MedDRA (19.1) | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA (19.1) | Systematic Assessment |
|
| Aphasia | Nervous system disorders | MedDRA (19.1) | Systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDRA (19.1) | Systematic Assessment |
|
| Dysgeusia | Nervous system disorders | MedDRA (19.1) | Systematic Assessment |
|
| Memory impairment | Nervous system disorders | MedDRA (19.1) | Systematic Assessment |
|
| Cognitive disorder | Nervous system disorders | MedDRA (19.1) | Systematic Assessment |
|
| Seizure | Nervous system disorders | MedDRA (19.1) | Systematic Assessment |
|
| Platelet count decreased | Investigations | MedDRA (19.1) | Systematic Assessment |
|
| Neutrophil count decreased | Investigations | MedDRA (19.1) | Systematic Assessment |
|
| Weight decreased | Investigations | MedDRA (19.1) | Systematic Assessment |
|
| Lymphocyte count decreased | Investigations | MedDRA (19.1) | Systematic Assessment |
|
| Alanine aminotransferase increased | Investigations | MedDRA (19.1) | Systematic Assessment |
|
| Blood cholesterol increased | Investigations | MedDRA (19.1) | Systematic Assessment |
|
| Aspartate aminotransferase increased | Investigations | MedDRA (19.1) | Systematic Assessment |
|
| Blood creatinine increased | Investigations | MedDRA (19.1) | Systematic Assessment |
|
| Urinary tract infection | Infections and infestations | MedDRA (19.1) | Systematic Assessment |
|
| Depression | Psychiatric disorders | MedDRA (19.1) | Systematic Assessment |
|
| Confusional state | Psychiatric disorders | MedDRA (19.1) | Systematic Assessment |
|
| Muscular weakness | Musculoskeletal and connective tissue disorders | MedDRA (19.1) | Systematic Assessment |
|
| Hypertension | Vascular disorders | MedDRA (19.1) | Systematic Assessment |
|
| Anaemia | Blood and lymphatic system disorders | MedDRA (19.1) | Systematic Assessment |
|
Not provided
| D009373 |
| Neoplasms, Germ Cell and Embryonal |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D009375 | Neoplasms, Glandular and Epithelial |
| D009380 | Neoplasms, Nerve Tissue |
| Grade 3 |
|
| Grade 4 |
|