Glioblastoma, Adult
Conditions
Keywords
newly diagnosed, unmethylated O6 methylguanine-methyltransferase (MGMT) promoter status
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).
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.
Interventions
DRUGPaxalisib (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.
Sponsors
Kazia Therapeutics Limited
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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;
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs) | Cycle 1, Days 1-28 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Serious Adverse Events (SAEs) | 24 months | 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 |
| Incidence of Treatment-emergent Adverse Events (TEAEs) | 24 months | 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 |
| Incidence of Treatment-emergent Grade 3/4 Treatment Emergent Adverse Events | 24 months | 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. |
| Number of Participants Who Experienced a Change in Electrocardiogram (ECG) Parameter QTc | 24 months | 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. |
| Number of Participants Who Experienced a Change Left Ventricular Ejection Fraction | 24 months | A change in left ventricular ejection fraction (LVEF) was defined as a reduction in LVEF to a value of ≤ 45% from baseline. |
| Progression-free Survival Interval Using Using mRANO Criteria/Investigator Review. | 24 months | Progression-free survival is defined as the duration of time from start of treatment to time of progression or death, whichever comes first. |
| Overall Survival Using RANO Criteria. | 24 months | Overall survival is defined as the duration of time from the first day of study treatment until the date of death. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics of Paxalisib as Time to Reach Cmax (Tmax). | 24 hours | 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. |
| Change in FDG-PET Uptake in Response to Paxalisib in Patients With Measurable Disease. | Cycle 1, Day 3 | 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 |
| Change in FDG-PET Uptake in Response to Paxalisib in Patients With Measurable Disease | Cycle 1, Day 7 | 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 |
| Disease Control Rate. | 24 months | 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. |
| Maximum Observed Plasma Concentration of Paxalisib (Cmax) | 24 hours | 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. |
| 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 | 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. |
Countries
United States
Participant flow
Recruitment details
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)
Pre-assignment details
Each stage started with a screening period (Days -28 to -1), followed by treatment and follow-up periods
Participants by arm
| Arm | Count |
|---|---|
| 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 | 3 |
| 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. | 6 |
| 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. | 10 |
| 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. | 11 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 | 1 |
| Overall Study | Death | 2 | 4 | 8 | 8 |
| Overall Study | Patient decision | 0 | 2 | 2 | 2 |
Baseline characteristics
| Characteristic | Dose-escalating Cohort 1: Paxalisib 60mg | Dose-escalating Cohort 2: Paxalisib 75 mg | Expansion Cohort: Paxalisib 60mg (Fed) | Expansion Cohort: Paxalisib 60mg (Fasted) | Total |
|---|---|---|---|---|---|
| Age, Continuous | 68 years STANDARD_DEVIATION 15.72 | 56 years STANDARD_DEVIATION 9.3 | 56 years STANDARD_DEVIATION 12.51 | 59.5 years STANDARD_DEVIATION 9.46 | 58.5 years STANDARD_DEVIATION 11.16 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 5 Participants | 10 Participants | 10 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Histological diagnosis | 3 Participants | 6 Participants | 10 Participants | 11 Participants | 30 Participants |
| Karnofsky Performance Status 100 | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Karnofsky Performance Status 40 or less | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Karnofsky Performance Status 50 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Karnofsky Performance Status 60 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Karnofsky Performance Status 70 | 0 Participants | 1 Participants | 2 Participants | 1 Participants | 4 Participants |
| Karnofsky Performance Status 80 | 3 Participants | 0 Participants | 2 Participants | 0 Participants | 5 Participants |
| Karnofsky Performance Status 90 | 0 Participants | 5 Participants | 4 Participants | 10 Participants | 19 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 2 Participants | 4 Participants | 9 Participants | 10 Participants | 25 Participants |
| Region of Enrollment United States | 3 participants | 6 participants | 10 participants | 11 participants | 30 participants |
| Sex: Female, Male Female | 0 Participants | 2 Participants | 3 Participants | 4 Participants | 9 Participants |
| Sex: Female, Male Male | 3 Participants | 4 Participants | 7 Participants | 7 Participants | 21 Participants |
| Time since diagnosis | 3.68 months STANDARD_DEVIATION 0.553 | 4.33 months STANDARD_DEVIATION 1.137 | 3.64 months STANDARD_DEVIATION 0.358 | 3.56 months STANDARD_DEVIATION 0.318 | 3.75 months STANDARD_DEVIATION 0.637 |
| Type of surgery Biopsy (Patients later had a complete resection) | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Type of surgery Complete resection | 2 Participants | 4 Participants | 9 Participants | 7 Participants | 22 Participants |
| Type of surgery Other (stereotactic biopsy) | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Type of surgery Partial resection | 1 Participants | 2 Participants | 0 Participants | 2 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 3 | 4 / 6 | 8 / 10 | 8 / 11 |
| other Total, other adverse events | 3 / 3 | 6 / 6 | 10 / 10 | 11 / 11 |
| serious Total, serious adverse events | 2 / 3 | 5 / 6 | 6 / 10 | 5 / 11 |
Outcome results
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.
Time frame: Cycle 1, Days 1-28
Population: All participants in Stage 1 (dose-escalating cohorts 1 and 2) who received at least one dose of paxalisib
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose-escalating Cohort 1: Paxalisib 60mg | Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs) | 0 Participants |
| Dose-escalating Cohort 2: Paxalisib 75 mg | Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs) | 2 Participants |
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
Time frame: 24 months
Population: Safety population: All participants who received at least 1 dose of paxalisib
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose-escalating Cohort 1: Paxalisib 60mg | Incidence of Serious Adverse Events (SAEs) | 2 Participants |
| Dose-escalating Cohort 2: Paxalisib 75 mg | Incidence of Serious Adverse Events (SAEs) | 5 Participants |
| Expansion Cohort: Paxalisib 60mg (Fed) | Incidence of Serious Adverse Events (SAEs) | 6 Participants |
| Expansion Cohort: Paxalisib 60mg (Fasted) | Incidence of Serious Adverse Events (SAEs) | 5 Participants |
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
Time frame: 24 months
Population: Safety population: All participants who received at least 1 dose of paxalisib
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose-escalating Cohort 1: Paxalisib 60mg | Incidence of Treatment-emergent Adverse Events (TEAEs) | 3 Participants |
| Dose-escalating Cohort 2: Paxalisib 75 mg | Incidence of Treatment-emergent Adverse Events (TEAEs) | 6 Participants |
| Expansion Cohort: Paxalisib 60mg (Fed) | Incidence of Treatment-emergent Adverse Events (TEAEs) | 10 Participants |
| Expansion Cohort: Paxalisib 60mg (Fasted) | Incidence of Treatment-emergent Adverse Events (TEAEs) | 11 Participants |
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.
Time frame: 24 months
Population: Safety population: All participants who received at least 1 dose of paxalisib
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose-escalating Cohort 1: Paxalisib 60mg | Incidence of Treatment-emergent Grade 3/4 Treatment Emergent Adverse Events | Grade 1 or 2 | 0 Participants |
| Dose-escalating Cohort 1: Paxalisib 60mg | Incidence of Treatment-emergent Grade 3/4 Treatment Emergent Adverse Events | Grade 4 | 0 Participants |
| Dose-escalating Cohort 1: Paxalisib 60mg | Incidence of Treatment-emergent Grade 3/4 Treatment Emergent Adverse Events | Grade 3 | 3 Participants |
| Dose-escalating Cohort 2: Paxalisib 75 mg | Incidence of Treatment-emergent Grade 3/4 Treatment Emergent Adverse Events | Grade 1 or 2 | 0 Participants |
| Dose-escalating Cohort 2: Paxalisib 75 mg | Incidence of Treatment-emergent Grade 3/4 Treatment Emergent Adverse Events | Grade 4 | 3 Participants |
| Dose-escalating Cohort 2: Paxalisib 75 mg | Incidence of Treatment-emergent Grade 3/4 Treatment Emergent Adverse Events | Grade 3 | 3 Participants |
| Expansion Cohort: Paxalisib 60mg (Fed) | Incidence of Treatment-emergent Grade 3/4 Treatment Emergent Adverse Events | Grade 1 or 2 | 1 Participants |
| Expansion Cohort: Paxalisib 60mg (Fed) | Incidence of Treatment-emergent Grade 3/4 Treatment Emergent Adverse Events | Grade 3 | 9 Participants |
| Expansion Cohort: Paxalisib 60mg (Fed) | Incidence of Treatment-emergent Grade 3/4 Treatment Emergent Adverse Events | Grade 4 | 0 Participants |
| Expansion Cohort: Paxalisib 60mg (Fasted) | Incidence of Treatment-emergent Grade 3/4 Treatment Emergent Adverse Events | Grade 1 or 2 | 0 Participants |
| Expansion Cohort: Paxalisib 60mg (Fasted) | Incidence of Treatment-emergent Grade 3/4 Treatment Emergent Adverse Events | Grade 4 | 1 Participants |
| Expansion Cohort: Paxalisib 60mg (Fasted) | Incidence of Treatment-emergent Grade 3/4 Treatment Emergent Adverse Events | Grade 3 | 10 Participants |
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.
Time frame: 24 months
Population: Safety population: All participants who received at least 1 dose of paxalisib
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose-escalating Cohort 1: Paxalisib 60mg | Number of Participants Who Experienced a Change in Electrocardiogram (ECG) Parameter QTc | 0 Participants |
| Dose-escalating Cohort 2: Paxalisib 75 mg | Number of Participants Who Experienced a Change in Electrocardiogram (ECG) Parameter QTc | 0 Participants |
| Expansion Cohort: Paxalisib 60mg (Fed) | Number of Participants Who Experienced a Change in Electrocardiogram (ECG) Parameter QTc | 0 Participants |
| Expansion Cohort: Paxalisib 60mg (Fasted) | Number of Participants Who Experienced a Change in Electrocardiogram (ECG) Parameter QTc | 0 Participants |
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.
Time frame: 24 months
Population: Safety population: All participants who received at least 1 dose of paxalisib
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose-escalating Cohort 1: Paxalisib 60mg | Number of Participants Who Experienced a Change Left Ventricular Ejection Fraction | 0 Participants |
| Dose-escalating Cohort 2: Paxalisib 75 mg | Number of Participants Who Experienced a Change Left Ventricular Ejection Fraction | 0 Participants |
| Expansion Cohort: Paxalisib 60mg (Fed) | Number of Participants Who Experienced a Change Left Ventricular Ejection Fraction | 0 Participants |
| Expansion Cohort: Paxalisib 60mg (Fasted) | Number of Participants Who Experienced a Change Left Ventricular Ejection Fraction | 1 Participants |
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.
Time frame: 24 months
Population: Intention to treat: All patients who were enrolled in the study, whether in Stage 1 or Stage 2.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose-escalating Cohort 1: Paxalisib 60mg | Overall Survival Using RANO Criteria. | 20.1 Months |
| Dose-escalating Cohort 2: Paxalisib 75 mg | Overall Survival Using RANO Criteria. | 11.8 Months |
| Expansion Cohort: Paxalisib 60mg (Fed) | Overall Survival Using RANO Criteria. | 12.0 Months |
| Expansion Cohort: Paxalisib 60mg (Fasted) | Overall Survival Using RANO Criteria. | 9.8 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.
Time frame: 24 months
Population: Intention to treat: All patients who were enrolled in the study, whether in Stage 1 or Stage 2.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose-escalating Cohort 1: Paxalisib 60mg | Progression-free Survival Interval Using Using mRANO Criteria/Investigator Review. | 14.5 Months |
| Dose-escalating Cohort 2: Paxalisib 75 mg | Progression-free Survival Interval Using Using mRANO Criteria/Investigator Review. | 4.7 Months |
| Expansion Cohort: Paxalisib 60mg (Fed) | Progression-free Survival Interval Using Using mRANO Criteria/Investigator Review. | 7.0 Months |
| Expansion Cohort: Paxalisib 60mg (Fasted) | Progression-free Survival Interval Using Using mRANO Criteria/Investigator Review. | 5.5 Months |
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
Time frame: Cycle 1, Day 7
Population: All participants in Stage 2 (dose-expansion cohorts) who received at least one dose of paxalisib and had measurable disease
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose-escalating Cohort 1: Paxalisib 60mg | Change in FDG-PET Uptake in Response to Paxalisib in Patients With Measurable Disease | -0.366 standardized uptake value | Standard Deviation 1.1814 |
| Dose-escalating Cohort 2: Paxalisib 75 mg | Change in FDG-PET Uptake in Response to Paxalisib in Patients With Measurable Disease | -0.432 standardized uptake value | Standard Deviation 0.5963 |
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
Time frame: Cycle 1, Day 3
Population: All participants in Stage 2 (dose-expansion cohorts) who received at least one dose of paxalisib and had measurable disease
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose-escalating Cohort 1: Paxalisib 60mg | Change in FDG-PET Uptake in Response to Paxalisib in Patients With Measurable Disease. | 0.036 standardized uptake value | Standard Deviation 0.7523 |
| Dose-escalating Cohort 2: Paxalisib 75 mg | Change in FDG-PET Uptake in Response to Paxalisib in Patients With Measurable Disease. | -0.442 standardized uptake value | Standard Deviation 0.3517 |
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.
Time frame: 24 months
Population: Safety population: All participants who received at least 1 dose of paxalisib
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose-escalating Cohort 1: Paxalisib 60mg | Disease Control Rate. | 3 Participants |
| Dose-escalating Cohort 2: Paxalisib 75 mg | Disease Control Rate. | 4 Participants |
| Expansion Cohort: Paxalisib 60mg (Fed) | Disease Control Rate. | 8 Participants |
| Expansion Cohort: Paxalisib 60mg (Fasted) | Disease Control Rate. | 9 Participants |
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.
Time frame: 24 hours
Population: Safety population: All participants who received at least 1 dose of paxalisib
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dose-escalating Cohort 1: Paxalisib 60mg | Maximum Observed Plasma Concentration of Paxalisib (Cmax) | 174 ng/mL | Geometric Coefficient of Variation 108 |
| Dose-escalating Cohort 2: Paxalisib 75 mg | Maximum Observed Plasma Concentration of Paxalisib (Cmax) | 118 ng/mL | Geometric Coefficient of Variation 67.4 |
| Expansion Cohort: Paxalisib 60mg (Fed) | Maximum Observed Plasma Concentration of Paxalisib (Cmax) | 176 ng/mL | Geometric Coefficient of Variation 24.2 |
| Expansion Cohort: Paxalisib 60mg (Fasted) | Maximum Observed Plasma Concentration of Paxalisib (Cmax) | 114 ng/mL | Geometric Coefficient of Variation 44.2 |
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.
Time frame: 24 hours
Population: Safety population: All participants who received at least 1 dose of paxalisib
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dose-escalating Cohort 1: Paxalisib 60mg | 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). | 1180 ng/mL*h | Geometric Coefficient of Variation 36.6 |
| Dose-escalating Cohort 2: Paxalisib 75 mg | 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). | 1120 ng/mL*h | Geometric Coefficient of Variation 91.4 |
| Expansion Cohort: Paxalisib 60mg (Fed) | 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). | 2190 ng/mL*h | Geometric Coefficient of Variation 34.5 |
| Expansion Cohort: Paxalisib 60mg (Fasted) | 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). | 1640 ng/mL*h | Geometric Coefficient of Variation 67.1 |
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.
Time frame: 24 hours
Population: Safety population: All participants who received at least 1 dose of paxalisib
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose-escalating Cohort 1: Paxalisib 60mg | Pharmacokinetics of Paxalisib as Time to Reach Cmax (Tmax). | 3.00 Hours |
| Dose-escalating Cohort 2: Paxalisib 75 mg | Pharmacokinetics of Paxalisib as Time to Reach Cmax (Tmax). | 2.50 Hours |
| Expansion Cohort: Paxalisib 60mg (Fed) | Pharmacokinetics of Paxalisib as Time to Reach Cmax (Tmax). | 4.00 Hours |
| Expansion Cohort: Paxalisib 60mg (Fasted) | Pharmacokinetics of Paxalisib as Time to Reach Cmax (Tmax). | 3.93 Hours |