Clinical trial NCT03522298: Safety, Pharmacokinetics and Efficacy of Paxalisib (GDC-0084) in Newly-diagnosed Glioblastoma
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Glioblastoma, Adult
Keywords: newly diagnosed
unmethylated O6 methylguanine-methyltransferase (MGMT) promoter status
Lead sponsor: Kazia Therapeutics Limited
Sponsor class: INDUSTRY
First posted: 2018-05-11
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
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.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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;

Primary outcomes:
measure: Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs)
timeFrame: Cycle 1, Days 1-28
Secondary outcomes:
measure: Incidence of Treatment-emergent Adverse Events (TEAEs)
timeFrame: 24 months
measure: Incidence of Serious Adverse Events (SAEs)
timeFrame: 24 months
measure: Incidence of Treatment-emergent Grade 3/4 Treatment Emergent Adverse Events
timeFrame: 24 months
measure: Number of Participants Who Experienced a Change in Electrocardiogram (ECG) Parameter QTc
timeFrame: 24 months
measure: Number of Participants Who Experienced a Change Left Ventricular Ejection Fraction
timeFrame: 24 months
measure: Progression-free Survival Interval Using Using mRANO Criteria/Investigator Review.
timeFrame: 24 months
measure: Overall Survival Using RANO Criteria.
timeFrame: 24 months
Other outcomes:
measure: 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).
timeFrame: 24 hours
measure: Maximum Observed Plasma Concentration of Paxalisib (Cmax)
timeFrame: 24 hours
measure: Pharmacokinetics of Paxalisib as Time to Reach Cmax (Tmax).
timeFrame: 24 hours
measure: Change in FDG-PET Uptake in Response to Paxalisib in Patients With Measurable Disease.
timeFrame: Cycle 1, Day 3
measure: Change in FDG-PET Uptake in Response to Paxalisib in Patients With Measurable Disease
timeFrame: Cycle 1, Day 7
measure: Disease Control Rate.
timeFrame: 24 months
Locations:
city: Los Angeles
country: United States
facility: University of California Los Angeles - Jonsson Comprehensive Cancer Center
state: California
city: Aurora
country: United States
facility: University of Colorado Cancer Center
state: Colorado
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Hackensack
country: United States
facility: John Theurer Cancer Center at Hackensack University Medical Center
state: New Jersey
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center (Stephenson Cancer Center)
state: Oklahoma
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
Study officials:
affiliation: Kazia Therapeutics Limited
name: James Garner, MD
role: STUDY_DIRECTOR
References: