Afuresertib is an AKT inhibitor, a new class of agents under development that may provide physicians with a new clinical option to control platinum resistant ovarian cancer (PROC) progression. Afuresertib plus chemotherapy has demonstrated anti-tumor efficacy and an acceptable safety profile in patients with PROC in a published Phase I/II study. Therefore, the combination of afuresertib plus weekly paclitaxel could represent a clinically meaningful step forward in the clinical management of these difficult-to-treat patients with PROC.
A total of approximately 141 patients with PROC are planned to be enrolled and randomized with a 2:1 ratio in an open label manner to the 2 arms (94 patients in the combination treatment arm and 47 patients in the paclitaxel arm) for efficacy and safety evaluation. The randomization will be stratified by country (the United States vs. China), prior bevacizumab use (yes vs. no), and number of prior platinum based therapy treatments (1-2 vs. 3-5 prior platinum regimens). The study will consist of 3 periods. The first period is the Screening Period (Day -24 to 1) during which patients are screened for eligibility according to the inclusion and exclusion criteria. The second period is a Treatment Evaluation Period with a randomized, open-label, two arm parallel design (from starting study treatment until patients have progressive disease \[PD\], unacceptable toxicity, death, or withdrawal of consent). The PK study will be applied to both the combination treatment arm and control arm. The third period is a Follow up Period (safety evaluation at 30 days after the last dose of study treatment and OS and/or PFS follow up). Patients will be tested at baseline for phosphoinositide 3 kinase (PI3K)/AKT/PTEN pathway alterations and BRCA1/2 mutations by NGS, and/or level of phospho AKT by IHC; the correlation of the efficacy endpoints and biomarker status will be analyzed retrospectively as an exploratory endpoint.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
150
Commercially available paclitaxel for IV administration will be obtained by clinical sites in US.
Each afuresertib 50 mg tablet, intended for oral administration, contains afuresertib (hydrochloride salt) equivalent to 50 mg of afuresertib (free base). Each afuresertib 75 mg tablet, intended for oral administration, contains afuresertib (hydrochloride salt) equivalent to 75 mg of afuresertib (free base)
PFS based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
Radiographic imaging will be performed and assessed by investigators
Time frame: Change from Baseline every 6 weeks × 30 weeks, then every 8 weeks through study completion, an average of 1 year
Overall survival (OS)
To further evaluate the clinical efficacy via OS collection
Time frame: From date of randomization until date of death, from any cause, assessed up to 1 year.
Objective response rate (ORR) according to RECIST 1.1
To further evaluate the clinical efficacy via ORR
Time frame: Change from Baseline every 6 weeks × 30 weeks, then every 8 weeks through study completion, an average 1 year.
Duration of response (DOR) according to RECIST 1.1
To further evaluate the clinical efficacy via DOR
Time frame: Change from Baseline every 6 weeks × 30 weeks, then every 8 weeks through study completion, an average of 1 year.
Disease control rate (DCR) according to RECIST 1.1
To further evaluate the clinical efficacy via DCR
Time frame: Change from Baseline every 6 weeks × 30 weeks, then every 8 weeks through study completion, an average of 1 year.
Best overall response (BOR) according to RECIST 1.1
To further evaluate the clinical efficacy via BOR
Time frame: Change form Baseline every 6 weeks × 30 weeks, then every 8 weeks through study completion, an average of 1 year.
Cancer antigen 125 (CA-125) response (Gynecological Cancer Intergroup [GCIG])
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Arizona Oncology Associates
Phoenix, Arizona, United States
Arizona Oncology
Tucson, Arizona, United States
Highlands Oncology Group
Rogers, Arkansas, United States
Gynecology Oncology Associates Newport Beach
Newport Beach, California, United States
Rocky Mountain Cancer Centers
Littleton, Colorado, United States
Kapiolani Medical Center for Women and Children
Honolulu, Hawaii, United States
University of Chicago
Chicago, Illinois, United States
Women's Cancer Care
Covington, Louisiana, United States
Tufts Medical Center
Boston, Massachusetts, United States
University of Massachusetts
Worcester, Massachusetts, United States
...and 37 more locations
To further evaluate the clinical efficacy via CA125 response
Time frame: Change from Baseline every 6 weeks × 30 weeks, then every 8 weeks through study completion, an average of 1 year.
Area under the curve in the inter-dose interval period after first dose (AUCτ)
To Characterize Pharmacokinetics (PK) of afuresertib and paclitaxel in patients with PROC under combination therapy of afuresertib plus paclitaxel, or paclitaxel alone at steady-state via AUCτ
Time frame: Samples collected on Cycle1Day1, Cycle2Day1, Cycle3Day1 and Cycle4Day1 will be assessed (a Cycle is 21 days)
Area under the curve in the inter-dose interval period at steady state (AUCτ_SS)
To Characterize Pharmacokinetics (PK) of afuresertib and paclitaxel in patients with PROC under combination therapy of afuresertib plus paclitaxel, or paclitaxel alone at steady-state via AUCτ\_SS
Time frame: Samples collected on Cycle1Day1, Cycle2Day1, Cycle3Day1 and Cycle4Day1 will be assessed (a Cycle is 21 days)
Maximum concentration after first dose (Cmax)
To Characterize Pharmacokinetics (PK) of afuresertib and paclitaxel in patients with PROC under combination therapy of afuresertib plus paclitaxel, or paclitaxel alone at steady-state via Cmax
Time frame: Samples collected on Cycle1Day1, Cycle2Day1, Cycle3Day1 and Cycle4Day1 will be assessed (a Cycle is 21 days)
Maximum concentration at steady state (Cmax_SS)
To Characterize Pharmacokinetics (PK) of afuresertib and paclitaxel in patients with PROC under combination therapy of afuresertib plus paclitaxel, or paclitaxel alone at steady-state via Cmax\_SS
Time frame: Samples collected on Cycle1Day1, Cycle2Day1, Cycle3Day1 and Cycle4Day1 will be assessed (a Cycle is 21 days)
Time to maximum concentration after first dose (Tmax) To explore potential effect of coadministration of afuresertib
To Characterize Pharmacokinetics (PK) of afuresertib and paclitaxel in patients with PROC under combination therapy of afuresertib plus paclitaxel, or paclitaxel alone at steady-state via Tmax
Time frame: Samples collected on Cycle1Day1, Cycle2Day1, Cycle3Day1 and Cycle4Day1 will be assessed(a Cycle is 21 days)
Time to maximum concentration at steady state (Tmax_SS)
To Characterize Pharmacokinetics (PK) of afuresertib and paclitaxel in patients with PROC under combination therapy of afuresertib plus paclitaxel, or paclitaxel alone at steady-state via Tmax\_SS
Time frame: Samples collected on Cycle1Day1, Cycle2Day1, Cycle3Day1 and Cycle4Day1 will be assessed (a Cycle is 21 days)
Half-life (T1/2) if data permit
To Characterize Pharmacokinetics (PK) of afuresertib and paclitaxel in patients with PROC under combination therapy of afuresertib plus paclitaxel, or paclitaxel alone at steady-state via T1/2
Time frame: Samples collected on Cycle1Day1, Cycle2Day1, Cycle3Day1 and Cycle4Day1 will be assessed(a Cycle is 21 days)
Trough concentration at steady state (Ctrough_SS)
To Characterize Pharmacokinetics (PK) of afuresertib and paclitaxel in patients with PROC under combination therapy of afuresertib plus paclitaxel, or paclitaxel alone at steady state via Ctrough\_SS
Time frame: Samples collected on Cycle1Day1, Cycle2Day1, Cycle3Day1 and Cycle4Day1 will be assessed (a Cycle is 21 days)
Rate and severity of treatment-emergent adverse events (TEAEs) based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0
Patients to be queried as to whether they have experienced adverse event
Time frame: From date of consent until 30 days following discontinuation of study treatment
Vital signs-Blood Pressure
Assessment of Blood Pressure
Time frame: Cycle1Day 1 and Cyle 1 D15, then on Day 1 of subsequent cycles
Vital signs-Heart Rate
Assessment of heart rate
Time frame: Cycle1Day 1 and Cyle 1 D15, then on Day 1 of subsequent cycles
Vital signs-Respiratory rate
Assessment of respiratory rate
Time frame: Cycle1Day 1 and Cyle 1 D15, then on Day 1 of subsequent cycles
Vital signs-body temperature
Assessment of body temperature.
Time frame: Cycle1Day 1 and Cyle 1 D15, then on Day 1 of subsequent cycles
Electrocardiogram (ECG)
ECG QT Interval
Time frame: Screening and repeated if clinically indicated through study completion, an average of 1 year.
Physical examinations
Assessment of head, eyes, ears, nose, and throat, chest, cardiac, abdominal, extremities, neurologic, and lymph node examinations
Time frame: Assessment to be complete every 2 weeks for first 2 cycles, then once per cycle (each Cycle is 21 days)
CBC
Assessment includes Platelet Count, Hemoglobin, WBC Count (absolute), Neutrophils, Lymphocytes, Eosinophils, Monocytes, Basophils
Time frame: Screening then Cycles1 and 2 Day 1, 8,and 15 and D1 of subsequent cycles through study completion, an average up to 1 year.
Clinical Chemistry
Assessment includes BUN, Creatinine, Glucose (fasting), Sodium, Total Protein, Magnesium , Potassium, Chloride, Total CO2, Calcium, Albumin, AST (SGOT), ALT (SGPT), Phosphorous, Alkaline phosphatase, Total and direct bilirubin
Time frame: Screening and Day1 of each cycle through study completion, an avergae up to 1 year.