The primary objective of this study was to determine the safety and tolerability of pamiparib, the maximum tolerated dose (MTD) or maximum administered dose (MAD) for pamiparib combined with TMZ, to select the recommended Phase 2 dose (RP2D) and schedule of pamiparib in combination with TMZ, and to determine the antitumor activity of pamiparib in combination with TMZ.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
139
Administered by mouth as a capsule twice daily
TMZ at various doses administered by mouth as a capsule once daily.
Start Midwest
Grand Rapids, Michigan, United States
Dose Escalation: Number of Participants With Dose Limiting Toxicities (DLTs)
A DLT is defined as one of the following toxicities occurring during the DLT assessment window: Grade ≥3 non-hematologic, non-hepatic major organ adverse event (AE) Grade 4 neutropenia lasting \>7 days Grade ≥3 febrile neutropenia Grade 3 thrombocytopenia with clinically significant bleeding Grade 4 thrombocytopenia lasting \> 3 days and requiring transfusion, or any decreased platelet count \<15,000/mm3/ \<15.0 x 109/L Grade ≥4 anemia Grade ≥3 total bilirubin or hepatic transaminases (ALT or AST)
Time frame: From first dose of study drug(s) to 28 days post-dose (up to approximately 1 year and 6 months)
Number of Participants Experiencing Adverse Events (AEs)
Number of participants with treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), including laboratory values, vital signs, physical examination findings, and electrocardiogram results, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), v4.03
Time frame: From the first dose of study drug(s) to 30 days after the last dose; up to approximately 5 years and 10 months
Objective Response Rate (ORR)
ORR is defined as the percentage of participants who have a best overall response (BOR) of complete response (CR) or partial response (PR) based on investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, where BOR is defined as the best response recorded from the first postbaseline tumor assessment until data cutoff date, disease progression or start of new anticancer treatment.
Time frame: Up to approximately 5 years and 10 months
Maximum Observed Plasma Concentration (Cmax) of Pamiparib
Pamiparib pharmakokinetic (PK) parameters were assessed in the first 20 participants enrolled in the dose escalation phase after a single dose on Day -2 and at steady state in combination with TMZ on Day 15.
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Washington University in St Louis
St Louis, Missouri, United States
Mount Sinai Prime
New York, New York, United States
Montefiore Medical Park At Eastchester Einstein Campus
The Bronx, New York, United States
Sarah Cannon Cancer Center
Nashville, Tennessee, United States
Texas Oncology (Loop) Usor
Dallas, Texas, United States
The University of Texas Md Anderson Cancer Center
Houston, Texas, United States
Chris Obrien Lifehouse
Camperdown, New South Wales, Australia
Saint Vincents Hospital Sydney
Darlinghurst, New South Wales, Australia
Icon Cancer Centre South Brisbane
South Brisbane, Queensland, Australia
...and 12 more locations
Time frame: 2 days before Cycle 1 Day 1 (Day -2) at predose, 30 min, 1, 2, 4, 6, 24, and 48 hours after dosing, and on Cycle 1 Day 15 at predose, 1, 2, and 4 hours postdose (each cycle is 28 days)
Plasma Trough Concentrations of Pamiparib (Ctrough)
Time frame: Cycle 1 Day 15 predose
Time to Reach Cmax (Tmax) of Pamiparib
Time frame: 2 days before Cycle 1 Day 1 (Day -2) at predose, 30 min, 1, 2, 4, 6, 24, and 48 hours after dosing, and on Cycle 1 Day 15 at predose, 1, 2, and 4 hours postdose.
Area Under the Curve From Time 0 to 4 Hours (AUC0-4h) of Pamiparib
Time frame: 2 days before Cycle 1 Day 1 (Day -2) at predose, 30 min, 1, 2, and 4 hours after dosing, and on Cycle 1 Day 15 at predose, 1, 2, and 4 hours postdose.
Area Under the Curve From Time 0 to Infinity (AUC0-inf) of Pamiparib
Time frame: 2 days before Cycle 1 Day 1 (Day -2) at predose, 30 min, 1, 2, 4, 6, 24, and 48 hours after dosing
Terminal Elimination Half-life (t1/2) of Pamiparib
Time frame: 2 days before Cycle 1 Day 1 (Day -2) at predose, 30 min, 1, 2, 4, 6, 24, and 48 hours after dosing (each cycle is 28 days)
Apparent Clearance (CL/F) of Pamiparib
Time frame: 2 days before Cycle 1 Day 1 (Day -2) at predose, 30 min, 1, 2, 4, 6, 24, and 48 hours after dosing (each cycle is 28 days)
Apparent Volume of Distribution During Terminal Phase (Vz/F) of Pamiparib
Time frame: 2 days before Cycle 1 Day 1 (Day -2) at predose, 30 min, 1, 2, 4, 6, 24, and 48 hours after dosing (each cycle is 28 days)
Plasma Concentration of Temozolomide (TMZ)
Time frame: Predose (within 30 min prior to dose) and 1 hour post dose on Cycle 1 Day 1 and Cycle 1 Day 7
Disease Control Rate (DCR)
DCR is defined as the percentage of participants with BOR of CR, PR, or stable disease (SD) based on investigator assessment using RECIST v1.1.
Time frame: Up to approximately 5 years and 10 months
Duration of Response (DOR)
DOR is defined as the time from the date of the earliest documented CR or PR (that is subsequently confirmed) to disease progression or death due to any cause, whichever occurs earlier, based on investigator assessment using RECIST v1.1. Only responders will be included in the assessment.
Time frame: Up to approximately 5 years and 10 months
Progression Free Survival (PFS)
PFS is defined as the time (months) from the date of the first dose of combination treatment to disease progression or death due to any cause, whichever occurs first, based on investigator assessment using RECIST v1.1
Time frame: Up to approximately 5 years and 10 months)
Overall Survival (OS)
OS is defined as the time from the date of the first dose of combination treatment to death due to any cause.
Time frame: Up to approximately 5 years and 10 months