This is a Phase 1, open-label, multicenter study evaluating the safety and PK profile of ABT-199 under a once daily dosing schedule. Two arms will be implemented for dose escalation: Arm A, CLL/SLL subjects and Arm B, NHL subjects. Arm A is designed to enroll approximately 116 subjects with relapsed or refractory CLL or SLL and Arm B is designed to enroll approximately 95 subjects with relapsed or refractory NHL. Fifty-six subjects were enrolled in Arm A and approximately 55 subjects will be enrolled in Arm B during the dose escalation portion of the study, with the objective of defining dose limiting toxicities (DLTs) and the MTD. Once the MTD is declared for the arm, approximately 60 additional CLL/SLL subjects in Arm A and approximately 20 additional DLBCL subjects and 20 additional follicular lymphoma subjects in Arm B will be enrolled in an expanded safety portion of the study at the recommended phase 2 dose (RPTD) and schedule.
Interventional Study Design - Primary Purpose: Determination of safety and tolerability.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
222
Arm A (Cohorts 1-8) and Arm B (Cohort 1-6): Subjects in dose escalation phase will receive 1 dose of ABT-199, followed by 6 days off drug, followed by continuous once daily dosing with ABT-199. Arm B (Cohorts 7+): Subjects in dose escalation phase will receive continuous once daily dosing with ABT-199. Arm A and Arm B: Subjects in expanded safety cohort will receive continuous once daily dosing with ABT-199.
University of Arizona Cancer Center - North Campus /ID# 52902
Tucson, Arizona, United States
Ucsd /Id# 48325
La Jolla, California, United States
Dana-Farber Cancer Institute /ID# 48324
Boston, Massachusetts, United States
Memorial Sloan Kettering Cancer Center /ID# 56810
New York, New York, United States
University of Texas MD Anderson Cancer Center /ID# 48326
Houston, Texas, United States
Swedish Medical Center /ID# 135853
Seattle, Washington, United States
Fred Hutchinson Cancer Research /ID# 52882
Seattle, Washington, United States
Univ of Wisconsin Hosp/Clinics /ID# 56811
Madison, Wisconsin, United States
Peter MacCallum Cancer Ctr /ID# 48323
Melbourne, Victoria, Australia
Royal Melbourne Hospital /ID# 48322
Parkville, Victoria, Australia
Determination of dose limiting toxicity (DLT), maximum tolerated dose (MTD), recommended phase two dose (RPTD), and lead-in period regimen
Protocol-defined events, which can not be attributed by the investigator to a clearly identifiable cause such as tumor progression, underlying illness, concurrent illness, or concomitant medication, will be considered a DLT. Dose limiting toxicities of tumor lysis syndrome observed during the lead-in period will be attributed to the lead-in period.
Time frame: Lead-in period (2-5 weeks) plus 3 weeks of study drug administration at the designated cohort dose (continuous dosing)
Number of subjects with adverse events
Time frame: First 16 weeks of study drug administration and every 4 weeks thereafter (continuous dosing for an anticipated maximum duration of 9 months)
Determination of plasma peak concentration (Cmax) of ABT-199
Blood and urine samples for pharmacokinetic analysis of ABT-199 will be collected at designated time points
Time frame: Up to Week 24 for ABT-199
Determination of trough concentration (Ctrough) of ABT-199
Blood and urine samples for pharmacokinetic analysis of ABT-199 will be collected at designated time points
Time frame: Up to Week 24 for ABT-199
Determination of area under the concentration versus time curve (AUC) of ABT-199
Blood and urine samples for pharmacokinetic analysis of ABT-199 will be collected at designated time points
Time frame: Up to Week 24 for ABT-199
Food Effect - Cmax
Pharmacokinetic (PK) parameter Cmax (maximum plasma concentration of ABT-199) between each diet (ABT-199 under fasting versus low-fat, and fasting versus high-fat conditions (Cohorts 1-6 in Arm B subjects only)
Time frame: Approximately 3 days
Preliminary efficacy assessment
Tumor response or clinical disease progression
Time frame: Starting Week 4 for clinical disease progression and Week 6 for tumor response; and every 4 weeks thereafter (continuous dosing for an anticipated maximum duration of 9 months)
Minimal residual disease collection (MRD)
MRD assessed in the peripheral blood and/or bone marrow (BM) either by four color flow cytometry or ASO-PCR, will be measured in CLL subjects achieving CR/CRi.
Time frame: At least 2 months after the CR, CRi criteria for tumor response are first met. Every 12 weeks thereafter, until MRD negativity has been achieved (in peripheral blood).
Food Effect - Tmax
Pharmacokinetic (PK) parameter Tmax (time to reach maximum plasma concentration of ABT-199) between each diet (ABT-199 under fasting versus low-fat, and fasting versus high-fat conditions (Cohorts 1-6 in Arm B subjects only)
Time frame: Approximately 3 days
Food Effect - AUC
Pharmacokinetic (PK) parameter AUC (area under the concentration-time curve from time zero to hour 24 of ABT-199) between each diet (ABT-199 under fasting versus low-fat, and fasting versus high-fat conditions (Cohorts 1-6 in Arm B subjects only)
Time frame: Approximately 3 days
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