The main objective of this study is to evaluate the efficacy of the combination of venetoclax plus ibrutinib for treating adults with T-cell prolymphocytic leukemia (T-PLL).
This study is planned as an adaptive 2-stage design as follows: Stage 1: Enroll 14 participants with relapsed or refractory (R/R) T-PLL and move to Stage 2 if 4 or more participants meet protocol-specified response criteria. Response assessment will be performed on a continued basis until all 14 participants have enrolled into Stage 1 and have completed the Week 24 disease assessment. Stage 2: Enroll up to an additional 23 participants. The study was stopped after Stage 1. Stage 2 was not conducted.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
14
Venetoclax tablets taken orally once a day (QD). Initially, venetoclax was administered utilizing a 5-step dose ramp-up over 5 days. Subjects were hospitalized and closely monitored for 7 days. The venetoclax ramp-up was administered in a daily manner: 20 mg on Week 1 Day 1, 50 mg on Week 1 Day 2, 100 mg on Week 1 Day 3, 200 mg on Week 1 Day 4, and 400 mg on Week 1 Day 5 and thereafter, once daily, until the end-of-treatment. The dose of venetoclax may have been increased to 600 mg QD at Week 8 or thereafter.
Ibrutinib capsules taken orally once a day, 420 mg/day until the end-of-treatment.
Dana-Farber Cancer Institute /ID# 207728
Boston, Massachusetts, United States
Mayo Clinic - Rochester /ID# 207692
Rochester, Minnesota, United States
Overall Response Rate (ORR)
ORR is defined as the percentage of participants achieving complete remission (CR), CR with incomplete bone marrow recovery (CRi), or partial remission (PR) as their best response per investigator assessment based on the T-PLL consensus criteria 2019. CR: All of the following response criteria must be met: Group A: * all lymph nodes \< 1 cm; * spleen \< 13 cm; * no constitutional symptoms; * circulating lymphocyte count \< 4 × 10\^9/L; * bone marrow T-PLL cells \< 5% of mononuclear cells; * no other specific site involvement Group B: * platelets ≥ 100 × 10\^9 /L; * hemoglobin ≥ 11.0 g/dL; * neutrophils ≥ 1.5 × 10\^9 /L. CRi: All of the CR response criteria in Group A met; at least 1 parameter in Group B not achieved, unrelated to T-PLL, but related to drug toxicity. PR: At least 2 of the parameters in Group A and 1 parameter in Group B need to improve if previously abnormal. If only 1 parameter of both Groups A and B is abnormal prior to therapy, only 1 parameter needs to improve.
Time frame: Clinical response was assessed at Weeks 4, 8, 12, 16, and 24 for ORR assessment
Progression-Free Survival (PFS)
Progression-free survival is defined as the time from the date of first dose of any study drug to the date of earliest disease progression or death. PFS was calculated using Kaplan-Meier methods. Response was assessed by the investigator based on the T-PLL consensus criteria 2019. Progressive disease (PD) is defined as meeting at least one of the criteria of Group A or Group B below: Group A: * lymph nodes increase in \> 20% in sum of long-axis diameters of up to 3 target lesions (SLD) from nadir; * spleen increase ≥ 50% in vertical length beyond normal from baseline; * circulating lymphocyte count increase ≥ 50% from baseline; * appearance of a new lesion; Group B: * platelet count decrease of ≥ 50% from baseline due to T-PLL (not due to drug toxicity); * hemoglobin decrease of ≥ 2 g/dL from baseline due to T-PLL; * neutrophils decrease of ≥ 50% from baseline due to T-PLL.
Time frame: From first dose of study drug to end of study; median time on study was 30.1 weeks.
Duration of Response (DOR)
Duration of response is defined for participants who achieved a best overall response of CR, CRi, or PR as the time from the date of first response (CR, CRi, or PR) to the earliest date of disease progression or death. DOR was calculated using Kaplan-Meier methods. Response was assessed by the investigator based on the T-PLL consensus criteria 2019. Progressive disease is defined as meeting at least one of the criteria of Group A or Group B below: Group A: * lymph nodes increase in \> 20% in SLD from nadir; * spleen increase ≥ 50% in vertical length beyond normal from baseline; * circulating lymphocyte count increase ≥ 50% from baseline; * appearance of a new lesion; Group B: * platelet count decrease of ≥ 50% from baseline due to T-PLL (not due to drug toxicity); * hemoglobin decrease of ≥ 2 g/dL from baseline due to T-PLL; * neutrophils decrease of ≥ 50% from baseline due to T-PLL.
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University of Texas MD Anderson Cancer Center /ID# 207746
Houston, Texas, United States
Peter MacCallum Cancer Ctr /ID# 209554
Melbourne, Victoria, Australia
Medizinische Universitaet Wien /ID# 208497
Vienna, Vienna, Austria
Helsinki University Hospital /ID# 208108
Helsinki, Uusimaa, Finland
HCL - Hôpital Lyon Sud /ID# 208731
Pierre-Bénite, Auvergne-Rhône-Alpes, France
CHRU Lille - Hopital Claude Huriez /ID# 208726
Lille, Hauts-de-France, France
Hopital Pitie Salpetriere /ID# 208730
Paris, France
University Hospital Cologne /ID# 208834
Cologne, Germany
...and 5 more locations
Time frame: From first dose of study drug to end of study; median time on study was 30.1 weeks.
Time to Progression (TTP)
Time to progression is defined as the time from the date of the participant's first dose of any study drug to the date of earliest disease progression. TTP was calculated using Kaplan-Meier methods. Clinical response (laboratory and physical examination assessments) was assessed by the investigator according to the T-PLL consensus criteria 2019. Progressive disease is defined as meeting at least one of the criteria of Group A or Group B below: Group A: * lymph nodes increase in \> 20% in SLD from nadir; * spleen increase ≥ 50% in vertical length beyond normal from baseline; * circulating lymphocyte count increase ≥ 50% from baseline; * appearance of a new lesion; Group B: * platelet count decrease of ≥ 50% from baseline due to T-PLL (not due to drug toxicity); * hemoglobin decrease of ≥ 2 g/dL from baseline due to T-PLL; * neutrophils decrease of ≥ 50% from baseline due to T-PLL.
Time frame: From first dose of study drug to end of study; median time on study was 30.1 weeks.
Event-free Survival (EFS)
Event-free survival is defined as time from participant's first dose of any study drug to the date of earliest disease progression, death, or start of a new anti-T-PLL therapy. EFS was calculated using Kaplan-Meier methods. Clinical response (laboratory and physical examination assessments) was assessed by the investigator according to the T-PLL consensus criteria 2019. Progressive disease is defined as meeting at least one of the criteria of Group A or Group B below: Group A: * lymph nodes increase in \> 20% in SLD from nadir; * spleen increase ≥ 50% in vertical length beyond normal from baseline; * circulating lymphocyte count increase ≥ 50% from baseline; * appearance of a new lesion; Group B: * platelet count decrease of ≥ 50% from baseline due to T-PLL (not due to drug toxicity); * hemoglobin decrease of ≥ 2 g/dL from baseline due to T-PLL; * neutrophils decrease of ≥ 50% from baseline due to T-PLL.
Time frame: From first dose of study drug to end of study; median time on study was 30.1 weeks.
Disease Control Rate (DCR)
DCR is defined as the percentage of participants who achieved CR, CRi, PR, or stable disease (SD) as best overall response per investigator assessment based on the T-PLL consensus criteria 2019. Stable disease is defined as meeting all of the following criteria for at least 3 months: * lymph nodes change of -29% to +20% in SLD; * spleen change of -49% to +49% beyond normal from baseline; * circulating lymphocyte count \> 30 × 10\^9 /L or change of -49% to +49%; * platelet count change of -49% to +49%; * hemoglobin \< 11.0 g/dL or change \< 50% from baseline or change \< 2 g/dL; * neutrophils change of -49% to +49%.
Time frame: Clinical response was assessed at Weeks 4, 8, 12, 16, and 24 for DCR assessment
Overall Survival (OS)
Overall survival is defined as the time from the date of the participant's first dose of any study drug to death from any cause. OS was calculated using Kaplan-Meier methods.
Time frame: From first dose of study drug to end of study; median time on study was 30.1 weeks.
Number of Eligible Participants Reaching Autologous or Allogeneic Transplantation
Participants eligible for autologous or allogeneic transplantation were transplant-naïve participants who achieved CR.
Time frame: From first dose of study drug to end of study; median time on study was 30.1 weeks.
Number of Participants With Treatment-emergent Adverse Events (TEAE)
An adverse event (AE) is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. Treatment-emergent AEs are any event with onset after the first dose of study drug and no more than 30 days after the last dose of study drug. A serious AE was an event that resulted in death, was life-threatening, resulted in hospitalization or prolongation of hospitalization, persistent or significant disability/incapacity, or an important medical event requiring medical or surgical intervention to prevent a serious outcome. The Investigator rated the severity of each AE according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0, where grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life-threatening and grade 5 = death. The Investigator assessed the relationship of the AE to the use of study drug.
Time frame: From first dose of study drug up to 30 days after last dose; median time on treatment was 13.86 weeks (range 1.0 to 44.4 weeks)