A Study Evaluating the Efficacy of Venetoclax Plus Ibrutinib in Participants With T-cell Prolymphocytic Leukemia

Study Overview
=================
Brief Summary
-----------------
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).

Detailed Description
-----------------
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.

Official Title
-----------------
A Prospective, Open-Label, Single-Arm, Phase 2, Multicenter Study Evaluating the Efficacy of Venetoclax Plus Ibrutinib in Subjects With T-Cell Prolymphocytic Leukemia

Conditions
-----------------
Leukemia, T-cell Prolymphocytic Leukemia (T-PLL), Cancer

Intervention / Treatment
-----------------
* Drug: Venetoclax
* Drug: Ibrutinib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adequate liver, kidney and hematology function per laboratory values as described in the protocol. Diagnosis of T-cell prolymphocytic leukemia (T-PLL) that requires treatment. Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2. Received prior alemtuzumab (unless unsuitable or unavailable). Has no malignancies other than T-PLL that: currently require systemic therapies; were not previously treated with curative intention (unless the malignant disease is in a stable remission due to the discretion of the treating physician); or developed signs of progression after curative treatment. Exclusion Criteria: History of or current decompensated cirrhosis including Child-Pugh class B or C, ascites, hepatic encephalopathy, or variceal bleeding. Has human T-cell lymphotropic virus, type 1. Prior allogeneic stem cell transplant within 6 months of study drug administration and requirement for graft versus host therapy. Has an uncontrolled or active infection including severe acute respiratory syndrome- coronavirus-2 (SARS-COV-2). Previously treated with a B-cell lymphoma (BCL)-2 inhibitor. Received a prohibited therapy within the specified time frame as described in the protocol.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Venetoclax + Ibrutinib<br>Participants received 400 mg venetoclax orally once a day after a 5-day ramp-up and 420 mg ibrutinib orally once a day for up to 2 years or until progressive disease, intolerability, or they became eligible for stem cell transplantation after achieving complete remission. | Drug: Venetoclax<br>* 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.<br>* Other names: Venclyxto®;Drug: Ibrutinib<br>* Ibrutinib capsules taken orally once a day, 420 mg/day until the end-of-treatment.<br>* Other names: Imbruvica®;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Clinical response was assessed at Weeks 4, 8, 12, 16, and 24 for ORR assessment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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%. | 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. | 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. | 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. | 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) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
T-cell Prolymphocytic Leukemia (T-PLL), Cancer, Venetoclax, Venclexta, Venclyxto, Ibrutinib, Imbruvica, Relapsed or Refractory T-lymphoid malignancy