Ignite Creation Date:
2024-05-06 @ 3:46 PM
Last Modification Date:
2024-10-26 @ 1:57 PM
Study NCT ID:
NCT04754035
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2023-10-03
First Post:
2017-07-07
Brief Title:
Clinical Study With Ibrutinib and Venetoclax for Patients With RelapsedRefractory Chronic Lymphocytic Leukemia
Sponsor:
Paolo Ghia
Organization:
IRCCS San Raffaele
Study Overview
Official Title:
A Multi-Center Open Label Uncontrolled Phase 2a Clinical Trial Evaluating the Safety and Efficacy of the Addition of Ibrutinib to Venetoclax Through a MRD-guided Approach in RelapsedRefractory Patients With Chronic Lymphocytic Leukemia CLL
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2023-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
IMPROVE
Brief Summary:
This is a Phase 2a multicenter open-label uncontrolled study aimed at determining therapeutic benefits of the addition of ibrutinib to venetoclax in patients with relapsedrefractory CLL based on a MRD-guided approach
Detailed Description:
Venetoclax will be administered initially as single agent orally once daily QD starting with 20 mg on Day 1 followed by weekly dose escalation up to 400 mg if well tolerated Ramp-up Period according to the modified Venetoclax schedule in Phase 2 and 3 clinical trials and continued thereafter At Cycle 12 Day 1 disease status renal function and risk of bleeding will be assessed Minimal residual disease MRD in the peripheral blood will be evaluated in patients with CR or PR by flow cytometry All MRD negative subjects defined as those with MRD level in the PB 10-4 in the PB and in the BM aspirate will discontinue venetoclax at the end of Cycle 12 ie Cycle 12 Day 28 All MRD positive subjects defined as those with MRD level in the PB 10-4 and patients with stable disease without any contraindications to ibrutinib treatment will continue venetoclax and start treatment with ibrutinib at the standard dose for CLL of 420 mg QD Venetoclax will be administered until unacceptable toxicity or disease progression or for a maximum of 2 years and ibrutinib will be continued until unacceptable toxicity confirmed MRD negativity or disease progression
MRD will be assessed every 3 months starting 3 months after treatment initiation MRD negativity at Cycle 12 Day 1 will be evaluated in PB BM aspirate
Patients experiencing clinical disease progression will discontinue study treatment and will be followed up for survival status and subsequent anti-cancer therapy
Inclusion criteria 1 Documented CLL requiring treatment according to the IWCLL criteria Hallek et al 2008 2 Relapsedrefractory CLL patients who received at least 1 prior therapy 3 Adequate bone marrow function without transfusion 2 weeks of screening as follows
a Absolute neutrophil count ANC 10 x 109L growth factors administration is allowed b Platelets 30 x 109L If thrombocytopenia due to BM involvement platelets should be 20 x 109L c Hemoglobin value 80 gdl exclusion criteria
1 Transformation of CLL to aggressive NHL Richters transformation or pro-lymphocytic leukemia
2 Known central nervous system CNS involvement
3 Inadequate renal function CrCl 30 mLmin
4 Previous treatment with BTK andor BCL2 inhibitors patients previously treated with PI3K inhibitors are eligible
5 Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia
6 Requires the use of warfarin marcumar or phenprocoumon potential drug-drug interaction increasing exposure of warfarin or phenprocoumon low molecular weight drugs eg heparin are acceptable
7 Treatment administration or consumption of any of the following within 3 days prior to the first dose of venetoclax see also Appendix G
1 Strong Cytochrome P450 3A CYP3A inhibitors
2 Moderate CYP3A inhibitors
3 Moderate or strong CYP3A inducers
4 PI3K inhibitors eg Idelalisib
5 Grapefruit or grapefruit products
6 Seville oranges including marmalade containing Seville oranges
7 Star fruit
8 Known history of human immunodeficiency virus HIV or active with hepatitis B virus HBV or hepatitis C virus HCV Subjects who are positive for hepatitis B core antibody hepatitis B surface antigen or hepatitis C antibody must have a negative polymerase chain reaction PCR result before enrollment Those who are PCR positive will be excluded
9 History of other malignancies except
1 Malignancy treated with curative intent and with no known active disease present for 3 years before the first dose of study drug and felt to be at low risk for recurrence by treating physician
2 Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
3 Adequately treated carcinoma in situ without current evidence of disease
Updated International Workshop on CLL IWCLL Hallek et al 2008 criteria will be used to determine rates of response and progression for patients with CLL with the modification to exclude lymphocytosis as an isolated criterion of progression in patients treated with agents inhibiting B-cell receptor signaling
The primary endpoint objective response rate MRD negativity as well as secondary efficacy endpoints eg ORR PR CR PFS will be derived from Investigator assessment
Patients who reach a complete and partial response as per standard criteria will be investigated using MRD testing for molecular response categories as described in IWCLL
The safety and tolerability of study drug treatments will be evaluated by means of AEs incidence and severity performance status physical examinations 12-lead resting electrocardiograms ECGs and laboratory safety evaluations
Laboratory and AE toxicities will be graded according to National Cancer Institute NCI Common Terminology Criteria for Adverse Events CTCAE version 403
biomarker assessment
Whole exome sequencing on leukemic samples before during and after treatment andor at relapse in order to dissect mechanisms of resistance
High-throughput sequencing for MRD detection
Biochemical assays on the circulating leukemic population during ibrutinib treatment to study activation of signaling pathways
Statistical considerations According to optimal Simon Two-Stage Phase 2 design with the null hypothesis P0 of a MRD-negative CR at 12 months of 5 this study will consider a satisfactory efficacy of the venetoclax ibrutinib combination worth of further investigation a P1 corresponding to a MRD-negative CR of 30 Considering a standard type I error α of 005 and a power of 95 29 MRD positive patients will be necessary for the expansion phase of the trial A first step analysis will be implemented when 9 MRD positive patients have been enrolled and study will proceed to complete the planned accrual if at least 19 patients will obtain a MRD negative CR at 12 months after starting Ibrutinib Considering that 5 of patients are expected to reach a MRD negative CR with venetoclax alone the target population to be enrolled into the trial is 31 patients
MRD will be assessed every 3 months starting 3 months after treatment initiation MRD negativity at Cycle 12 Day 1 will be evaluated in PB BM aspirate
Patients experiencing clinical disease progression will discontinue study treatment and will be followed up for survival status and subsequent anti-cancer therapy
Inclusion criteria 1 Documented CLL requiring treatment according to the IWCLL criteria Hallek et al 2008 2 Relapsedrefractory CLL patients who received at least 1 prior therapy 3 Adequate bone marrow function without transfusion 2 weeks of screening as follows
a Absolute neutrophil count ANC 10 x 109L growth factors administration is allowed b Platelets 30 x 109L If thrombocytopenia due to BM involvement platelets should be 20 x 109L c Hemoglobin value 80 gdl exclusion criteria
1 Transformation of CLL to aggressive NHL Richters transformation or pro-lymphocytic leukemia
2 Known central nervous system CNS involvement
3 Inadequate renal function CrCl 30 mLmin
4 Previous treatment with BTK andor BCL2 inhibitors patients previously treated with PI3K inhibitors are eligible
5 Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia
6 Requires the use of warfarin marcumar or phenprocoumon potential drug-drug interaction increasing exposure of warfarin or phenprocoumon low molecular weight drugs eg heparin are acceptable
7 Treatment administration or consumption of any of the following within 3 days prior to the first dose of venetoclax see also Appendix G
1 Strong Cytochrome P450 3A CYP3A inhibitors
2 Moderate CYP3A inhibitors
3 Moderate or strong CYP3A inducers
4 PI3K inhibitors eg Idelalisib
5 Grapefruit or grapefruit products
6 Seville oranges including marmalade containing Seville oranges
7 Star fruit
8 Known history of human immunodeficiency virus HIV or active with hepatitis B virus HBV or hepatitis C virus HCV Subjects who are positive for hepatitis B core antibody hepatitis B surface antigen or hepatitis C antibody must have a negative polymerase chain reaction PCR result before enrollment Those who are PCR positive will be excluded
9 History of other malignancies except
1 Malignancy treated with curative intent and with no known active disease present for 3 years before the first dose of study drug and felt to be at low risk for recurrence by treating physician
2 Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
3 Adequately treated carcinoma in situ without current evidence of disease
Updated International Workshop on CLL IWCLL Hallek et al 2008 criteria will be used to determine rates of response and progression for patients with CLL with the modification to exclude lymphocytosis as an isolated criterion of progression in patients treated with agents inhibiting B-cell receptor signaling
The primary endpoint objective response rate MRD negativity as well as secondary efficacy endpoints eg ORR PR CR PFS will be derived from Investigator assessment
Patients who reach a complete and partial response as per standard criteria will be investigated using MRD testing for molecular response categories as described in IWCLL
The safety and tolerability of study drug treatments will be evaluated by means of AEs incidence and severity performance status physical examinations 12-lead resting electrocardiograms ECGs and laboratory safety evaluations
Laboratory and AE toxicities will be graded according to National Cancer Institute NCI Common Terminology Criteria for Adverse Events CTCAE version 403
biomarker assessment
Whole exome sequencing on leukemic samples before during and after treatment andor at relapse in order to dissect mechanisms of resistance
High-throughput sequencing for MRD detection
Biochemical assays on the circulating leukemic population during ibrutinib treatment to study activation of signaling pathways
Statistical considerations According to optimal Simon Two-Stage Phase 2 design with the null hypothesis P0 of a MRD-negative CR at 12 months of 5 this study will consider a satisfactory efficacy of the venetoclax ibrutinib combination worth of further investigation a P1 corresponding to a MRD-negative CR of 30 Considering a standard type I error α of 005 and a power of 95 29 MRD positive patients will be necessary for the expansion phase of the trial A first step analysis will be implemented when 9 MRD positive patients have been enrolled and study will proceed to complete the planned accrual if at least 19 patients will obtain a MRD negative CR at 12 months after starting Ibrutinib Considering that 5 of patients are expected to reach a MRD negative CR with venetoclax alone the target population to be enrolled into the trial is 31 patients
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None