Venetoclax and Ibrutinib in Patients With Relapsed/Refractory CLL or SLL

• Sponsor: Steven E. Coutre (Other)
• Overall Status: Completed
• CT.gov ID: NCT03045328
• Collaborator: (none)
• Enrollment: 22
• Locations: 2
• Arm: 1
• Actual Duration (Months): 46.3
• Patients Per Site: 11
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This is an open-label non-randomized two-center phase 2 study evaluating the safety and efficacy of concurrent therapy with ibrutinib and venetoclax in subjects with relapsed or refractory CLL/SLL.

Condition or Disease	Intervention/Treatment	Phase
Recurrent Chronic Lymphocytic Leukemia; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Small Lymphocytic Lymphoma	Drug: Ibrutinib; Drug: Venetoclax	Phase 2

Detailed Description

The primary objective of this study is to evaluate the efficacy of concurrent therapy with ibrutinib and venetoclax in patients with relapsed and refractory chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL).

The secondary objectives of this study are to define the safety, tolerability, and dose-limiting toxicity (DLT) within 28 days of completion of dose-escalation.

Study Design

• Study Type: Interventional
• Actual Enrollment: 22 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open Label Phase 2 Trial of Venetoclax With Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma
• Actual Study Start Date: Sep 26, 2017
• Actual Primary Completion Date: May 19, 2020
• Actual Study Completion Date: Aug 5, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (ibrutinib, venetoclax) Patients receive ibrutinib PO QD beginning on week 1 day 1. Treatment with ibrutinib continues in the absence of disease progression or unacceptable toxicity. Patients also receive venetoclax PO QD beginning on week 9 day 1. Treatment with venetoclax continues up to week 61 day 7 in the absence of disease progression or unacceptable toxicity.	Drug: Ibrutinib; Administered at 420 mg/day, as oral capsules (3 x 140 mg), starting Day 1, Week 1.; Other Names: BTK Inhibitor PCI-32765 CRA-032765 Imbruvica PCI-32765 ; Drug: Venetoclax; Administered as tablets, starting Day 1, Week 9, with dose increasing every 7 days through 5 dose levels (20 mg; 50 mg; 100 mg; 200 mg; 400 mg).; Other Names: ABT-0199 ABT-199 ABT199 GDC-0199 RG7601 Venclexta

Outcome Measures

Primary Outcome Measures

1. Complete Response (CR) [62 weeks]

   Complete Response (CR) will be assessed as the number of participants who, based on investigator assessment based on the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria, achieve a complete remission. IWCLL complete remission is defined as follows. Lymphadenopathy: none > 1.5 cm Blood lymphocytes: < 4,000/µL Hepatomegaly: none Splenomegaly: none Bone marrow: normocellular with < 30 lymphocytes, no B lymphoid nodules. The outcome is reported as the number of participants who achieve CR, a number without dispersion.

Secondary Outcome Measures

1. Duration of Response (DoR) [117 weeks]

   Duration of response (DoR) refers to a participant maintaining clinical response after achieving either complete response (CR) or partial response (PR). The outcome is reported as the number of subjects who have maintained clinical response through 117 weeks. Response defined as the following. CR. Lymphadenopathy: none > 1.5 cm Blood lymphocytes: < 4,000/µL Hepatomegaly: none Splenomegaly: none Bone marrow: normocellular with < 30 lymphocytes, no B lymphoid nodules. PR. Lymphadenopathy: decrease ≥ 50% Blood lymphocytes: decrease ≥ 50% Hepatomegaly: decrease ≥ 50% Splenomegaly: decrease ≥ 50% Bone marrow: not considered.

2. Minimal Residual Disease (MRD) [117 weeks]

   Minimal residual disease (MRD) refers to the small numbers of leukemic cells that can remain in the participant after treatment, and may not be associated with any symptoms (remission). Although the participant may feel "healthy," the MRD is a major cause of eventual leukemic relapse. "MRD-negative" is the ideal treatment outcome. MRD negativity was defined as less than one leukemic cell per 10,000 leukocytes as assessed by bone marrow-based flow cytometry. The outcome is reported as the number of participants who were positive for MRD, or negative.

3. Overall Response (OR) [62 weeks]

   Overall response (OR) is the overall number of subjects that begin treatment and achieve a complete response (CR); partial response (PR); or Stable Disease (SD) 62 weeks after the beginning of treatment, according to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria. IWCLL CR is defined as follows. The outcome is reported as the number of participants who achieve CR, PR, or SD, and number without dispersion. CR: Lymphadenopathy: none > 1.5 cm Blood lymphocytes: < 4,000/µL Hepatomegaly: none Splenomegaly: none Bone marrow: normocellular with < 30 lymphocytes, no B lymphoid nodules. PR: Lymphadenopathy: decrease ≥ 50% Blood lymphocytes: decrease ≥ 50% Hepatomegaly: decrease ≥ 50% Splenomegaly: decrease ≥ 50% Bone marrow: not considered. SD: Lymphadenopathy: change of ± 49% Blood lymphocytes: change of ± 49% Hepatomegaly: change of ± 49% Splenomegaly: change of ± 49% Bone marrow: not considered.

4. Overall Survival (OS) [Through 117 weeks]

   Overall survival (OS) represents the amount of time the participants remain alive after treatment. The outcome is reported as the number of participants remaining alive at 117 weeks (about 2 years and 3 months) after the start of treatment, a number without dispersion.

5. Progression-free Survival (PFS) [117 weeks]

   Progression-free survival (PFS) is a term that means to remain alive with progressive disease (PD). PD is defined as Lymphadenopathy: Increase ≥ 50% Blood lymphocytes: Increase ≥ 50% Hepatomegaly: Increase ≥ 50% Splenomegaly: Increase ≥ 50% Bone marrow: not considered. The outcome is reported as the number of participants who remained alive without PD 117 weeks after the beginning of treatment.

6. Time-to-progression (TTP) [Through 117 weeks]

   Time-to-progression (TTP) is a measure of the length of time from the beginning of treatment until progressive disease (PD). PD is defined as Lymphadenopathy: Increase ≥ 50% Blood lymphocytes: Increase ≥ 50% Hepatomegaly: Increase ≥ 50% Splenomegaly: Increase ≥ 50% Bone marrow: not considered. The outcome will be reported as the median TTP as determined by Kaplan-Meier methodology, with 95% confidence interval (95% CI).

Other Outcome Measures

1. Time-to-next-treatment (TTNT) [Through 117 weeks]

   The time-to-next-treatment (TTNT) is a measure of the period of time from the beginning of treatment until the patient has to receive a different treatment for his/her disease. TTNT was assessed as the time period until the participants next anti-chronic lymphocytic leukemia (CLL) treatment. The outcome will be reported as the median TTNT as determined by Kaplan-Meier methodology, with 95% confidence interval (95% CI).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subject must voluntarily sign and date an informed consent approved by the Institutional Review Board prior to initiation of any study specific procedures

• Subject must have a diagnosis of CLL that meets International Workshop on Chronic Lymphocytic Leukemia (IWCLL)/National Cancer Institute (NCI)-Working Group (WG) criteria

• Subject must have relapsed/refractory disease with an indication for treatment according to the 2008 IWCLL/NCI WG criteria

• Measurable nodal disease by computed tomography (CT)

• Absolute neutrophil count > 750 cells/mm^{3 (0.75 x 10}9/L)

• Platelet count > 30,000 cells/mm^{3 (30 x 10}9/L)

• Hemoglobin > 8.0 g/dL

• Serum aspartate transaminase (AST) or alanine transaminase (ALT) =< 2.5 x upper limit of normal (ULN)

• Estimated creatinine clearance >= 30 mL/min (Cockcroft-Gault)

• Bilirubin =< 1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin)

• Prothrombin time/international normalized ratio (PT/INR) < 1.5 x ULN and partial thromboplastin time (PTT) (activated [a]PTT) < 1.5 x ULN

• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

• Female subjects who are of non-reproductive potential (ie, post-menopausal by history

• no menses for >= 1 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy); female subjects of childbearing potential must have a negative serum pregnancy test upon study entry

• Male and female subjects must agree to use highly effective methods of birth control (eg, condoms, implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], sexual abstinence, or sterilized partner) during the period of therapy and for 90 days after the last dose of study drug

Exclusion Criteria:

• Subject has previously received either venetoclax or ibrutinib

• Subject has received a live virus vaccine within 28 days prior to the initiation of study treatment

• Subject has undergone an allogeneic stem cell transplant in the past 1 year and must not have active chronic graft versus host disease (cGVHD) if over 1 year post allogeneic transplant

• Subject has developed Richter's transformation confirmed by biopsy

• Chemotherapy =< 21 days prior to first administration of study treatment and/or monoclonal antibody =< 6 weeks prior to first administration of study treatment

• History of other malignancies, except:

• 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

• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease

• Adequately treated carcinoma in situ without evidence of disease

• Concurrent systemic immunosuppressant therapy (eg, cyclosporine A, tacrolimus, etc, or chronic administration [> 14 days] of > 20 mg/day of prednisone) within 28 days of the first dose of study drug

• Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug

• Recent infection requiring systemic treatment that was completed =< 14 days before the first dose of study drug

• Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to Common Terminology Criteria for Adverse Event (CTCAE, version [v]4), grade =< 1, or to the levels dictated in the inclusion/exclusion criteria with the exception of alopecia

• Known bleeding disorders (eg, von Willebrand's disease) or hemophilia

• History of stroke or intracranial hemorrhage within 6 months prior to enrollment

• Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus (HCV) or hepatitis B virus (HBV); subjects who are positive for hepatitis B core antibody or hepatitis B surface antigen must have a negative polymerase chain reaction (PCR) result before enrollment; those who are PCR positive will be excluded

• Any uncontrolled active systemic infection

• Major surgery within 4 weeks of first dose of study drug

• Any life threatening illness, medical condition, or organ system dysfunction that, in the investigator's opinion, could compromise the subject's safety or put the study outcomes at undue risk

• Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization

• Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction

• Concomitant use of warfarin or other vitamin K antagonists

• Requires treatment with a strong cytochrome P450 (CYP) 3A4/5 inhibitor

• Lactating or pregnant

• Unwilling or unable to participate in all required study evaluations and procedures

• Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form (ICF) and authorization to use protected health information (in accordance with national and local subject privacy regulations)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope	Duarte	California	United States	91010
2	Stanford University, School of Medicine	Stanford	California	United States	94305

Sponsors and Collaborators

• Steven E. Coutre

Investigators

• Principal Investigator: Steven Coutre, Stanford University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 27, 2020
• Informed Consent Form - Nov 14, 2018

More Information

Publications

None provided.

• Responsible Party: Steven E. Coutre, Professor of Medicine, Stanford University
• ClinicalTrials.gov Identifier: NCT03045328
• Other Study ID Numbers: IRB-36705; NCI-2017-00124; HEM0048
• First Posted: Feb 7, 2017
• Last Update Posted: Sep 29, 2021
• Last Verified: Sep 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Lymphoma; Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Recurrence; Venetoclax

Study Results

Participant Flow

Arm/Group Title	Treatment (Ibrutinib, Venetoclax)
Arm/Group Description	Patients receive ibrutinib PO QD beginning on week 1 day 1. Treatment with ibrutinib continues in the absence of disease progression or unacceptable toxicity. Patients also receive venetoclax PO QD beginning on week 9 day 1. Treatment with venetoclax continues up to week 61 day 7 in the absence of disease progression or unacceptable toxicity. Ibrutinib: Administered at 420 mg/day, as oral capsules (3 x 140 mg), starting Day 1, Week 1. Venetoclax: Administered as tablets, starting Day 1, Week 9, with dose increasing every 7 days through 5 dose levels (20 mg; 50 mg; 100 mg; 200 mg; 400 mg).
Period Title: Overall Study
STARTED	22
COMPLETED	20
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Treatment (Ibrutinib, Venetoclax)
Arm/Group Description	Patients receive ibrutinib PO QD beginning on week 1 day 1. Treatment with ibrutinib continues in the absence of disease progression or unacceptable toxicity. Patients also receive venetoclax PO QD beginning on week 9 day 1. Treatment with venetoclax continues up to week 61 day 7 in the absence of disease progression or unacceptable toxicity. Ibrutinib: Administered at 420 mg/day, as oral capsules (3 x 140 mg), starting Day 1, Week 1. Venetoclax: Administered as tablets, starting Day 1, Week 9, with dose increasing every 7 days through 5 dose levels (20 mg; 50 mg; 100 mg; 200 mg; 400 mg).
Overall Participants	22
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	8 36.4%
>=65 years	14 63.6%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65.3 (9.16)
Sex: Female, Male (Count of Participants)
Female	9 40.9%
Male	13 59.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	22 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	2 9.1%
White	19 86.4%
More than one race	1 4.5%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	22 100%

Outcome Measures

1. Primary Outcome

Title	Complete Response (CR)
Description	Complete Response (CR) will be assessed as the number of participants who, based on investigator assessment based on the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria, achieve a complete remission. IWCLL complete remission is defined as follows. Lymphadenopathy: none > 1.5 cm Blood lymphocytes: < 4,000/µL Hepatomegaly: none Splenomegaly: none Bone marrow: normocellular with < 30 lymphocytes, no B lymphoid nodules. The outcome is reported as the number of participants who achieve CR, a number without dispersion.
Time Frame	62 weeks

Outcome Measure Data

Analysis Population Description

Some participants withdrew consent before the assessment.

Arm/Group Title	Treatment (Ibrutinib, Venetoclax)
Arm/Group Description	Patients receive ibrutinib PO QD beginning on week 1 day 1. Treatment with ibrutinib continues in the absence of disease progression or unacceptable toxicity. Patients also receive venetoclax PO QD beginning on week 9 day 1. Treatment with venetoclax continues up to week 61 day 7 in the absence of disease progression or unacceptable toxicity. Ibrutinib: Administered at 420 mg/day, as oral capsules (3 x 140 mg), starting Day 1, Week 1. Venetoclax: Administered as tablets, starting Day 1, Week 9, with dose increasing every 7 days through 5 dose levels (20 mg; 50 mg; 100 mg; 200 mg; 400 mg).
Measure Participants	20
Count of Participants [Participants]	12 54.5%

2. Secondary Outcome

Title	Duration of Response (DoR)
Description	Duration of response (DoR) refers to a participant maintaining clinical response after achieving either complete response (CR) or partial response (PR). The outcome is reported as the number of subjects who have maintained clinical response through 117 weeks. Response defined as the following. CR. Lymphadenopathy: none > 1.5 cm Blood lymphocytes: < 4,000/µL Hepatomegaly: none Splenomegaly: none Bone marrow: normocellular with < 30 lymphocytes, no B lymphoid nodules. PR. Lymphadenopathy: decrease ≥ 50% Blood lymphocytes: decrease ≥ 50% Hepatomegaly: decrease ≥ 50% Splenomegaly: decrease ≥ 50% Bone marrow: not considered.
Time Frame	117 weeks

Outcome Measure Data

Analysis Population Description

Some participants withdrew consent before the assessment.

Arm/Group Title	Treatment (Ibrutinib, Venetoclax)
Arm/Group Description	Patients receive ibrutinib PO QD beginning on week 1 day 1. Treatment with ibrutinib continues in the absence of disease progression or unacceptable toxicity. Patients also receive venetoclax PO QD beginning on week 9 day 1. Treatment with venetoclax continues up to week 61 day 7 in the absence of disease progression or unacceptable toxicity. Ibrutinib: Administered at 420 mg/day, as oral capsules (3 x 140 mg), starting Day 1, Week 1. Venetoclax: Administered as tablets, starting Day 1, Week 9, with dose increasing every 7 days through 5 dose levels (20 mg; 50 mg; 100 mg; 200 mg; 400 mg).
Measure Participants	17
Count of Participants [Participants]	15 68.2%

3. Secondary Outcome

Title	Minimal Residual Disease (MRD)
Description	Minimal residual disease (MRD) refers to the small numbers of leukemic cells that can remain in the participant after treatment, and may not be associated with any symptoms (remission). Although the participant may feel "healthy," the MRD is a major cause of eventual leukemic relapse. "MRD-negative" is the ideal treatment outcome. MRD negativity was defined as less than one leukemic cell per 10,000 leukocytes as assessed by bone marrow-based flow cytometry. The outcome is reported as the number of participants who were positive for MRD, or negative.
Time Frame	117 weeks

Outcome Measure Data

Analysis Population Description

Test results were not available for all participants. "Negligible" was considered as negative.

Arm/Group Title	Treatment (Ibrutinib, Venetoclax)
Arm/Group Description	Patients receive ibrutinib PO QD beginning on week 1 day 1. Treatment with ibrutinib continues in the absence of disease progression or unacceptable toxicity. Patients also receive venetoclax PO QD beginning on week 9 day 1. Treatment with venetoclax continues up to week 61 day 7 in the absence of disease progression or unacceptable toxicity. Ibrutinib: Administered at 420 mg/day, as oral capsules (3 x 140 mg), starting Day 1, Week 1. Venetoclax: Administered as tablets, starting Day 1, Week 9, with dose increasing every 7 days through 5 dose levels (20 mg; 50 mg; 100 mg; 200 mg; 400 mg).
Measure Participants	16
Minimal residual disease (MRD)-negative	13 59.1%
Minimal residual disease (MRD)-positive	3 13.6%

4. Secondary Outcome

Title	Overall Response (OR)
Description	Overall response (OR) is the overall number of subjects that begin treatment and achieve a complete response (CR); partial response (PR); or Stable Disease (SD) 62 weeks after the beginning of treatment, according to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria. IWCLL CR is defined as follows. The outcome is reported as the number of participants who achieve CR, PR, or SD, and number without dispersion. CR: Lymphadenopathy: none > 1.5 cm Blood lymphocytes: < 4,000/µL Hepatomegaly: none Splenomegaly: none Bone marrow: normocellular with < 30 lymphocytes, no B lymphoid nodules. PR: Lymphadenopathy: decrease ≥ 50% Blood lymphocytes: decrease ≥ 50% Hepatomegaly: decrease ≥ 50% Splenomegaly: decrease ≥ 50% Bone marrow: not considered. SD: Lymphadenopathy: change of ± 49% Blood lymphocytes: change of ± 49% Hepatomegaly: change of ± 49% Splenomegaly: change of ± 49% Bone marrow: not considered.
Time Frame	62 weeks

Outcome Measure Data

Analysis Population Description

Some participants withdrew before the assessment.

Arm/Group Title	Treatment (Ibrutinib, Venetoclax)
Arm/Group Description	Patients receive ibrutinib PO QD beginning on week 1 day 1. Treatment with ibrutinib continues in the absence of disease progression or unacceptable toxicity. Patients also receive venetoclax PO QD beginning on week 9 day 1. Treatment with venetoclax continues up to week 61 day 7 in the absence of disease progression or unacceptable toxicity. Ibrutinib: Administered at 420 mg/day, as oral capsules (3 x 140 mg), starting Day 1, Week 1. Venetoclax: Administered as tablets, starting Day 1, Week 9, with dose increasing every 7 days through 5 dose levels (20 mg; 50 mg; 100 mg; 200 mg; 400 mg).
Measure Participants	20
Complete Response (CR)	12 54.5%
Partial Response (PR)	8 36.4%
Stable Disease (SD)	0 0%

5. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall survival (OS) represents the amount of time the participants remain alive after treatment. The outcome is reported as the number of participants remaining alive at 117 weeks (about 2 years and 3 months) after the start of treatment, a number without dispersion.
Time Frame	Through 117 weeks

Outcome Measure Data

Analysis Population Description

Those participants who withdrew consent or were withdrawn for other medical treatments before 117 weeks are not included.

Arm/Group Title	Treatment (Ibrutinib, Venetoclax)
Arm/Group Description	Patients receive ibrutinib PO QD beginning on week 1 day 1. Treatment with ibrutinib continues in the absence of disease progression or unacceptable toxicity. Patients also receive venetoclax PO QD beginning on week 9 day 1. Treatment with venetoclax continues up to week 61 day 7 in the absence of disease progression or unacceptable toxicity. Ibrutinib: Administered at 420 mg/day, as oral capsules (3 x 140 mg), starting Day 1, Week 1. Venetoclax: Administered as tablets, starting Day 1, Week 9, with dose increasing every 7 days through 5 dose levels (20 mg; 50 mg; 100 mg; 200 mg; 400 mg).
Measure Participants	16
Count of Participants [Participants]	16 72.7%

6. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	Progression-free survival (PFS) is a term that means to remain alive with progressive disease (PD). PD is defined as Lymphadenopathy: Increase ≥ 50% Blood lymphocytes: Increase ≥ 50% Hepatomegaly: Increase ≥ 50% Splenomegaly: Increase ≥ 50% Bone marrow: not considered. The outcome is reported as the number of participants who remained alive without PD 117 weeks after the beginning of treatment.
Time Frame	117 weeks

Outcome Measure Data

Analysis Population Description

Some participants withdrew consent before the assessment.

Arm/Group Title	Treatment (Ibrutinib, Venetoclax)
Arm/Group Description	Patients receive ibrutinib PO QD beginning on week 1 day 1. Treatment with ibrutinib continues in the absence of disease progression or unacceptable toxicity. Patients also receive venetoclax PO QD beginning on week 9 day 1. Treatment with venetoclax continues up to week 61 day 7 in the absence of disease progression or unacceptable toxicity. Ibrutinib: Administered at 420 mg/day, as oral capsules (3 x 140 mg), starting Day 1, Week 1. Venetoclax: Administered as tablets, starting Day 1, Week 9, with dose increasing every 7 days through 5 dose levels (20 mg; 50 mg; 100 mg; 200 mg; 400 mg).
Measure Participants	17
Count of Participants [Participants]	15 68.2%

7. Secondary Outcome

Title	Time-to-progression (TTP)
Description	Time-to-progression (TTP) is a measure of the length of time from the beginning of treatment until progressive disease (PD). PD is defined as Lymphadenopathy: Increase ≥ 50% Blood lymphocytes: Increase ≥ 50% Hepatomegaly: Increase ≥ 50% Splenomegaly: Increase ≥ 50% Bone marrow: not considered. The outcome will be reported as the median TTP as determined by Kaplan-Meier methodology, with 95% confidence interval (95% CI).
Time Frame	Through 117 weeks

Outcome Measure Data

Analysis Population Description

An insufficient number of participants have experienced disease progression to determine a median value for that time period. This is expressed statistically as "Median Not Reached."

Arm/Group Title	Treatment (Ibrutinib, Venetoclax)
Arm/Group Description	Patients receive ibrutinib PO QD beginning on week 1 day 1. Treatment with ibrutinib continues in the absence of disease progression or unacceptable toxicity. Patients also receive venetoclax PO QD beginning on week 9 day 1. Treatment with venetoclax continues up to week 61 day 7 in the absence of disease progression or unacceptable toxicity. Ibrutinib: Administered at 420 mg/day, as oral capsules (3 x 140 mg), starting Day 1, Week 1. Venetoclax: Administered as tablets, starting Day 1, Week 9, with dose increasing every 7 days through 5 dose levels (20 mg; 50 mg; 100 mg; 200 mg; 400 mg).
Measure Participants	17
Median (95% Confidence Interval) [months]	NA

8. Other Pre-specified Outcome

Title	Time-to-next-treatment (TTNT)
Description	The time-to-next-treatment (TTNT) is a measure of the period of time from the beginning of treatment until the patient has to receive a different treatment for his/her disease. TTNT was assessed as the time period until the participants next anti-chronic lymphocytic leukemia (CLL) treatment. The outcome will be reported as the median TTNT as determined by Kaplan-Meier methodology, with 95% confidence interval (95% CI).
Time Frame	Through 117 weeks

Outcome Measure Data

Analysis Population Description

An insufficient number of participants have advanced to a next treatment to determine a median value for that time period. This is expressed statistically as "Median Not Reached."

Arm/Group Title	Treatment (Ibrutinib, Venetoclax)
Arm/Group Description	Patients receive ibrutinib PO QD beginning on week 1 day 1. Treatment with ibrutinib continues in the absence of disease progression or unacceptable toxicity. Patients also receive venetoclax PO QD beginning on week 9 day 1. Treatment with venetoclax continues up to week 61 day 7 in the absence of disease progression or unacceptable toxicity. Ibrutinib: Administered at 420 mg/day, as oral capsules (3 x 140 mg), starting Day 1, Week 1. Venetoclax: Administered as tablets, starting Day 1, Week 9, with dose increasing every 7 days through 5 dose levels (20 mg; 50 mg; 100 mg; 200 mg; 400 mg).
Measure Participants	17
Median (95% Confidence Interval) [months]	NA

Adverse Events

Time Frame	117 weeks
Arm/Group Title	Treatment (Ibrutinib, Venetoclax)
Arm/Group Description	Patients receive ibrutinib PO QD beginning on week 1 day 1. Treatment with ibrutinib continues in the absence of disease progression or unacceptable toxicity. Patients also receive venetoclax PO QD beginning on week 9 day 1. Treatment with venetoclax continues up to week 61 day 7 in the absence of disease progression or unacceptable toxicity. Ibrutinib: Administered at 420 mg/day, as oral capsules (3 x 140 mg), starting Day 1, Week 1. Venetoclax: Administered as tablets, starting Day 1, Week 9, with dose increasing every 7 days through 5 dose levels (20 mg; 50 mg; 100 mg; 200 mg; 400 mg).
All Cause Mortality
	Treatment (Ibrutinib, Venetoclax)
	Affected / at Risk (%)	# Events
Total	0/22 (0%)
Serious Adverse Events
	Treatment (Ibrutinib, Venetoclax)
	Affected / at Risk (%)	# Events
Total	10/22 (45.5%)
Blood and lymphatic system disorders
Febrile Neutropenia	1/22 (4.5%)	1
Anemia	1/22 (4.5%)	1
Cardiac disorders
Acute heart failure	1/22 (4.5%)	1
Aortic valve disease; Critical Stenosis	1/22 (4.5%)	1
Atrial fibrillation	1/22 (4.5%)	1
Ear and labyrinth disorders
Mastoiditis	1/22 (4.5%)	1
Gastrointestinal disorders
Diarrhea	1/22 (4.5%)	1
Infections and infestations
Sepsis	2/22 (9.1%)	2
Injury, poisoning and procedural complications
Fracture Skull	1/22 (4.5%)	1
Injury, poisoning and procedural complications - Other, Prostatectomy Pros	1/22 (4.5%)	1
Metabolism and nutrition disorders
Tumor lysis syndrome	1/22 (4.5%)	1
Dehydration	1/22 (4.5%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) -Other Hodgkins Lymphoma	1/22 (4.5%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps) -Other Squamous cell Carcinoma	1/22 (4.5%)	1
Renal and urinary disorders
Chronic Kidney Disease	1/22 (4.5%)	1
Respiratory, thoracic and mediastinal disorders
Aspiration	3/22 (13.6%)	3
Skin and subcutaneous tissue disorders
Cellulitis	1/22 (4.5%)	1
Vascular disorders
Hematoma	1/22 (4.5%)	1
Thromboembolic event	1/22 (4.5%)	1
Other (Not Including Serious) Adverse Events
	Treatment (Ibrutinib, Venetoclax)
	Affected / at Risk (%)	# Events
Total	22/22 (100%)
Blood and lymphatic system disorders
Anemia	18/22 (81.8%)	45
Leukocytosis	13/22 (59.1%)	16
Febrile neutropenia	3/22 (13.6%)	3
Cardiac disorders
Heart failure	1/22 (4.5%)	1
Cardiac disorders-Other, ablation	1/22 (4.5%)	1
Bradycardia	1/22 (4.5%)	1
Aortic valve disease; Critical Stenosis	1/22 (4.5%)	1
Ear and labyrinth disorders
Middle ear inflammation	1/22 (4.5%)	1
Hearing impaired	1/22 (4.5%)	1
Ear and labyrinth disorders-Others, Tympanomastoidectomy	1/22 (4.5%)	1
Eye disorders
Eye disorders-Other, Bilateral optic neuropathy	1/22 (4.5%)	1
Glaucoma	1/22 (4.5%)	1
Eye disorders-Other, cataracts, bilateral surgery	3/22 (13.6%)	3
Blurred vision	1/22 (4.5%)	1
Gastrointestinal disorders
Diarrhea	17/22 (77.3%)	26
Nausea	11/22 (50%)	14
Gastroesophageal reflux disease	7/22 (31.8%)	8
Constipation	4/22 (18.2%)	4
Mucositis oral	4/22 (18.2%)	4
Gastrointestinal disorders-others, upper gastrointestinal bleeding	1/22 (4.5%)	1
Vomiting	1/22 (4.5%)	1
Dry mouth	1/22 (4.5%)	1
Gastrointestinal disorders-others, Oral stomatitis	1/22 (4.5%)	1
Fatigue	10/22 (45.5%)	12
Fever	3/22 (13.6%)	3
General disorders
Edema limbs	8/22 (36.4%)	8
Infections and infestations
Upper respiratory infection	9/22 (40.9%)	11
Sinusitis	2/22 (9.1%)	2
Sepsis	2/22 (9.1%)	2
Infections and Infestations, other, HSV	1/22 (4.5%)	1
Paronychia	1/22 (4.5%)	1
Injury, poisoning and procedural complications
Bruising	13/22 (59.1%)	13
Investigations
Neutrophil count decreased	19/22 (86.4%)	47
Lymphocyte count decreased	8/22 (36.4%)	8
Investigations - Other, Absolute monocyte	3/22 (13.6%)	6
Investigations - Other, Phosphorous level elevated	1/22 (4.5%)	1
White blood cell decreased	20/22 (90.9%)	41
Platelet count decreased	18/22 (81.8%)	33
Creatinine increased	6/22 (27.3%)	7
Investigations. Other Lactate dehydrogenase increase	2/22 (9.1%)	2
Blood bilirubin increased	3/22 (13.6%)	5
Metabolism and nutrition disorders
Hypocalcemia	10/22 (45.5%)	18
Hypoalbuminemia	7/22 (31.8%)	18
Hyperphosphatemia	9/22 (40.9%)	9
Hypernatremia	2/22 (9.1%)	2
Hyponatremia	1/22 (4.5%)	1
Hyperkalemia	1/22 (4.5%)	1
Metabolism and Nutrition disorders-Others. Hypogammaglobulinemia	5/22 (22.7%)	9
Hyperuricemia	1/22 (4.5%)	1
Musculoskeletal and connective tissue disorders
Arthalgia	4/22 (18.2%)	4
Myalgia	3/22 (13.6%)	4
Back pain	1/22 (4.5%)	1
Musculoskeletal and Connective Tissue Disorders, Other, Varicose veins	1/22 (4.5%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)-Others prostate cancer	2/22 (9.1%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)-Others, Lentigo melanoma	1/22 (4.5%)	1
Nervous system disorders
Peripheral Neuropathy	1/22 (4.5%)	1
Headache	2/22 (9.1%)	2
Paresthesia	1/22 (4.5%)	1
Psychiatric disorders
Insomnia	3/22 (13.6%)	3
Anxiety	1/22 (4.5%)	1
Renal and urinary disorders
Acute kidney Injury	2/22 (9.1%)	2
Chronic kidney disease	1/22 (4.5%)	1
Urinary tract infection	1/22 (4.5%)	1
Respiratory, thoracic and mediastinal disorders
Aspiration	2/22 (9.1%)	2
Nasal congestion	5/22 (22.7%)	5
Dyspnea	3/22 (13.6%)	3
Epistaxis	1/22 (4.5%)	1
Allergic rhinitis	1/22 (4.5%)	1
Cough	1/22 (4.5%)	1
Skin and subcutaneous tissue disorders
Pruritis	5/22 (22.7%)	6
Rash	5/22 (22.7%)	6
Bullous dermatitis	4/22 (18.2%)	4
Skin and Subcutaneous Tissue Disorders-Other, Cellulitis	2/22 (9.1%)	2
Skin hyperpigmentation	1/22 (4.5%)	1
Skin and Subcutaneous Tissue Disorders-Other, subcutaneous tissue disorder	1/22 (4.5%)	1
Skin and Subcutaneous Tissue Disorders-Other, Rosacea	1/22 (4.5%)	1
Skin and Subcutaneous Tissue Disorders-Other, Eczema	1/22 (4.5%)	1
Vascular disorders
Hypertension	5/22 (22.7%)	8
Chest pain	2/22 (9.1%)	2
Hypotension	1/22 (4.5%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.