VENICE I: A Study to Evaluate the Efficacy of Venetoclax in Relapsed/Refractory Participants With Chronic Lymphocytic Leukemia (CLL) Including Those With 17p Deletion or TP53 Mutation or Those Who Have Received a Prior B-cell Receptor Inhibitor

• Sponsor: AbbVie (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02756611
• Collaborator: (none)
• Enrollment: 258
• Locations: 67
• Arm: 1
• Actual Duration (Months): 68.8
• Patients Per Site: 3.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy of venetoclax monotherapy in participants with relapsed/refractory CLL including those with the 17p deletion or TP53 mutation OR those who have received prior treatment with a B-cell receptor inhibitor.

Condition or Disease	Intervention/Treatment	Phase
Chronic Lymphocytic Leukemia	Drug: Venetoclax	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 258 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Open-Label, Single Arm, Phase 3b, Multi-Center Study Evaluating the Efficacy of Venetoclax (ABT 199) in Relapsed/Refractory Subjects With Chronic Lymphocytic Leukemia (CLL)
• Actual Study Start Date: Jun 22, 2016
• Actual Primary Completion Date: Apr 10, 2019
• Actual Study Completion Date: Mar 17, 2022

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Venetoclax Venetoclax will be administered orally once daily (QD) beginning with a dose-titration phase. The initial venetoclax dose is 20 mg QD. After 1 week of treatment at 20 mg QD, the dose will be escalated to 50 mg QD followed by subsequent increases, each after 1 week, to 100 mg QD, 200 mg QD and the maximum dose of 400 mg QD. Participants may continue to receive venetoclax for up to 2 years provided they continue to tolerate the drug, have no evidence of disease progression (based on investigator's assessment), do not have unacceptable toxicity, and do not meet any of the criteria for discontinuation. In countries where venetoclax is not commercially available, participants who continue to derive benefit after 2 years of treatment may be able to extend their treatment for up to 2 additional years, determined on a case by case basis.

Drug: Venetoclax; Tablets for oral administration; Other Names: ABT-199 VENCLEXTA®

Outcome Measures

Primary Outcome Measures

1. Complete Remission Rate in Participants Not Previously Treated With BCRi Therapy [From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months.]

   Complete remission rate is defined as the percentage of participants achieving a complete remission (CR) or complete remission with incomplete marrow recovery (CRi) as their best response assessed by the investigator based on 2008 Modified International Workshop for Chronic Lymphocytic Leukemia National Cancer Institute-Working Group (IWCLL NCI-WG) criteria. CR required all of the following: Peripheral blood lymphocytes <4000/μL Absence of lymphadenopathy by physical examination and computed tomography scan No hepatomegaly or splenomegaly by physical examination Absence of disease or constitutional symptoms (unexplained fevers >38°C, drenching night sweats, >10% weight loss in last 6 months) Blood counts above the following: Neutrophils >1500/μL Platelets >100,000/μL Hemoglobin >110 g/L Bone marrow at least normocellular for age, <30% lymphocytes CRi was defined as participants with CR who had persistent cytopenia unrelated to CLL but related to drug toxicity.

Secondary Outcome Measures

1. Complete Remission Rate in Participants Previously Treated With BCRi Therapy [From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months.]

   Complete remission rate is defined as the percentage of participants achieving a complete remission (CR) or complete remission with incomplete marrow recovery (CRi) as their best response assessed by the investigator based on 2008 Modified International Workshop for Chronic Lymphocytic Leukemia National Cancer Institute-Working Group (IWCLL NCI-WG) criteria. CR required all of the following: Peripheral blood lymphocytes <4000/μL Absence of lymphadenopathy by physical examination and computed tomography scan No hepatomegaly or splenomegaly by physical examination Absence of disease or constitutional symptoms (unexplained fevers >38°C, drenching night sweats, >10% weight loss in last 6 months) Blood counts above the following: Neutrophils >1500/μL Platelets >100,000/μL Hemoglobin >110 g/L Bone marrow at least normocellular for age, <30% lymphocytes CRi was defined as participants with CR who had persistent cytopenia unrelated to CLL but related to drug toxicity.

2. Overall Response Rate (ORR) [From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months.]

   Overall response rate was defined as the percentage of participants with an overall best response of CR, CRi, nodular partial remission (nPR), or confirmed partial remission (PR) based on the 2008 Modified IWCLL NCI-WG criteria as assessed by investigator. CR and CRi are defined above. nPR is defined as participants with CR but for whom bone marrow nodules could be identified histologically. For PR at least 2 of the following must be met: ≥ 50% decrease in peripheral blood lymphocyte count from the pretreatment baseline value ≥ 50% reduction in lymphadenopathy ≥ 50% reduction in the size of the liver and/or spleen (if abnormal prior to therapy) and at least one of the following criteria must be met: Neutrophils > 1,500/μL or ≥ 50% improvement over baseline Platelets > 100,000/μL or ≥ 50% improvement over baseline Hemoglobin > 11.0 g/dL or ≥ 50% improvement over baseline without transfusions or exogenous growth factors. PR must be confirmed at least 7 weeks later.

3. Duration of Overall Response (DoR) [From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months.]

   Duration of response is defined as the time from the date of first response (CR, CRi, nPR, or PR) to the earliest date that progressive disease (PD) is objectively documented (radiographic or clinical) or death. Duration of response was analyzed by Kaplan-Meier (K-M) methodology. If a participant was still responding their data was censored at the date of the last available disease assessment prior to the data cutoff date.

4. Time to Progression (TTP) [From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months.]

   Time to progression is defined as the time from the date of first dose of venetoclax to the date of earliest PD (radiographic or clinical). Participants who did not experience disease progression were censored at the date of the last available disease assessment prior to the data cutoff date; participants with no post-baseline disease assessments were censored at the first dose date plus 1 day. Time to progression was estimated using Kaplan-Meier methodology.

5. Progression-Free Survival (PFS) [From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months.]

   Progression-free survival (PFS) was defined as the time from the date of first dose of venetoclax to the date of earliest PD (radiographic or clinical) or death. Participants who did not experience disease progression or death were censored at the date of the last available disease assessment prior to the data cutoff date; participants with no post-baseline tumor assessment or clinical assessment for progression, were censored at the date of first dose plus 1 day. Progression-free survival was analyzed by Kaplan-Meier methodology.

6. Overall Survival (OS) [From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months.]

   Overall survival (time to death) will be defined as the number of days from the first dose date of venetoclax to the date of death. If a participant had not died their data were censored at the date when they were last known to be alive prior to the cutoff date. Overall survival was analyzed using Kaplan-Meier methodology.

7. Functional Assessment of Cancer Therapy - Leukemia Questionnaire (FACT-Leu) [Measured up to approximately 3 years after the last participant has enrolled into the study.]

   The FACT-Leu is a 44-item, leukemia-specific questionnaire designed to assess patient health-related quality of life (HRQoL) and leukemia-specific symptoms.

8. Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT-F) [Measured up to approximately 3 years after the last participant has enrolled into the study.]

   The FACIT-F questionnaire measures fatigue and its effect on functioning and daily activities. The FACIT-F has 13 items answered on a 5-point rating scale based on a 7-day recall period.

9. EuroQoL 5 Dimension 5 Level Questionnaire (EQ-5D-5L) [Measured up to approximately 3 years after the last participant has enrolled into the study.]

   Five items in the EQ-5D-5L questionnaire (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) are rated on 5 levels of severity.

Other Outcome Measures

1. Minimal Residual Disease (MRD) Negativity Rate [From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months.]

   The MRD negativity rate is defined as the percentage of participants who had MRD negative status with less than one CLL cell per 10,000 leukocytes (< 10-⁴) in peripheral blood and bone marrow. MRD was evaluated using next-generation sequencing. Per protocol, peripheral blood MRD assessments were to be collected from all participants at Week 24 and Week 48 and at the time the bone marrow assessment for confirmation of CR/CRi, and bone marrow (BM) MRD assessments were to be collected for participants undergoing a bone marrow procedure for confirmation of CR/CRi. Participants with no blood or BM MRD assessments were included in the calculation of MRD negativity rate as not having MRD negative status.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 99 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Participant has Eastern Cooperative Oncology Group (ECOG) performance score of less than or equal to 2

• Participant has relapsed/refractory disease (received at least 1 prior therapy)

• Participant has diagnosis of CLL that meets published 2008 Modified International Workshop for Chronic Lymphocytic Leukemia National Cancer Institute Working Group (IWCLL NCI-WG) Guidelines and:

• has an indication for treatment according to the 2008 Modified IWCLL NCI-WG criteria

• has clinically measurable disease (lymphocytosis greater than 5 × 10^9/L and/or palpable and measurable nodes by physical exam and/or organomegaly assessed by physical exam)

• In addition, participants:

• with or without 17p deletion or TP53 mutation, assessed by a local laboratory in bone marrow or peripheral blood AND/OR

• may have been previously treated with a prior B-cell receptor inhibitor

• Participant must have adequate bone marrow function, coagulation profile, renal, and hepatic function, per laboratory reference range at Screening

Exclusion Criteria:

• Participant has developed Richter's transformation or Prolymphocytic leukemia

• Participant has previously received venetoclax

• History of active malignancies other than CLL within the past 2 years prior to first dose of venetoclax, with the exception of:

• adequately treated in situ carcinoma of the cervix uteri

• adequately treated basal cell carcinoma or localized squamous cell carcinoma of the skin

• previous malignancy confined and surgically resected (or treated with other modalities) with curative intent

• Participant has active and uncontrolled autoimmune cytopenias (for 2 weeks prior to Screening), including autoimmune hemolytic anemia and idiopathic thrombocytopenic purpura despite low dose corticosteroids

• Participant has undergone an allogeneic stem cell transplant

• Treatment with any of the following within five half-lives or 14 days (if half-life unknown) as applicable prior to the first dose of venetoclax, or clinically significant adverse effect(s)/toxicity(s) of the previous therapy have not resolved to < National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 Grade 2:

• Any anti-cancer therapy including chemotherapy, or radiotherapy;

• Investigational therapy, including targeted small molecule agents

• Participant is human immunodeficiency virus (HIV) positive

• Participant has known allergy to both xanthine oxidase inhibitors and rasburicase

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Norton Cancer Institute /ID# 149788	Louisville	Kentucky	United States	40202-3700
2	St. Agnes Cancer Center /ID# 149782	Baltimore	Maryland	United States	21229
3	Hackensack Univ Med Ctr /ID# 151574	Hackensack	New Jersey	United States	07601
4	Utah Cancer Specialists /ID# 151604	Salt Lake City	Utah	United States	84106
5	Cancer Care Northwest /ID# 151605	Spokane	Washington	United States	99202
6	West Virginia Univ School Med /ID# 151602	Morgantown	West Virginia	United States	26506
7	LKH-Univ. Klinikum Graz /ID# 147547	Graz		Austria	8036
8	LKH Salzburg and Paracelsus /ID# 147549	Salzburg		Austria	5020
9	Hanusch Krankenhaus der WGKK /ID# 147548	Wien		Austria	1140
10	Cliniques Universitaires Saint Luc /ID# 147388	Woluwe-Saint-Lambert	Bruxelles-Capitale	Belgium	1200
11	UZ Leuven /ID# 147387	Leuven		Belgium	3000
12	BC Cancer Agency /ID# 153091	Vancouver	British Columbia	Canada	V5Z 1L3
13	Qe Ii Hsc /Id# 147460	Halifax	Nova Scotia	Canada	B3H 1V7
14	Juravinski Cancer Clinic /ID# 149152	Hamilton	Ontario	Canada	L8V 1C3
15	Sunnybrook Health Sciences Ctr /ID# 147462	Toronto	Ontario	Canada	M4N 3M5
16	CHU de Quebec-Universite Laval /ID# 150299	Quebec City	Quebec	Canada	G1R 2J6
17	Herlev Hospital /ID# 150183	Herlev	Hovedstaden	Denmark	2730
18	Aarhus University Hospital /ID# 147409	Aarhus N	Midtjylland	Denmark	8200
19	Turku University Hospital /ID# 147551	Turku		Finland	20520
20	CHU Dupuytren /ID# 147552	Limoges CEDEX 1	Franche-Comte	France	87042
21	CHU de la miletrie /ID# 147484	Poitiers	Poitou-Charentes	France	86021
22	Institut Bergonie /ID# 147482	Bordeaux		France	33076
23	CHRU de Brest - Hopital Morvan /ID# 147485	Brest		France	29200
24	clinique Sainte Anne /ID# 147556	Strasbourg		France	67085
25	Onkologische Schwerpunktpraxis /ID# 147516	Berlin		Germany	10707
26	Cent fuer Haematologie und Onk /ID# 147511	Frankfurt		Germany	60389
27	OncoResearch Lerchenfeld GmbH /ID# 164044	Hamburg		Germany	22081
28	Mannheimer Onkologiepraxis /ID# 147512	Mannheim		Germany	68161
29	Staedt. Klinikum Schwabing /ID# 147510	Munich		Germany	80804
30	General Hospital of Athens Laiko /ID# 147517	Athens	Attiki	Greece	115 27
31	G. Papanikolaou Hospital /ID# 147518	Thessaloniki		Greece	57010
32	St. James's Hospital /ID# 147519	Dublin 8	Dublin	Ireland	D08 E9P6
33	Beaumont Hospital /ID# 147522	Dublin		Ireland	D09 XR63
34	Tel Aviv Sourasky Medical Ctr /ID# 151624	Tel Aviv-Yafo	Tel-Aviv	Israel	6423906
35	Galilee Medical Center /ID# 159971	Nahariya		Israel	22100
36	Sheba Medical Center /ID# 147509	Ramat Gan		Israel	5262100
37	A.O.U. Policlinico S.Orsola-Malpighi /ID# 147505	Bologna	Emilia-Romagna	Italy	40138
38	AP Romano Umberto I /ID# 147500	Rome	Lazio	Italy	00161
39	ASST Grande Ospedale Metropolitano Niguarda /ID# 147503	Milano	Lombardia	Italy	20162
40	Ospedale San Raffaele IRCCS /ID# 147504	Milan		Italy	20132
41	AO Maggiore della Carita /ID# 147499	Novara		Italy	28100
42	Academisch Medisch Centrum /ID# 147494	Amsterdam	Noord-Holland	Netherlands	1105 AZ
43	Albert Schweitzer Ziekenhuis /ID# 147495	Dordrecht	Zuid-Holland	Netherlands	3318 AT
44	Haukeland University Hospital /ID# 147382	Bergen	Hordaland	Norway	5021
45	Rikshospitalet OUS HF /ID# 201812	Oslo		Norway	0450
46	IPO Lisboa FG, EPE /ID# 147385	Lisboa		Portugal	1099-023
47	IPO Porto FG, EPE /ID# 147389	Porto		Portugal	4200-072
48	Puerto Rico Hematology Oncolog /ID# 150003	San Juan		Puerto Rico	00959
49	Hospital Santa Creu i Sant Pau /ID# 151230	Barcelona		Spain	08026
50	Fundacion Jimenez Diaz /ID# 151231	Madrid		Spain	28040
51	Hosp Univ Puerta de Hierro /ID# 147391	Majadahonda		Spain	28222
52	Hospital Clinico Univ de Salamanca /ID# 147392	Salamanca		Spain	37007
53	Hosp Clin Univ de Valencia /ID# 147396	València		Spain	46010
54	Skanes Universitetssjukhus Lund /ID# 147439	Lund	Skane Lan	Sweden	222 41
55	Akademiska Sjukhuset /ID# 150184	Uppsala	Uppsala Lan	Sweden	751 85
56	Hopitaux Universitaires de Geneve /ID# 147930	Genève	Geneve	Switzerland	1205
57	University Hospital Zurich /ID# 157910	Zurich	Zuerich	Switzerland	8006
58	Ospedale Regional Bellinzona e /ID# 151232	Bellinzona		Switzerland	6501
59	Ankara Univ Medical Faculty /ID# 147443	Ankara		Turkey	6100
60	Istanbul University Istanbul Medical Faculty /ID# 156040	Istanbul		Turkey	34093
61	Vehbi Koc vakfi Amerikan Hasta /ID# 147325	Istanbul		Turkey	34365
62	Dokuz Eylul University /ID# 147442	Izmir		Turkey	35340
63	Ondokuz mayis University Facul /ID# 147326	Samsun		Turkey	55139
64	Blackpool Teaching Hosp NHS /ID# 149581	Blackpool		United Kingdom	FY3 8NR
65	Univ Hosp Bristol NHS Foundati /ID# 147647	Bristol		United Kingdom	BS2 8EG
66	Southampton General Hospital /ID# 147646	Southampton		United Kingdom	SO16 6YD
67	The Royal Wolverhampton NHS Tr /ID# 147945	Wolverhampton		United Kingdom	WV10 0QP

Sponsors and Collaborators

• AbbVie

Investigators

• Study Director: AbbVie Inc., AbbVie

Study Documents (Full-Text)

• Study Protocol - Jun 6, 2018
• Statistical Analysis Plan - Dec 20, 2018

More Information

Publications

None provided.

• Responsible Party: AbbVie
• ClinicalTrials.gov Identifier: NCT02756611
• Other Study ID Numbers: M15-550; 2015-003667-11
• First Posted: Apr 29, 2016
• Last Update Posted: Apr 12, 2022
• Last Verified: Mar 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by AbbVie: Oncology; Chronic Lymphocytic Leukemia; 17p Deletion; TP53 Mutation; Relapsed; Refractory; B-Cell receptor inhibitor
• Additional relevant MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Venetoclax

Study Results

Participant Flow

Recruitment Details	Participants were enrolled at 59 sites in 19 countries. This study is currently ongoing. Results are reported up to the primary analysis data cut-off date of 30 June 2019, which occurred after all participants completed the Week 48 disease assessment.

Arm/Group Title	Venetoclax
Arm/Group Description	Participants received venetoclax on a once daily (QD) dosing schedule for up to 108 weeks. The starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg.
Period Title: Overall Study
STARTED	258
COMPLETED	2
NOT COMPLETED	256

Baseline Characteristics

Arm/Group Title	Venetoclax
Arm/Group Description	Participants received venetoclax on a once daily (QD) dosing schedule for up to 108 weeks. The starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg.
Overall Participants	258
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	67.7 (9.04)
Age, Customized (Count of Participants)
< 65 years	94 36.4%
>= 65 years	164 63.6%
Sex: Female, Male (Count of Participants)
Female	78 30.2%
Male	180 69.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	9 3.5%
Not Hispanic or Latino	248 96.1%
Unknown or Not Reported	1 0.4%
Race/Ethnicity, Customized (Count of Participants)
White	252 97.7%
Black or African American	3 1.2%
Asian	2 0.8%
Missing	1 0.4%
Geographic Region (Count of Participants)
Europe	161 62.4%
North America	28 10.9%
Rest of the World	69 26.7%
Prior Treatment With B-cell Receptor Inhibitor (BCRi) (Count of Participants)
BCRi-naive	191 74%
BCRi-exposed	67 26%

Outcome Measures

1. Primary Outcome

Title	Complete Remission Rate in Participants Not Previously Treated With BCRi Therapy
Description	Complete remission rate is defined as the percentage of participants achieving a complete remission (CR) or complete remission with incomplete marrow recovery (CRi) as their best response assessed by the investigator based on 2008 Modified International Workshop for Chronic Lymphocytic Leukemia National Cancer Institute-Working Group (IWCLL NCI-WG) criteria. CR required all of the following: Peripheral blood lymphocytes <4000/μL Absence of lymphadenopathy by physical examination and computed tomography scan No hepatomegaly or splenomegaly by physical examination Absence of disease or constitutional symptoms (unexplained fevers >38°C, drenching night sweats, >10% weight loss in last 6 months) Blood counts above the following: Neutrophils >1500/μL Platelets >100,000/μL Hemoglobin >110 g/L Bone marrow at least normocellular for age, <30% lymphocytes CRi was defined as participants with CR who had persistent cytopenia unrelated to CLL but related to drug toxicity.
Time Frame	From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months.

Outcome Measure Data

Analysis Population Description

All enrolled participants treated with at least one dose of venetoclax who had not previously received treatment with BCRi

Arm/Group Title	Venetoclax
Arm/Group Description	Participants received venetoclax on a once daily (QD) dosing schedule for up to 108 weeks. The starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg.
Measure Participants	191
Number (95% Confidence Interval) [percentage of participants]	35.1 13.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Venetoclax
	Comments	The null hypothesis stated that the CR rate for BCRi-naïve participants would be ≤ 6%, based on the CR rate reported for current therapies at the time the study was designed, with an alternative hypothesis that the CR rate would be > 6%. If the p-value for this test was < 0.025, the null hypothesis would be rejected.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Binomial test
	Comments

2. Secondary Outcome

Title	Complete Remission Rate in Participants Previously Treated With BCRi Therapy
Description	Complete remission rate is defined as the percentage of participants achieving a complete remission (CR) or complete remission with incomplete marrow recovery (CRi) as their best response assessed by the investigator based on 2008 Modified International Workshop for Chronic Lymphocytic Leukemia National Cancer Institute-Working Group (IWCLL NCI-WG) criteria. CR required all of the following: Peripheral blood lymphocytes <4000/μL Absence of lymphadenopathy by physical examination and computed tomography scan No hepatomegaly or splenomegaly by physical examination Absence of disease or constitutional symptoms (unexplained fevers >38°C, drenching night sweats, >10% weight loss in last 6 months) Blood counts above the following: Neutrophils >1500/μL Platelets >100,000/μL Hemoglobin >110 g/L Bone marrow at least normocellular for age, <30% lymphocytes CRi was defined as participants with CR who had persistent cytopenia unrelated to CLL but related to drug toxicity.
Time Frame	From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months.

Outcome Measure Data

Analysis Population Description

All enrolled participants treated with at least one dose of venetoclax who were previously treated with BCRi

Arm/Group Title	Venetoclax
Arm/Group Description	Participants received venetoclax on a once daily (QD) dosing schedule for up to 108 weeks. The starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg.
Measure Participants	67
Number (95% Confidence Interval) [percentage of participants]	25.4 9.8%

3. Secondary Outcome

Title	Overall Response Rate (ORR)
Description	Overall response rate was defined as the percentage of participants with an overall best response of CR, CRi, nodular partial remission (nPR), or confirmed partial remission (PR) based on the 2008 Modified IWCLL NCI-WG criteria as assessed by investigator. CR and CRi are defined above. nPR is defined as participants with CR but for whom bone marrow nodules could be identified histologically. For PR at least 2 of the following must be met: ≥ 50% decrease in peripheral blood lymphocyte count from the pretreatment baseline value ≥ 50% reduction in lymphadenopathy ≥ 50% reduction in the size of the liver and/or spleen (if abnormal prior to therapy) and at least one of the following criteria must be met: Neutrophils > 1,500/μL or ≥ 50% improvement over baseline Platelets > 100,000/μL or ≥ 50% improvement over baseline Hemoglobin > 11.0 g/dL or ≥ 50% improvement over baseline without transfusions or exogenous growth factors. PR must be confirmed at least 7 weeks later.
Time Frame	From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months.

Outcome Measure Data

Analysis Population Description

All enrolled participants treated with at least one dose of venetoclax

Arm/Group Title	Venetoclax
Arm/Group Description	Participants received venetoclax on a once daily (QD) dosing schedule for up to 108 weeks. The starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg.
Measure Participants	258
Number (95% Confidence Interval) [percentage of participants]	79.8 30.9%

4. Secondary Outcome

Title	Duration of Overall Response (DoR)
Description	Duration of response is defined as the time from the date of first response (CR, CRi, nPR, or PR) to the earliest date that progressive disease (PD) is objectively documented (radiographic or clinical) or death. Duration of response was analyzed by Kaplan-Meier (K-M) methodology. If a participant was still responding their data was censored at the date of the last available disease assessment prior to the data cutoff date.
Time Frame	From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months.

Outcome Measure Data

Analysis Population Description

Enrolled participants treated with at least one dose of venetoclax who had an overall response of CR, CRi, nPR, or confirmed PR.

Arm/Group Title	Venetoclax
Arm/Group Description	Participants received venetoclax on a once daily (QD) dosing schedule for up to 108 weeks. The starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg.
Measure Participants	205
Median (95% Confidence Interval) [months]	25.2

5. Secondary Outcome

Title	Time to Progression (TTP)
Description	Time to progression is defined as the time from the date of first dose of venetoclax to the date of earliest PD (radiographic or clinical). Participants who did not experience disease progression were censored at the date of the last available disease assessment prior to the data cutoff date; participants with no post-baseline disease assessments were censored at the first dose date plus 1 day. Time to progression was estimated using Kaplan-Meier methodology.
Time Frame	From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months.

Outcome Measure Data

Analysis Population Description

Enrolled participants treated with at least one dose of venetoclax

Arm/Group Title	Venetoclax
Arm/Group Description	Participants received venetoclax on a once daily (QD) dosing schedule for up to 108 weeks. The starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg.
Measure Participants	258
Median (95% Confidence Interval) [months]	30.5

6. Secondary Outcome

Title	Progression-Free Survival (PFS)
Description	Progression-free survival (PFS) was defined as the time from the date of first dose of venetoclax to the date of earliest PD (radiographic or clinical) or death. Participants who did not experience disease progression or death were censored at the date of the last available disease assessment prior to the data cutoff date; participants with no post-baseline tumor assessment or clinical assessment for progression, were censored at the date of first dose plus 1 day. Progression-free survival was analyzed by Kaplan-Meier methodology.
Time Frame	From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months.

Outcome Measure Data

Analysis Population Description

Enrolled participants treated with at least one dose of venetoclax

Arm/Group Title	Venetoclax
Arm/Group Description	Participants received venetoclax on a once daily (QD) dosing schedule for up to 108 weeks. The starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg.
Measure Participants	258
Median (95% Confidence Interval) [months]	30.5

7. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall survival (time to death) will be defined as the number of days from the first dose date of venetoclax to the date of death. If a participant had not died their data were censored at the date when they were last known to be alive prior to the cutoff date. Overall survival was analyzed using Kaplan-Meier methodology.
Time Frame	From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months.

Outcome Measure Data

Analysis Population Description

Enrolled participants treated with at least one dose of venetoclax

Arm/Group Title	Venetoclax
Arm/Group Description	Participants received venetoclax on a once daily (QD) dosing schedule for up to 108 weeks. The starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg.
Measure Participants	258
Median (95% Confidence Interval) [months]	NA

8. Secondary Outcome

Title	Functional Assessment of Cancer Therapy - Leukemia Questionnaire (FACT-Leu)
Description	The FACT-Leu is a 44-item, leukemia-specific questionnaire designed to assess patient health-related quality of life (HRQoL) and leukemia-specific symptoms.
Time Frame	Measured up to approximately 3 years after the last participant has enrolled into the study.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Secondary Outcome

Title	Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT-F)
Description	The FACIT-F questionnaire measures fatigue and its effect on functioning and daily activities. The FACIT-F has 13 items answered on a 5-point rating scale based on a 7-day recall period.
Time Frame	Measured up to approximately 3 years after the last participant has enrolled into the study.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Secondary Outcome

Title	EuroQoL 5 Dimension 5 Level Questionnaire (EQ-5D-5L)
Description	Five items in the EQ-5D-5L questionnaire (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) are rated on 5 levels of severity.
Time Frame	Measured up to approximately 3 years after the last participant has enrolled into the study.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

11. Other Pre-specified Outcome

Title	Minimal Residual Disease (MRD) Negativity Rate
Description	The MRD negativity rate is defined as the percentage of participants who had MRD negative status with less than one CLL cell per 10,000 leukocytes (< 10-⁴) in peripheral blood and bone marrow. MRD was evaluated using next-generation sequencing. Per protocol, peripheral blood MRD assessments were to be collected from all participants at Week 24 and Week 48 and at the time the bone marrow assessment for confirmation of CR/CRi, and bone marrow (BM) MRD assessments were to be collected for participants undergoing a bone marrow procedure for confirmation of CR/CRi. Participants with no blood or BM MRD assessments were included in the calculation of MRD negativity rate as not having MRD negative status.
Time Frame	From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months.

Outcome Measure Data

Analysis Population Description

All enrolled participants who received at least one dose of venetoclax

Arm/Group Title	Venetoclax
Arm/Group Description	Participants received venetoclax on a once daily (QD) dosing schedule for up to 108 weeks. The starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg.
Measure Participants	258
Peripheral blood	39.9 15.5%
Bone marrow	9.7 3.8%

Adverse Events

Time Frame	From the first dose of venetoclax and up to 30 days after the last dose of venetoclax, up to the data cut-off date of 30 June 2019. Median (minimum, maximum) duration of treatment was 90.7 (0.1, 145.6) weeks. Mortality data are reported up to the end of study, as of the data cut-off date.
Arm/Group Title	Venetoclax
Arm/Group Description	Participants received venetoclax on a once daily (QD) dosing schedule for up to 108 weeks. The starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg. Participants who continued to derive benefit after 2 years of treatment may have continued venetoclax therapy for up to 2 additional years.
All Cause Mortality
	Venetoclax
	Affected / at Risk (%)	# Events
Total	42/258 (16.3%)
Serious Adverse Events
	Venetoclax
	Affected / at Risk (%)	# Events
Total	121/258 (46.9%)
Blood and lymphatic system disorders
Anaemia	4/258 (1.6%)	4
Aplasia pure red cell	1/258 (0.4%)	1
Autoimmune haemolytic anaemia	3/258 (1.2%)	6
Febrile neutropenia	15/258 (5.8%)	18
Haemolysis	1/258 (0.4%)	1
Intravascular haemolysis	1/258 (0.4%)	2
Leukocytosis	1/258 (0.4%)	1
Neutropenia	4/258 (1.6%)	4
Pancytopenia	2/258 (0.8%)	2
Thrombocytopenia	3/258 (1.2%)	4
Cardiac disorders
Aortic valve stenosis	1/258 (0.4%)	1
Atrial fibrillation	1/258 (0.4%)	1
Cardiac failure	2/258 (0.8%)	2
Cardiac failure congestive	2/258 (0.8%)	2
Coronary artery disease	1/258 (0.4%)	1
Congenital, familial and genetic disorders
Hydrocele	1/258 (0.4%)	1
Ear and labyrinth disorders
Deafness neurosensory	1/258 (0.4%)	1
Gastrointestinal disorders
Abdominal pain	1/258 (0.4%)	1
Ascites	1/258 (0.4%)	1
Diarrhoea	5/258 (1.9%)	5
Diverticulum intestinal haemorrhagic	1/258 (0.4%)	1
Inguinal hernia	2/258 (0.8%)	2
Intestinal obstruction	1/258 (0.4%)	1
Rectal perforation	1/258 (0.4%)	1
Vomiting	1/258 (0.4%)	1
General disorders
Chest pain	1/258 (0.4%)	1
Death	1/258 (0.4%)	1
Fatigue	1/258 (0.4%)	1
General physical health deterioration	1/258 (0.4%)	1
Malaise	1/258 (0.4%)	1
Mucosal haemorrhage	1/258 (0.4%)	1
Pyrexia	9/258 (3.5%)	9
Hepatobiliary disorders
Bile duct stone	1/258 (0.4%)	1
Biliary colic	1/258 (0.4%)	1
Cholangitis	1/258 (0.4%)	1
Cholelithiasis	1/258 (0.4%)	1
Gallbladder necrosis	1/258 (0.4%)	1
Hepatic cirrhosis	1/258 (0.4%)	1
Immune system disorders
Drug hypersensitivity	1/258 (0.4%)	1
Hypersensitivity	1/258 (0.4%)	1
Infections and infestations
Abscess limb	1/258 (0.4%)	1
Arthritis bacterial	1/258 (0.4%)	1
Bronchiolitis	1/258 (0.4%)	1
Bronchitis	2/258 (0.8%)	2
Cellulitis	2/258 (0.8%)	2
Diverticulitis	1/258 (0.4%)	1
Endophthalmitis	1/258 (0.4%)	1
Escherichia infection	1/258 (0.4%)	2
Gastroenteritis	2/258 (0.8%)	2
Herpes zoster	2/258 (0.8%)	2
Influenza	2/258 (0.8%)	2
Localised infection	1/258 (0.4%)	1
Lower respiratory tract infection	3/258 (1.2%)	3
Neutropenic sepsis	1/258 (0.4%)	1
Pneumonia	19/258 (7.4%)	27
Pneumonia bacterial	1/258 (0.4%)	1
Progressive multifocal leukoencephalopathy	1/258 (0.4%)	1
Pyelonephritis	1/258 (0.4%)	1
Respiratory syncytial virus infection	2/258 (0.8%)	2
Respiratory tract infection	1/258 (0.4%)	1
Sepsis	1/258 (0.4%)	1
Septic shock	2/258 (0.8%)	2
Skin infection	1/258 (0.4%)	1
Staphylococcal infection	1/258 (0.4%)	1
Tonsillitis	1/258 (0.4%)	1
Upper respiratory tract infection	2/258 (0.8%)	2
Urosepsis	1/258 (0.4%)	1
Injury, poisoning and procedural complications
Brain contusion	1/258 (0.4%)	1
Clavicle fracture	1/258 (0.4%)	1
Contusion	1/258 (0.4%)	1
Fall	2/258 (0.8%)	4
Femoral neck fracture	1/258 (0.4%)	1
Head injury	1/258 (0.4%)	1
Hip fracture	1/258 (0.4%)	1
Infusion related reaction	1/258 (0.4%)	1
Pelvic fracture	1/258 (0.4%)	1
Investigations
Aspartate aminotransferase increased	3/258 (1.2%)	3
Blood bilirubin increased	1/258 (0.4%)	1
Blood creatinine increased	2/258 (0.8%)	2
Blood lactate dehydrogenase increased	4/258 (1.6%)	4
Blood phosphorus increased	1/258 (0.4%)	1
Blood potassium increased	3/258 (1.2%)	3
General physical condition abnormal	1/258 (0.4%)	1
Platelet count decreased	1/258 (0.4%)	1
Weight decreased	2/258 (0.8%)	2
Metabolism and nutrition disorders
Cachexia	1/258 (0.4%)	1
Diabetes mellitus	1/258 (0.4%)	1
Fluid retention	1/258 (0.4%)	1
Hyperglycaemia	1/258 (0.4%)	1
Hyperkalaemia	4/258 (1.6%)	7
Hyperphosphataemia	3/258 (1.2%)	4
Hypoglycaemia	1/258 (0.4%)	1
Tumour lysis syndrome	2/258 (0.8%)	2
Musculoskeletal and connective tissue disorders
Arthritis	1/258 (0.4%)	1
Back pain	1/258 (0.4%)	1
Haematoma muscle	1/258 (0.4%)	1
Osteoarthritis	1/258 (0.4%)	2
Osteoporosis	1/258 (0.4%)	1
Pain in extremity	1/258 (0.4%)	1
Spinal pain	1/258 (0.4%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenoma benign	1/258 (0.4%)	1
Adrenal adenoma	1/258 (0.4%)	1
Bladder cancer	1/258 (0.4%)	1
Chronic lymphocytic leukaemia transformation	1/258 (0.4%)	2
Diffuse large B-cell lymphoma	1/258 (0.4%)	1
Infected neoplasm	1/258 (0.4%)	1
Lung adenocarcinoma	2/258 (0.8%)	2
Lung neoplasm malignant	1/258 (0.4%)	1
Myelodysplastic syndrome	2/258 (0.8%)	2
Rectal adenocarcinoma	1/258 (0.4%)	1
Squamous cell carcinoma	1/258 (0.4%)	1
Squamous cell carcinoma of skin	1/258 (0.4%)	1
Nervous system disorders
Ataxia	1/258 (0.4%)	1
Dizziness	1/258 (0.4%)	1
Facial paralysis	1/258 (0.4%)	1
Haemorrhage intracranial	1/258 (0.4%)	1
Ischaemic stroke	1/258 (0.4%)	1
Metabolic encephalopathy	1/258 (0.4%)	1
Sciatica	1/258 (0.4%)	1
Somnolence	1/258 (0.4%)	1
Subarachnoid haemorrhage	1/258 (0.4%)	1
Syncope	2/258 (0.8%)	3
Psychiatric disorders
Confusional state	2/258 (0.8%)	3
Depression	1/258 (0.4%)	1
Mental status changes	1/258 (0.4%)	2
Renal and urinary disorders
Bladder mass	1/258 (0.4%)	1
Urinary incontinence	1/258 (0.4%)	1
Reproductive system and breast disorders
Benign prostatic hyperplasia	1/258 (0.4%)	1
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	2/258 (0.8%)	2
Asthma	1/258 (0.4%)	1
Atelectasis	1/258 (0.4%)	1
Bronchiectasis	1/258 (0.4%)	1
Chronic obstructive pulmonary disease	1/258 (0.4%)	1
Cough	2/258 (0.8%)	2
Dyspnoea	4/258 (1.6%)	4
Dyspnoea exertional	1/258 (0.4%)	1
Epistaxis	1/258 (0.4%)	1
Oropharyngeal pain	1/258 (0.4%)	1
Pharyngeal disorder	1/258 (0.4%)	1
Pharyngeal swelling	1/258 (0.4%)	1
Pleural effusion	3/258 (1.2%)	4
Pneumonitis	1/258 (0.4%)	1
Pulmonary embolism	1/258 (0.4%)	1
Pulmonary hypertension	1/258 (0.4%)	2
Skin and subcutaneous tissue disorders
Paraneoplastic pemphigus	1/258 (0.4%)	1
Rash	1/258 (0.4%)	1
Vascular disorders
Aneurysm	1/258 (0.4%)	1
Other (Not Including Serious) Adverse Events
	Venetoclax
	Affected / at Risk (%)	# Events
Total	242/258 (93.8%)
Blood and lymphatic system disorders
Anaemia	54/258 (20.9%)	77
Neutropenia	106/258 (41.1%)	238
Thrombocytopenia	51/258 (19.8%)	83
Gastrointestinal disorders
Abdominal pain	17/258 (6.6%)	19
Constipation	33/258 (12.8%)	39
Diarrhoea	88/258 (34.1%)	153
Nausea	67/258 (26%)	94
Vomiting	19/258 (7.4%)	22
General disorders
Asthenia	30/258 (11.6%)	39
Fatigue	38/258 (14.7%)	49
Oedema peripheral	13/258 (5%)	17
Pyrexia	42/258 (16.3%)	53
Infections and infestations
Influenza	14/258 (5.4%)	14
Nasopharyngitis	38/258 (14.7%)	57
Upper respiratory tract infection	43/258 (16.7%)	60
Urinary tract infection	20/258 (7.8%)	29
Investigations
Neutrophil count decreased	28/258 (10.9%)	44
Platelet count decreased	19/258 (7.4%)	24
Weight decreased	19/258 (7.4%)	21
Metabolism and nutrition disorders
Decreased appetite	23/258 (8.9%)	28
Hyperkalaemia	21/258 (8.1%)	31
Hyperphosphataemia	20/258 (7.8%)	23
Hyperuricaemia	15/258 (5.8%)	15
Hypocalcaemia	15/258 (5.8%)	19
Hypokalaemia	13/258 (5%)	17
Musculoskeletal and connective tissue disorders
Arthralgia	27/258 (10.5%)	31
Back pain	28/258 (10.9%)	30
Muscle spasms	16/258 (6.2%)	19
Nervous system disorders
Dizziness	18/258 (7%)	23
Headache	26/258 (10.1%)	28
Psychiatric disorders
Insomnia	23/258 (8.9%)	25
Respiratory, thoracic and mediastinal disorders
Cough	47/258 (18.2%)	56
Dyspnoea	20/258 (7.8%)	23
Oropharyngeal pain	13/258 (5%)	14
Skin and subcutaneous tissue disorders
Dry skin	17/258 (6.6%)	20
Pruritus	22/258 (8.5%)	25
Rash	18/258 (7%)	29
Vascular disorders
Hypertension	22/258 (8.5%)	26

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

AbbVie requests that any investigator or institution that plans on presenting/publishing results disclosure, provide written notification of their request 60 days prior to their presentation/publication. AbbVie requests that no presentation/publication will be instituted until 12 months after a study is completed, or after the first presentation/publication whichever occurs first. A delay may be proposed of a presentation/publication if AbbVie needs to secure patent or proprietary protection.