VENCLEXTA® (venetoclax) | CLL14 & MURANO Clinical Trial Study Designs

Break free from chemotherapy and continuous oral treatment in CLL. VENCLEXTA offers the only chemo-free regimens with a fixed duration of 12 months in 1L CLL with VEN+G and ~24 months in R/R CLL with VEN+R.¹

Designed for patients to complete treatment in 12 months¹

The CLL14 trial evaluated PFS with VEN+G, a fixed duration treatment regimen
CLL14 was a multicenter, open-label, actively controlled, phase 3 trial (randomized 1:1)

After the first treatment cycle of GAZYVA and before the VENCLEXTA dose ramp-up, patients' ALC was reduced by 98%. Per the trial protocol, tumor burden was assessed based on ALC and lymph node size. The effect of the first GAZYVA treatment cycle on lymph node size was not evaluated. The trial started with an initial cycle of GAZYVA followed by the 5-week VENCLEXTA dose ramp-up, and reduced median lymphocyte count from 55 x 10 to the ninth power cells/L at Day 15. Median lymphocyte counts are descriptive in nature and not powered for any type of comparison. Changes in TLS risk status based on ALC reduction were at the discretion of the trial investigators.

Select inclusion criteria

Coexisting medical conditions (total CIRS >6 or CLcr <70 mL/min), age ≥18 years¹

Select clinical endpoints^1,2

Primary endpoint: PFS (IRC-assessed PFS was the basis for FDA approval of VEN+G)
Select secondary endpoints: MRD in bone marrow, CR/CRi (INV-assessed), MRD in peripheral blood, MRD in CR/CRi in bone marrow, MRD in CR/CRi in peripheral blood, ORR (INV-assessed)

*VENCLEXTA oral tablets were administered according to the 5-week dose ramp-up schedule: 20 mg daily during Cycle 1, Days 22-28; 50 mg daily during Cycle 2, Days 1-7; 100 mg daily during Cycle 2, Days 8-14; 200 mg daily during Cycle 2, Days 15-21; 400 mg daily during Cycle 2, Days 22-28 and on Days 1-28 of all subsequent cycles until the end of Cycle 12.
^†GAZYVA intravenous (IV) infusion was administered at 1000 mg on Day 1 (the first dose could be split as 100 mg and 900 mg on Days 1 and 2), and on Days 8 and 15 of Cycle 1. For all subsequent 28-day cycles, GAZYVA 1000 mg was administered on Day 1 for a total of 6 cycles.
^‡Chlorambucil was administered at 0.5 mg/kg orally on Days 1 and 15 of each 28-day cycle for 12 cycles.

ALC=absolute lymphocyte count; CIRS=Cumulative Illness Rating Scale; CLcr=creatinine clearance; IRC=Independent Review Committee; CRi=complete remission with incomplete bone marrow recovery; INV=investigator; ORR=overall response rate; TLS=tumor lysis syndrome.

VEN+G was studied in patients whose age and disease characteristics were representative of the broad CLL patient population^2-4

Baseline demographics and disease characteristics^2II

Characteristic	VEN+G (N=216)	GClb (N=216)
Age, years; median (range)	72 (43-89)	71 (41-89)
Age ≥70, %	62	59
Male, %	68	66
Binet stage, %
Binet stage A	21	20
Binet stage B	36	37
Binet stage C	43	43
Median CIRS score (range)	9 (0-23)	8 (1-28)
CLcr <70 mL/min, %	60	55
CLL subsets, %
17p deletion	9	7
TP53 mutation	9	6
11q deletion	18	20
lgVH unmutated	56	57
lgVH mutated	35	38
High TLS risk category, %^#	22	20
Lymph nodes ≥10 cm	5	5
Lymph nodes ≥5 cm and ALC ≥25 x 10⁹/L	14	12
Medium TLS risk, %	64	68
Low TLS risk, %	13	12
ECOG performance status, %
0	41	48
1	46	41
2	13	12
Baseline ALC (x 10⁹/L); median	56	58

^IIPatients with missing results not included.
^#TLS risk category was chosen based on investigator discretion, lymph node size, and ALC.

GClb=GAZYVA + chlorambucil; TP53=tumor protein 53; lgVH=immunoglobulin heavy-chain variable gene; ECOG=Eastern Cooperative Oncology Group.

See 1L PFS — Next ›

Designed to stop treatment at ~24 months¹*

Relapsed/refractory treatment study design chart

MURANO was a phase 3, multicenter, open-label, actively controlled trial (randomized 1:1)
The 5-week VENCLEXTA dose ramp-up was designed to gradually reduce tumor burden (debulk) and decrease the risk of TLS
Tumor burden assessments, including radiographic evaluation and blood chemistry assessment, are recommended prior to VENCLEXTA initiation to assess the risk for TLS

Select inclusion criteria

≥18 years of age; 1-3 prior lines of therapy, including at least 1 chemo-containing regimen; and prior bendamustine only if duration of response (DoR) ≥24 months⁵

Select clinical endpoints

Primary endpoint: PFS (IRC-assessed PFS was the basis for approval of VEN+R)¹
Select secondary endpoints: IRC-assessed CR/CRi, IRC-assessed ORR, OS, INV-assessed PFS, undetectable MRD^5,6
- Key secondary endpoints were ranked for hierarchical testing as: (1) IRC-assessed CR/CRi rate, (2) IRC-assessed ORR, and (3) OS. Because the study did not reach significance at the first key secondary endpoint (IRC-assessed CR/CRi rate), the remaining key secondary endpoints could not be tested for statistical significance

*From Cycle 1, Day 1 of rituximab, in the absence of disease progression or unacceptable toxicity.
^†VENCLEXTA oral tablets were administered according to the 5-week dose ramp-up schedule: 20 mg daily in Week 1, 50 mg daily in Week 2, 100 mg daily in Week 3, 200 mg daily in Week 4, and 400 mg daily from Week 5 through all subsequent weeks for 24 months from Cycle 1, Day 1 of rituximab.
^‡Rituximab was administered after the initial VENCLEXTA dose ramp-up and was infused on Day 1 of each 28-day cycle for 6 cycles, with a dose of 375 mg/m² for Cycle 1 and 500 mg/m² for Cycles 2-6.
^§Patients randomized to bendamustine + rituximab received bendamustine at 70 mg/m² on Days 1 and 2 for 6 cycles (28-day cycle) and rituximab at the above-described dose and schedule.

R/R=relapsed/refractory; VEN+R=VENCLEXTA + rituximab; PFS=progression-free survival; TLS=tumor lysis syndrome; ALC=absolute lymphocyte count; CIRS=Cumulative Illness Rating Scale; CLcr=creatinine clearance; IRC=Independent Review Committee; FDA=Food and Drug Administration; MRD=minimal residual disease; CR=complete remission; CRi=complete remission with incomplete bone marrow recovery; INV=investigator; ORR=overall response rate; OS=overall survival.

Baseline patient characteristics were generally well balanced between study arms^6,7

MURANO demographics and baseline characteristics^II

Characteristic	VEN+R (N=194)	BR (N=195)
Age, years; median (range)	65 (28-83)	66 (22-85)
Male, %	70	77
ECOG performance status, %
0	57	56
1	42	43
2	1	1
Tumor burden, %
Absolute lymphocyte count ≥25 x 10⁹/L	67	69
1 or more nodes ≥5 cm	46	48
Fludarabine refractory, %	14	16
CLL subsets, %
17p deletion	27	27
11q deletion	35	38
TP53 mutation	25	28
lgVH unmutated	68	68
Time since diagnosis, years; median (range)	6.44 (0.5-28.4)	7.11 (0.3-29.5)

^IIPatients with missing results not included.

GClb=GAZYVA + chlorambucil; TP53=tumor protein 53; lgVH=immunoglobulin heavy-chain variable gene; ECOG=Eastern Cooperative Oncology Group.

The majority of patients in the study had 1 prior therapy. Chemotherapy with or without anti-CD20 was the most common prior therapy^1,6-8

MURANO prior therapies

Number of prior lines of therapy, %	VEN+R (N=194)	BR (N=195)
Median number (range)	1 (1-5)
1	57	60
2	30	22
≥3	13	18
Previous CLL regimens
Median number (range)	1 (1-5)
Prior alkylating agents, %	95	93
Prior purine analogs, %	81	81
Prior anti-CD20 antibodies, %	76	79
Prior B-cell receptor pathway inhibitors, %	2	3
Prior FCR, %	54	55
Prior BR, %	2	3

BR=bendamustine + rituximab; FCR=fludarabine, cyclophosphamide, rituximab.

See R/R PFS — Next ›

PFS results

Review progression-free survival, including time off treatment

View data ›

Safety data

See VENCLEXTA’s well-studied safety profile for patients with 1L and R/R CLL¹

View data ›

Initiation

Find resources to help start your patients on VENCLEXTA

VENCLEXTA regimens were designed to stop after a fixed treatment duration 1

Designed for patients to complete treatment in 12 months 1

VEN+G was studied in patients whose age and disease characteristics were representative of the broad CLL patient population 2-4

Baseline demographics and disease characteristics 2II

Age, years; median (range)

Male, %

Binet stage, %

Median CIRS score (range)

CLcr <70 mL/min, %

CLL subsets, %

High TLS risk category, %#

Medium TLS risk, %

Low TLS risk, %

ECOG performance status, %

Baseline ALC (x 109/L); median

See 1L PFS — Next ›

Designed to stop treatment at ~24 months 1*

Baseline patient characteristics were generally well balanced between study arms 6,7

MURANO demographics and baseline characteristicsII

Age, years; median (range)

Male, %

ECOG performance status, %

Tumor burden, %

Fludarabine refractory, %

CLL subsets, %

Time since diagnosis, years; median (range)

The majority of patients in the study had 1 prior therapy. Chemotherapy with or without anti-CD20 was the most common prior therapy 1,6-8

MURANO prior therapies

See R/R PFS — Next ›

PFS results

View data ›

Safety data

View data ›

Initiation

Explore Starting VENCLEXTA ›

Important Safety Information & Indication

Important Safety Information

Contraindication

Tumor Lysis Syndrome

Neutropenia

Infections

Immunization

Embryo-Fetal Toxicity

Increased Mortality in Patients with Multiple Myeloma when VENCLEXTA is Added to Bortezomib and Dexamethasone

Adverse Reactions

Drug Interactions

Lactation

Females and Males of Reproductive Potential

Hepatic Impairment

Indication

VENCLEXTA regimens were designed to stop after a fixed treatment duration¹

Designed for patients to complete treatment in 12 months¹

VEN+G was studied in patients whose age and disease characteristics were representative of the broad CLL patient population^2-4

Baseline demographics and disease characteristics^2II

High TLS risk category, %^#

Baseline ALC (x 10⁹/L); median

Designed to stop treatment at ~24 months¹*

Baseline patient characteristics were generally well balanced between study arms^6,7

MURANO demographics and baseline characteristics^II

The majority of patients in the study had 1 prior therapy. Chemotherapy with or without anti-CD20 was the most common prior therapy^1,6-8