Venclexta (venetoclax) - 2 indications

Scroll down for more information on each indication:

• for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion; approved April 2016. Expanded to include patients with CLL or small lymphocytic lymphoma (SLL), with or without 17p deletion, who have received at least one prior therapy in June 2018
• for the treatment of patients with newly-diagnosed acute myeloid leukemia (AML) in combination with azacitidine or decitabine or low-dose cytarabine; approved November 2018

General Information

Venclexta (venetoclax) is a BCL-2 inhibitor, an antiapoptotic protein.

Venclexta is specifically indicated for the following:

• for the treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), with or without 17p deletion, who have received at least one prior therapy. Approved for use in combination with Rituxan (rituximab) and for use in combination with Gazyva (obinutuzumab)
• for use the treatment newly-diagnosed acute myeloid leukemia (AML) in combination with azacitidine or decitabine or low-dose cytarabine ) in adults 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy.

Venclexta is supplied as a tablet for oral administration. Scroll down for recommended dosing/administration for each indication.

Mechanism of Action

Venclexta (venetoclax) is a selective and orally bioavailable small-molecule inhibitor of BCL-2, an antiapoptotic protein. Overexpression of BCL-2 has been demonstrated in CLL cells where it mediates tumor cell survival and has been associated with resistance to chemotherapeutics. Venetoclax helps restore the process of apoptosis by binding directly to the BCL-2 protein, displacing pro-apoptotic proteins like BIM, triggering mitochondrial outer membrane permeabilization and the activation of caspases.

Side Effects

Adverse effects associated with the use of Venclexta may include, but are not limited to, the following:

• neutropenia
• diarrhea
• nausea
• anemia
• upper respiratory tract infection
• thrombocytopenia
• fatigue

Adverse effects associated with the use of Venclexta plus Gazyva may include, but are not limited to, the following:

• low white blood cell count
• diarrhea
• fatigue
• nausea
• low red blood cell count
• upper respiratory tract infection

Adverse effects associated with the use of Venclexta plus Rituxan may include, but are not limited to, the following:

• low white blood cell count
• diarrhea
• upper respiratory tract infection
• cough
• fatigue
• nausea

Indication 1 - for the treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), with or without 17p deletion, who have received at least one prior therapy 

approved April 2016, June 2018

Dosing/Administration

Venclexta dosing begins with a 5-week ramp-up. The 5-week ramp-up dosing schedule is designed to gradually reduce tumor burden (debulk) and decrease the risk of tumor lysis syndrome (TLS)

Venclexta 5-week Dose Ramp-Up Schedule

Administer Venclexta according to the 5-week ramp-up dosing schedule to the recommended dosage of 400 mg orally once daily as shown in the table below:

Week 1	20 mg oral daily dose
Week 2	50 mg oral daily dose
Week 3	100 mg oral daily dose
Week 4	200 mg oral daily dose
Week 5 and beyond	400 mg oral daily dose

In Combination with Obinutuzumab

Start obinutuzumab administration at 100 mg on Cycle 1 Day 1, followed by 900 mg on Cycle 1 Day 2. Administer 1000 mg on Days 8 and 15 of Cycle 1 and on Day 1 of each subsequent 28- day cycle for a total of 6 cycles. Refer to the obinutuzumab prescribing information for additional dosing information. On Cycle 1 Day 22, start Venclexta according to the 5-week ramp-up dosing schedule. After completing the ramp-up phase on Cycle 2 Day 28, continue Venclexta at a dose of 400 mg orally once daily from Cycle 3 Day 1 until the last day of Cycle 12.

In Combination with Rituximab

Start rituximab administration after the patient has completed the 5-week ramp-up dosing schedule for Venclexta and has received Venclexta at the recommended dosage of 400 mg orally once daily for 7 days. Administer rituximab on Day 1 of each 28-day cycle for 6 cycles, at a dose of 375 mg/m2 intravenously for Cycle 1 and 500 mg/m2 intravenously for Cycles 2-6. Continue Venclexta 400 mg orally once daily for 24 months from Cycle 1 Day 1 of rituximab. Refer to the rituximab prescribing information for additional dosing information.

Venclexta Monotherapy

The recommended dosage of Venclexta is 400 mg once daily after completion of the 5-week ramp-up dosing schedule. Continue Venclexta until disease progression or unacceptable toxicity.

Clinical Trial Results

The FDA approval of Venclexta for CLL was based on an open-label, single-arm, multicenter clinical trial of 106 patients with CLL with 17p deletion who had received at least one prior therapy. Patients received Venclexta via a weekly ramp-up schedule starting at 20 mg and ramping to 50 mg, 100 mg, 200 mg and finally 400 mg once daily. Patients continued to receive 400 mg of Venclexta orally once daily until disease progression or unacceptable toxicity. The efficacy of Venclexta was evaluated by overall response rate (ORR) as assessed by an Independent Review Committee (IRC) using the International Workshop for Chronic Lymphocytic Leukemia (IWCLL) updated National Cancer Institute-sponsored Working Group (NCI-WG) guidelines. The ORR was 85%. The median time to first response was 0.8 months. Median duration of response (DOR) had not been reached with approximately 12 months median follow-up. The DOR ranged from 2.9 to 19.0+ months.

The FDA approval of the Gazyva Venclexta combination was based on results of the randomized Phase III CLL14 study. The trial enrolled 432 patients with previously untreated CLL who were randomly assigned to receive either a 12-month duration of Venclexta alongside six-month duration of Gazyva (Arm A) or six-month duration of Gazyva plus chlorambucil followed by an additional six-month duration of chlorambucil (Arm B). Arm A started with an initial cycle of Gazyva followed by a five-week Venclexta dose ramp-up to help reduce tumor burden. The primary endpoint of the study was investigator-assessed progression-free survival (PFS). Results showed the combination of Venclexta plus Gazyva produced a durable and significant reduction in the risk of disease worsening or death (progression-free survival (PFS), as assessed by Independent Review Committee) by 67 percent compared to Gazyva plus chlorambucil, a current standard of care. Venclexta plus Gazyva showed deep and clinically meaningful responses characterized by a higher rate of minimal residual disease (MRD)-negativity in the bone marrow compared to Gazyva plus chlorambucil (MRD-negativity of 57 percent vs. 17 percent) and peripheral blood (MRD-negativity of 76 percent vs. 35 percent).

The FDA approval of the Venclexta plus Rituxan combination for CLL or SLL was based on MURANO, a Phase III open-label, international, multicenter, randomized study evaluating the efficacy and safety of Venclexta in combination with Rituxan compared to bendamustine in combination with Rituxan (BR). All treatments were of fixed duration. Following a five-week dose ramp-up schedule for Venclexta, patients on the Venclexta plus Rituxan arm received six cycles of Venclexta plus Rituxan followed by Venclexta monotherapy for up to two years total. Patients on the BR arm received six cycles of BR. The study included 389 patients with chronic lymphocytic leukemia (CLL) who had been previously treated with at least one line of therapy. Patients were randomly assigned in a 1:1 ratio to receive either Venclexta plus Rituxan or BR. The primary endpoint of the study was progression-free survival (PFS). The results showed that a fixed duration of treatment with Venclexta plus Rituxan significantly reduced the risk of disease progression or death (PFS) by 81 percent compared with bendamustine plus Rituxan, a current standard of care.

Indication 2 - for the treatment of patients with newly-diagnosed acute myeloid leukemia (AML) in combination with azacitidine or decitabine or low-dose cytarabine

approved November 2018

Dosing/Administration

The recommended dosage and ramp-up of Venclexta depends upon the combination agent. Follow the dosing schedule, including the 3-day or 4-day dose ramp-up, as shown in the table below. Start Venclexta administration on Cycle 1 Day 1 in combination with:

• Azacitidine 75 mg/m2 intravenously or subcutaneously once daily on Days 1-7 of each 28- day cycle; OR
• Decitabine 20 mg/m2 intravenously once daily on Days 1-5 of each 28-day cycle; OR
• Cytarabine 20 mg/m2 subcutaneously once daily on Days 1-10 of each 28-day cycle.

Day 1	100 mg	x
Day 2	200 mg	x
Day 3	400 mg	x
Day 4 and beyond	400 mg orally once daily of each 28- day cycle in combination with azacitidine or decitabine	600 mg orally once daily of each 28- day cycle in combination with low-dose cytarabine

Continue Venclexta, in combination with azacitidine or decitabine or low-dose cytarabine, until disease progression or unacceptable toxicity.

Clinical Trial Results

FDA approval was for AML based on the results of two phase 3 studies: VIALE-A and VIALE-C. 

VIALE-A: this randomized, double-blind, placebo-controlled multicenter study evaluated the efficacy and safety of Venclexta plus azacitidine, a hypomethylating agent, compared to placebo with azacitidine, in 431 people with previously untreated acute myeloid leukemia who were ineligible for intensive chemotherapy. Two-thirds of patients (n=286) received 400 mg Venclexta daily, in combination with azacitidine, and the remaining patients (n=145) received placebo tablets in combination with azacitidine. Venclexta plus azacitidine significantly reduced the risk of death by 34% (overall survival; OS) compared to azacitidine alone (median OS=14.7 months vs. 9.6 months). People treated with Venclexta plus azacitidine had significantly higher rates of complete remission (CR) with 37% compared to 18% in people treated with azacitidine alone. The Venclexta plus azacitidine combination also led to higher rates of CR and CR with partial hematologic recovery (CR + CRh), with the combination showing a CR + CRh of 65% compared to 23% with azacitidine alone.

VIALE-C: this randomized, double-blind, placebo-controlled multicenter study evaluated the efficacy and safety of Venclexta (venetoclax) plus LDAC, compared to placebo with LDAC, in 211 people with previously untreated acute myeloid leukemia who are ineligible for intensive chemotherapy. Two-thirds of patients (n=143) received 600 mg Venclexta daily in combination with LDAC and the remaining patients (n=68) received placebo in combination with LDAC. Twenty-seven percent of people treated with Venclexta plus LDAC achieved a CR (median duration of CR (DOCR)=11.1 months) vs. 7.4%  of people treated with LDAC alone (median DOCR=8.3 months). The median OS for people treated with Venclexta plus LDAC was 7.2 months vs. 4.1 months for people treated with LDAC alone. These OS results were not statistically significant.