1.1 Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

VENCLEXTA is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

1.2 Acute Myeloid Leukemia

VENCLEXTA is indicated in combination with azacitidine, or decitabine, or low-dose cytarabine for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy.

This indication is approved under accelerated approval based on response rates [see Clinical Studies (14.2)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

2.1 Recommended Dosage

Assess patient-specific factors for level of risk of tumor lysis syndrome (TLS) and provide prophylactic hydration and anti-hyperuricemics to patients prior to first dose of VENCLEXTA to reduce risk of TLS [see Dosage and Administration (2.2) and Warnings and Precautions (5.1)].

Instruct patients to take VENCLEXTA tablets with a meal and water at approximately the same time each day. VENCLEXTA tablets should be swallowed whole and not chewed, crushed, or broken prior to swallowing.

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

VENCLEXTA dosing begins with a 5-week ramp-up.

VENCLEXTA 5-week Dose Ramp-Up Schedule

Administer the VENCLEXTA dose according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg as shown in Table 1. The 5-week ramp-up dosing schedule is designed to gradually reduce tumor burden (debulk) and decrease the risk of TLS.

The CLL/SLL Starting Pack provides the first 4 weeks of VENCLEXTA according to the ramp-up schedule. The 400 mg dose is achieved using 100 mg tablets supplied in bottles [see How Supplied/Storage and Handling (16)].

VENCLEXTA 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 recommended obinutuzumab dosing information.

On Cycle 1 Day 22, start VENCLEXTA according to the 5-week ramp-up schedule (see Table 1). After completing the ramp-up schedule on Cycle 2 Day 28, patients should continue VENCLEXTA 400 mg once daily from Cycle 3 Day 1 until the last day of Cycle 12.

VENCLEXTA in Combination with Rituximab

Start rituximab administration after the patient has completed the 5-week dose ramp-up schedule with VENCLEXTA (see Table 1) and has received the 400 mg dose of VENCLEXTA for 7 days. Administer rituximab on Day 1 of each 28-day cycle for 6 cycles, with rituximab dosed at 375 mg/m2 intravenously for Cycle 1 and 500 mg/m2 intravenously for Cycles 2-6.

Patients should continue VENCLEXTA 400 mg once daily for 24 months from Cycle 1 Day 1 of rituximab.

VENCLEXTA as Monotherapy

The recommended dose of VENCLEXTA is 400 mg once daily after the patient has completed the 5-week dose ramp-up schedule. VENCLEXTA should be taken orally once daily until disease progression or unacceptable toxicity is observed.

Acute Myeloid Leukemia

The dose of VENCLEXTA depends upon the combination agent.

The VENCLEXTA dosing schedule (including ramp-up) is shown in Table 2. Initiate the azacitidine or decitabine or low-dose cytarabine on Day 1.

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

2.2 Risk Assessment and Prophylaxis for Tumor Lysis Syndrome

Patients treated with VENCLEXTA may develop tumor lysis syndrome. Refer to the appropriate section below for specific details on management. Assess patient-specific factors for level of risk of tumor lysis syndrome (TLS) and provide prophylactic hydration and anti-hyperuricemics to patients prior to first dose of VENCLEXTA to reduce risk of TLS.

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

VENCLEXTA can cause rapid reduction in tumor and thus poses a risk for TLS in the initial 5-week ramp-up phase. Changes in blood chemistries consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of VENCLEXTA and at each dose increase.

The risk of TLS is a continuum based on multiple factors, including tumor burden and comorbidities. Reduced renal function (creatinine clearance [CLcr] <80 mL/min) further increases the risk. Perform tumor burden assessments, including radiographic evaluation (e.g., CT scan), assess blood chemistry (potassium, uric acid, phosphorus, calcium, and creatinine) in all patients and correct pre-existing abnormalities prior to initiation of treatment with VENCLEXTA. The risk may decrease as tumor burden decreases [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

Table 3 below describes the recommended TLS prophylaxis and monitoring during VENCLEXTA treatment based on tumor burden determination from clinical trial data. Consider all patient comorbidities before final determination of prophylaxis and monitoring schedule.

Acute Myeloid Leukemia

• All patients should have white blood cell count less than 25 × 109/L prior to initiation of VENCLEXTA. Cytoreduction prior to treatment may be required.
• Prior to first VENCLEXTA dose, provide all patients with prophylactic measures including adequate hydration and anti-hyperuricemic agents and continue during ramp-up phase.
• Assess blood chemistry (potassium, uric acid, phosphorus, calcium, and creatinine) and correct pre-existing abnormalities prior to initiation of treatment with VENCLEXTA.
• Monitor blood chemistries for TLS at pre-dose, 6 to 8 hours after each new dose during ramp-up and 24 hours after reaching final dose.
• For patients with risk factors for TLS (e.g., circulating blasts, high burden of leukemia involvement in bone marrow, elevated pretreatment lactate dehydrogenase (LDH) levels, or reduced renal function) additional measures should be considered, including increased laboratory monitoring and reducing VENCLEXTA starting dose.

2.3 Dose Modifications Based on Toxicities

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Interrupt dosing or reduce dose for toxicities. See Table 4 and Table 5 for recommended dose modifications for toxicities related to VENCLEXTA. For patients who have had a dosing interruption greater than 1 week during the first 5 weeks of ramp-up phase or greater than 2 weeks after completing the ramp-up phase, reassess for risk of TLS to determine if reinitiation with a reduced dose is necessary (e.g., all or some levels of the dose ramp-up schedule) [see Dosage and Administration (2.1, 2.2)].

Acute Myeloid Leukemia

Monitor blood counts frequently through resolution of cytopenias. Management of some adverse reactions [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)] may require dose interruptions or permanent discontinuation of VENCLEXTA. Table 6 shows the dose modification guidelines for hematologic toxicities.

2.4 Dosage Modifications for Concomitant Use with Strong or Moderate CYP3A Inhibitors or P-gp Inhibitors

Table 7 describes VENCLEXTA contraindication or dosage modification based on concomitant use with a strong or moderate CYP3A inhibitor or P-gp inhibitor [see Drug Interactions (7.1)] at initiation, during, or after the ramp-up phase.

Resume the VENCLEXTA dosage that was used prior to concomitant use of a strong or moderate CYP3A inhibitor or P-gp inhibitor 2 to 3 days after discontinuation of the inhibitor [see Dosage and Administration (2.3) and Drug Interactions (7.1)].

2.5 Missed Dose

If the patient misses a dose of VENCLEXTA within 8 hours of the time it is usually taken, the patient should take the missed dose as soon as possible and resume the normal daily dosing schedule. If a patient misses a dose by more than 8 hours, the patient should not take the missed dose and should resume the usual dosing schedule the next day.

If the patient vomits following dosing, no additional dose should be taken that day. The next prescribed dose should be taken at the usual time.

5.1 Tumor Lysis Syndrome

Tumor lysis syndrome (TLS), including fatal events and renal failure requiring dialysis, has occurred in patients with high tumor burden when treated with VENCLEXTA [see Adverse Reactions (6.1, 6.2)].

In patients with CLL who followed the current (5 week) dose ramp-up and the TLS prophylaxis and monitoring measures, the rate of TLS was 2% in the VENCLEXTA CLL monotherapy studies. The rate of TLS remained consistent with VENCLEXTA in combination with obinutuzumab or rituximab. With a 2 to 3 week dose ramp-up and higher starting dose in patients with CLL/SLL, the TLS rate was 13% and included deaths and renal failure [see Adverse Reactions (6.1)].

VENCLEXTA can cause rapid reduction in tumor and thus poses a risk for TLS at initiation and during the ramp-up phase. Changes in blood chemistries consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of VENCLEXTA and at each dose increase.

The risk of TLS is a continuum based on multiple factors, including tumor burden and comorbidities. Reduced renal function further increases the risk. Patients should be assessed for risk and should receive appropriate prophylaxis for TLS, including hydration and anti-hyperuricemics. Monitor blood chemistries and manage abnormalities promptly. Interrupt dosing if needed. Employ more intensive measures (intravenous hydration, frequent monitoring, hospitalization) as overall risk increases [see Dosage and Administration (2.2, 2.3) and Use in Specific Populations (8.6)].

Concomitant use of VENCLEXTA with P-gp inhibitors or strong or moderate CYP3A inhibitors increases venetoclax exposure, may increase the risk of TLS at initiation and during ramp-up phase and requires VENCLEXTA dose adjustment [see Dosage and Administration (2.4) and Drug Interactions (7.1)].

5.2 Neutropenia

In patients with CLL, Grade 3 or 4 neutropenia developed in 63% to 64% of patients and Grade 4 neutropenia developed in 31% to 33% of patients treated with VENCLEXTA in combination and monotherapy studies (see Tables 10, 12, 14). Febrile neutropenia occurred in 4% to 6% of patients treated with VENCLEXTA in combination and monotherapy studies[see Adverse Reactions (6.1)].

In patients with AML, baseline neutrophil counts worsened in 97% to 100% of patients treated with VENCLEXTA in combination with azacitidine or decitabine or low-dose cytarabine. Neutropenia can recur with subsequent cycles of therapy.

Monitor complete blood counts throughout the treatment period. Interrupt dosing or reduce dose for severe neutropenia. Consider supportive measures including antimicrobials for signs of infection and use of growth factors (e.g., G-CSF) [see Dosage and Administration (2.3)].

5.3 Infections

Fatal and serious infections such as pneumonia and sepsis have occurred in patients treated with VENCLEXTA [see Adverse Reactions (6.1)]. Monitor patients closely for signs and symptoms of infection and treat promptly. Withhold VENCLEXTA for Grade 3 and higher infection [see Dosage and Administration (2.3)].

5.4 Immunization

Do not administer live attenuated vaccines prior to, during, or after treatment with VENCLEXTA until B-cell recovery occurs. The safety and efficacy of immunization with live attenuated vaccines during or following VENCLEXTA therapy have not been studied. Advise patients that vaccinations may be less effective.

5.5 Embryo-Fetal Toxicity

Based on its mechanism of action and findings in animals, VENCLEXTA may cause embryo-fetal harm when administered to a pregnant woman. In an embryo-fetal study conducted in mice, administration of venetoclax to pregnant animals at exposures equivalent to that observed in patients at a dose of 400 mg daily resulted in post-implantation loss and decreased fetal weight. There are no adequate and well-controlled studies in pregnant women using VENCLEXTA. Advise females of reproductive potential to avoid pregnancy during treatment. If VENCLEXTA is used during pregnancy or if the patient becomes pregnant while taking VENCLEXTA, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].

6.1 Clinical Trial Experience with CLL/SLL

CLL14

The safety of VENCLEXTA in combination with obinutuzumab (VEN+G) versus obinutuzumab in combination with chlorambucil (GClb) was evaluated in a randomized, open-label, actively controlled trial in patients with previously untreated CLL.

Patients randomized to the VEN+G arm were treated with VENCLEXTA and obinutuzumab in combination for six cycles, then with VENCLEXTA as monotherapy for an additional six cycles. Patients initiated the first dose of the 5 week ramp-up for VENCLEXTA on Day 22 of Cycle 1 and once completed, continued VENCLEXTA 400 mg once daily for a total of 12 cycles. Details of the study treatment are described in Section 14 [see Clinical Studies (14.1)]. The trial required a total Cumulative Illness Rating Scale (CIRS) >6 or CLcr <70 mL/min, hepatic transaminases and total bilirubin ≤2 times upper limit of normal, and excluded patients with any individual organ/system impairment score of 4 by CIRS except eye, ear, nose, and throat organ system.

A total of 426 patients were treated (212 with VEN+G, 214 with GClb). The median duration of exposure to VENCLEXTA was 10.5 months (range: 0 to 13.5 months). The median number of cycles was 6 for obinutuzumab and 12 for chlorambucil.

In the VEN+G arm, fatal adverse reactions that occurred in the absence of disease progression and with onset within 28 days of the last study treatment were reported in 2% (4/212) of patients, most often from infection. Serious adverse reactions were reported in 49% of patients in the VEN+G arm, most often due to febrile neutropenia and pneumonia (5% each).

In the VEN+G arm, adverse reactions led to treatment discontinuation in 16% of patients, dose reduction in 21%, and dose interruption in 74%. In the VEN+G arm, neutropenia led to dose interruption of VENCLEXTA in 41% of patients, reduction in 13%, and discontinuation in 2%.

Table 9 and Table 10 present adverse reactions and laboratory abnormalities identified in the CLL14 trial, respectively. The most common (≥15%) adverse reactions observed with VEN+G were neutropenia, diarrhea, fatigue, nausea, anemia, and upper respiratory tract infection.

Other clinically important adverse reactions (all Grades) reported in <10% of patients treated with VEN+G are presented below:

Blood & lymphatic system disorders: febrile neutropenia (6%)

Infection and infestations (all include multiple adverse reaction terms): pneumonia (9%), urinary tract infection (6%), sepsis (4%)

Metabolism and nutrition disorder: tumor lysis syndrome (1%)

During treatment with single agent VENCLEXTA after completion of VEN+G combination treatment, the most common all grade adverse reaction (≥10% patients) reported was neutropenia (26%). The most common grade ≥3 adverse reactions (≥2% patients) were neutropenia (23%), and anemia (2%).

Grade 4 laboratory abnormalities developing in ≥2% of patients treated with VEN+G include neutropenia (32%), leukopenia and lymphopenia (10%), thrombocytopenia (8%), hypocalcemia (8%), hyperuricemia (7%), blood creatinine increased (3%), hypercalcemia (3%), and hypokalemia (2%).

MURANO

The safety of VENCLEXTA in combination with rituximab (VEN+R) versus bendamustine in combination with rituximab (B+R), was evaluated in an open-label randomized study, in patients with CLL who had received at least one prior therapy.

Patients randomized to VEN+R completed the scheduled ramp-up (5 weeks) and received VENCLEXTA 400 mg once daily in combination with rituximab for 6 cycles followed by single agent VENCLEXTA for a total of 24 months after ramp-up. Patients randomized to B+R received 6 cycles (28 days per cycle) for a total of 6 months. Details of the study treatment are described in Section 14 [see Clinical Studies (14.1)].

At the time of analysis, the median duration of exposure was 22 months in the VEN+R arm compared with 6 months in the B+R arm.

In the VEN+R arm, fatal adverse reactions that occurred in the absence of disease progression and within 30 days of the last VENCLEXTA treatment and/or 90 days of last rituximab were reported in 2% (4/194) of patients. Serious adverse reactions were reported in 46% of patients in the VEN+R arm, with most frequent (≥5%) being pneumonia (9%).

In the VEN+R arm, adverse reactions led to treatment discontinuation in 16% of patients, dose reduction in 15%, and dose interruption in 71%. In the B+R arm, adverse reactions led to treatment discontinuation in 10% of patients, dose reduction in 15%, and dose interruption in 40%. In the VEN+R arm, neutropenia led to dose interruption of VENCLEXTA in 46% of patients and discontinuation in 3%, and thrombocytopenia led to discontinuation in 3% of patients.

Table 11 and Table 12 present adverse reactions and laboratory abnormalities, respectively, identified in the MURANO trial. The MURANO trial was not designed to demonstrate a statistically significant difference in adverse reaction rates for VEN+R as compared with B+R, for any specific adverse reaction or laboratory abnormality.

Other adverse reactions (all Grades) reported in ≥10% of patients in the VEN+R arm in MURANO, and other important adverse reactions are presented below:

Blood & lymphatic system disorders: anemia (16%), thrombocytopenia (15%), febrile neutropenia (4%)

Gastrointestinal disorders: nausea (21%), constipation (14%), abdominal pain (13%), mucositis (10%), vomiting (8%)

Respiratory disorders: cough (22%)

General disorders and administration site conditions: fatigue (22%), pyrexia (15%)

Skin disorders: rash (13%)

Nervous system and psychiatric disorders: headache (11%), insomnia (11%)

Infections & infestations: pneumonia (10%), sepsis (1%)

During treatment with single agent VENCLEXTA after completion of VEN+R combination treatment, the most common all grade adverse reactions (≥10% patients) reported were upper respiratory tract infection (21%), diarrhea (19%), neutropenia (16%), and lower respiratory tract infections (11%).The most common grade 3 or 4 adverse reaction (≥2% patients) were neutropenia (12%) and anemia (3%).

Laboratory Abnormalities

Table 12 describes common treatment-emergent laboratory abnormalities identified in the MURANO trial.

New Grade 4 laboratory abnormalities reported in ≥2% of patients treated with VEN+R included neutropenia (31%), lymphopenia (16%), leukopenia (6%), thrombocytopenia (6%), hyperuricemia (4%), hypocalcemia (2%), hypoglycemia (2%), and hypermagnesemia (2%).

Monotherapy Studies (M13-982, M14-032, and M12-175)

The safety of single agent VENCLEXTA at the 400 mg recommended daily dose following a dose ramp-up schedule is based on pooled data from three single-arm trials (M13-982, M14-032, and M12-175). In the pooled dataset, consisting of 352 patients with previously treated CLL or SLL, the median age was 66 years (range: 28 to 85 years), 93% were white, and 68% were male. The median number of prior therapies was 3 (range: 0 to 15). The median duration of treatment with VENCLEXTA at the time of data analysis was 14.5 months (range: 0 to 50 months). Fifty-two percent of patients received VENCLEXTA for more than 60 weeks.

Fatal adverse reactions that occurred in the absence of disease progression and within 30 days of venetoclax treatment were reported in 2% of patients in the VENCLEXTA monotherapy studies, most commonly (2 patients) from septic shock. Serious adverse reactions were reported in 52% of patients, with the most frequent (≥5%) being pneumonia (9%), febrile neutropenia (5%), and sepsis (5%).

Adverse reactions led to treatment discontinuation in 9% of patients, dose reduction in 13%, and dose interruption in 36%. The most frequent adverse reactions leading to drug discontinuation were thrombocytopenia and autoimmune hemolytic anemia. The most frequent adverse reaction (≥5%) leading to dose reductions or interruptions was neutropenia (8%).

Adverse reactions identified in these trials of single-agent VENCLEXTA are presented in Table 13.

Laboratory Abnormalities

Table 14 describes common laboratory abnormalities reported throughout treatment that were new or worsening from baseline. The most common (>5%) Grade 4 laboratory abnormalities observed with VENCLEXTA monotherapy were hematologic laboratory abnormalities, including neutropenia (33%), leukopenia (11%), thrombocytopenia (15%), and lymphopenia (9%).

Important Adverse Reactions

Tumor Lysis Syndrome

Tumor lysis syndrome is an important identified risk when initiating VENCLEXTA.

CLL14

The incidence of TLS was 1% (3/212) in patients treated with VEN+G [see Warnings and Precautions (5.1)]. All three events of TLS resolved and did not lead to withdrawal from the study. Obinutuzumab administration was delayed in two cases in response to the TLS events.

MURANO

In the open-label randomized phase 3 study, the incidence of TLS was 3% (6/194) in patients treated with VEN+R. After 77/389 patients were enrolled in the study, the protocol was amended to incorporate the current TLS prophylaxis and monitoring measures described in sections 2.1 and 2.2 [see Dosage and Administration (2.1, 2.2)]. All events of TLS occurred during the VENCLEXTA ramp-up period and were resolved within two days. All six patients completed the ramp-up and reached the recommended daily dose of 400 mg of VENCLEXTA. No clinical TLS was observed in patients who followed the current 5-week ramp-up schedule and TLS prophylaxis and monitoring measures described in sections 2.1 and 2.2 [see Dosage and Administration (2.1, 2.2)]. Rates of laboratory abnormalities relevant to TLS for patients treated with VEN+R are presented in Table 12.

Monotherapy Studies (M13-982 and M14-032)

In 168 patients with CLL treated according to recommendations described in sections 2.1 and 2.2, the rate of TLS was 2% [see Dosage and Administration (2.1, 2.2)]. All events either met laboratory TLS criteria (laboratory abnormalities that met ≥2 of the following within 24 hours of each other: potassium >6 mmol/L, uric acid >476 µmol/L, calcium <1.75 mmol/L, or phosphorus >1.5 mmol/L); or were reported as TLS events. The events occurred in patients who had a lymph node(s) ≥5 cm and/or ALC ≥25 x 109/L. All events resolved within 5 days. No TLS with clinical consequences such as acute renal failure, cardiac arrhythmias or sudden death and/or seizures was observed in these patients. All patients had CLcr ≥50 mL/min. Laboratory abnormalities relevant to TLS were hyperkalemia (17% all Grades, 1% Grade ≥3), hyperphosphatemia (14% all Grades, 2% Grade ≥3), hypocalcemia (16% all Grades, 2% Grade ≥3), and hyperuricemia (10% all Grades, <1% Grade ≥3).

In the initial Phase 1 dose-finding trials, which had shorter (2-3 week) ramp-up phase and higher starting doses, the incidence of TLS was 13% (10/77; 5 laboratory TLS, 5 clinical TLS), including 2 fatal events and 3 events of acute renal failure, 1 requiring dialysis. After this experience, TLS risk assessment, dosing regimen, TLS prophylaxis and monitoring measures were revised [see Dosage and Administration (2.1, 2.2)].

6.2 Clinical Trial Experience with AML

The safety of VENCLEXTA (400 mg daily dose) in combination with azacitidine (n=67) or decitabine (n= 13) and VENCLEXTA (600 mg daily dose) in combination with low-dose cytarabine (n= 61) is based on two non-randomized trials of patients with newly-diagnosed AML [see Clinical Studies (14.3)]. The median duration of exposure for patients taking VENCLEXTA in combination with azacitidine and decitabine was 6.5 months (range: 0.1 to 31.9 months) and 8.4 months (range: 0.5 to 22.3 months), respectively. The median duration of exposure for patients taking VENCLEXTA in combination with low dose cytarabine was 3.9 months (range: 0.2 to 29.2 months).

VENCLEXTA in Combination with Azacitidine or Decitabine

Azacitidine

The most common adverse reactions (≥30%) of any grade were nausea, diarrhea, constipation, neutropenia, thrombocytopenia, hemorrhage, peripheral edema, vomiting, fatigue, febrile neutropenia, rash, and anemia.

Serious adverse reactions were reported in 75% of patients. The most frequent serious adverse reactions (≥5%) were febrile neutropenia, pneumonia (excluding fungal), sepsis (excluding fungal), respiratory failure, and multiple organ dysfunction syndrome.

The incidence of fatal adverse drug reactions was 1.5% within 30 days of starting treatment. No reaction had an incidence of ≥2%.

Discontinuations due to adverse reactions occurred in 21% of patients. The most frequent adverse reactions leading to drug discontinuation (≥2%) were febrile neutropenia and pneumonia (excluding fungal).

Dosage interruptions due to adverse reactions occurred in 61% of patients. The most frequent adverse reactions leading to dose interruption (≥5%) were neutropenia, febrile neutropenia, and pneumonia (excluding fungal).

Dosage reductions due to adverse reactions occurred in 12% of patients. The most frequent adverse reaction leading to dose reduction (≥5%) was neutropenia.

Decitabine

The most common adverse reactions (≥30%) of any grade were febrile neutropenia, constipation, fatigue, thrombocytopenia, abdominal pain, dizziness, hemorrhage, nausea, pneumonia (excluding fungal), sepsis (excluding fungal), cough, diarrhea, neutropenia, back pain, hypotension, myalgia, oropharyngeal pain, peripheral edema, pyrexia, and rash.

Serious adverse reactions were reported in 85% of patients. The most frequent serious adverse reactions (≥5%) were febrile neutropenia, sepsis (excluding fungal), pneumonia (excluding fungal), diarrhea, fatigue, cellulitis, and localized infection.

One (8%) fatal adverse drug reaction of bacteremia occurred within 30 days of starting treatment.

Discontinuations due to adverse reactions occurred in 38% of patients. The most frequent adverse reaction leading to drug discontinuation (≥5%) was pneumonia (excluding fungal).

Dosage interruptions due to adverse reactions occurred in 62% of patients. The most frequent adverse reactions leading to dose interruption (≥5%) were febrile neutropenia, neutropenia, and pneumonia (excluding fungal).

Dosage reductions due to adverse reactions occurred in 15% of patients. The most frequent adverse reaction leading to dose reduction (≥5%) was neutropenia.

Adverse reactions reported in patients with newly-diagnosed AML using VENCLEXTA in combination with azacitidine or decitabine are presented in Table 15.

Laboratory Abnormalities

Table 16 describes common laboratory abnormalities reported throughout treatment that were new or worsening from baseline.

VENCLEXTA in Combination with Low-Dose Cytarabine

The most common adverse reactions (≥30%) of any grade were nausea, thrombocytopenia, hemorrhage, febrile neutropenia, neutropenia, diarrhea, fatigue, constipation, and dyspnea.

Serious adverse reactions were reported in 95% of patients. The most frequent serious adverse reactions (≥5%) were febrile neutropenia, sepsis (excluding fungal), hemorrhage, pneumonia (excluding fungal), and device-related infection.

The incidence of fatal adverse drug reactions was 4.9% within 30 days of starting treatment with no reaction having an incidence of ≥2%.

Discontinuations due to adverse reactions occurred in 33% of patients. The most frequent adverse reactions leading to drug discontinuation (≥2%) were hemorrhage and sepsis (excluding fungal).

Dosage interruptions due to adverse reactions occurred in 52% of patients. The most frequent adverse reactions leading to dose interruption (≥5%) were thrombocytopenia, neutropenia, and febrile neutropenia.

Dosage reductions due to adverse reactions occurred in 8% of patients. The most frequent adverse reaction leading to dose reduction (≥2%) was thrombocytopenia.

Adverse reactions reported in patients with newly-diagnosed AML receiving VENCLEXTA in combination with low-dose cytarabine are presented in Table 17.

Laboratory Abnormalities

Table 18 describes common laboratory abnormalities reported throughout treatment that were new or worsening from baseline.

Tumor Lysis Syndrome

Tumor lysis syndrome is an important risk when initiating treatment in patients with AML. The incidence of TLS was 3% (2/61) with VENCLEXTA in combination with low-dose cytarabine with implementation of dose ramp-up schedule in addition to standard prophylaxis and monitoring measures. All events were laboratory TLS, and all patients were able to reach the target dose.

7.1 Effects of Other Drugs on VENCLEXTA

Strong or Moderate CYP3A Inhibitors or P-gp Inhibitors

Concomitant use with a strong or moderate CYP3A inhibitor or a P-gp inhibitor increases venetoclax Cmax and AUCinf[see Clinical Pharmacology (12.3)], which may increase VENCLEXTA toxicities, including the risk of TLS [see Warnings and Precautions (5)].

Concomitant use with a strong CYP3A inhibitor at initiation and during the ramp-up phase in patients with CLL/SLL is contraindicated [see Contraindications (4)].

In patients with CLL/SLL taking a steady daily dosage (after ramp-up phase), consider alternative medications or adjust VENCLEXTA dosage and closely monitor for signs of VENCLEXTA toxicities [see Dosage and Administration (2.3, 2.4)].

In patients with AML, adjust VENCLEXTA dosage and closely monitor for signs of VENCLEXTA toxicities [see Dosage and Administration (2.3, 2.4)].

Resume the VENCLEXTA dosage that was used prior to concomitant use with a strong or moderate CYP3A inhibitor or a P-gp inhibitor 2 to 3 days after discontinuation of the inhibitor [see Dosage and Administration (2.3, 2.4)].

Avoid grapefruit products, Seville oranges, and starfruit during treatment with VENCLEXTA, as they contain inhibitors of CYP3A.

Strong or Moderate CYP3A Inducers

Concomitant use with a strong CYP3A inducer decreases venetoclax Cmax and AUCinf[see Clinical Pharmacology (12.3)], which may decrease VENCLEXTA efficacy. Avoid concomitant use of VENCLEXTA with strong CYP3A inducers or moderate CYP3A inducers.

7.2 Effect of VENCLEXTA on Other Drugs

Warfarin

Concomitant use of VENCLEXTA increases warfarin Cmax and AUCinf[see Clinical Pharmacology (12.3)], which may increase the risk of bleeding. Closely monitor international normalized ratio (INR) in patients using warfarin concomitantly with VENCLEXTA.

P-gp Substrates

Concomitant use of VENCLEXTA increases Cmax and AUCinf of P-gp substrates [see Clinical Pharmacology (12.3)], which may increase toxicities of these substrates. Avoid concomitant use of VENCLEXTA with a P-gp substrate. If a concomitant use is unavoidable, separate dosing of the P-gp substrate at least 6 hours before VENCLEXTA.

8.1 Pregnancy

Risk Summary

There are no available data on VENCLEXTA use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. Based on toxicity observed in mice, VENCLEXTA may cause fetal harm when administered to pregnant women. In mice, venetoclax was fetotoxic at exposures 1.2 times the human clinical exposure based on AUC at a human dose of 400 mg daily. If VENCLEXTA is used during pregnancy or if the patient becomes pregnant while taking VENCLEXTA, the patient should be apprised of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

Data

Animal data

In embryo-fetal development studies, venetoclax was administered to pregnant mice and rabbits during the period of organogenesis. In mice, venetoclax was associated with increased post-implantation loss and decreased fetal body weight at 150 mg/kg/day (maternal exposures approximately 1.2 times the human AUC exposure at a dose of 400 mg daily). No teratogenicity was observed in either the mouse or the rabbit.

8.2 Lactation

Risk Summary

There are no data on the presence of VENCLEXTA in human milk, the effects of VENCLEXTA on the breastfed child, or the effects of VENCLEXTA on milk production. Venetoclax was present in the milk when administered to lactating rats (see Data).

Because many drugs are excreted in human milk and because the potential for serious adverse reactions in a breastfed child from VENCLEXTA is unknown, advise nursing women to discontinue breastfeeding during treatment with VENCLEXTA.

Data

Animal Data

Venetoclax was administered (single dose; 150 mg/kg oral) to lactating rats 8 to 10 days parturition. Venetoclax in milk was 1.6 times lower than in plasma. Parent drug (venetoclax) represented the majority of the total drug-related material in milk, with trace levels of three metabolites.

8.3 Females and Males of Reproductive Potential

VENCLEXTA may cause fetal harm [see Warnings and Precautions (5.5) and Use in Specific Populations (8.1)].

Pregnancy Testing

Conduct pregnancy testing in females of reproductive potential before initiation of VENCLEXTA [see Use in Specific Populations (8.1)].

Contraception

Advise females of reproductive potential to use effective contraception during treatment with VENCLEXTA and for at least 30 days after the last dose [see Use in Specific Populations (8.1)].

Infertility

Based on findings in animals, male fertility may be compromised by treatment with VENCLEXTA [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

Safety and effectiveness have not been established in pediatric patients.

In a juvenile toxicology study, mice were administered venetoclax at 10, 30, or 100 mg/kg/day by oral gavage from 7 to 60 days of age. Clinical signs of toxicity included decreased activity, dehydration, skin pallor, and hunched posture at ≥30 mg/kg/day. In addition, mortality and body weight effects occurred at 100 mg/kg/day. Other venetoclax-related effects were reversible decreases in lymphocytes at ≥10 mg/kg/day; a dose of 10 mg/kg/day is approximately 0.06 times the clinical dose of 400 mg on a mg/m2 basis for a 20 kg child.

8.5 Geriatric Use

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Of the 352 patients with previously treated CLL/SLL evaluated for safety from 3 open-label trials of VENCLEXTA monotherapy, 57% (201/352) were ≥65 years of age and 18% (62/352) were ≥75 years of age.

No clinically meaningful differences in safety and effectiveness were observed between older and younger patients in the combination and monotherapy studies.

Acute Myeloid Leukemia

Of the 67 patients treated with VENCLEXTA in combination with azacitidine in the clinical trial, 96% were ≥65 years of age and 50% were ≥ 75 years of age. Of the 13 patients treated with VENCLEXTA in combination with decitabine in the clinical trial, 100% were ≥65 years of age and 26% were ≥ 75 years of age. Of the 61 patients treated with VENCLEXTA in combination with low-dose cytarabine, 97% were ≥65 years of age and 66% were ≥75 years of age.

The efficacy and safety data presented in the Adverse Reactions and Clinical Studies sections were obtained from these patients [see Adverse Reactions (6.2) and Clinical Studies (14.2)]. There are insufficient patient numbers to show differences in safety and effectiveness between geriatric and younger patients.

8.6 Renal Impairment

Due to the increased risk of TLS, patients with reduced renal function (CLcr <80 mL/min, calculated by Cockcroft-Gault formula) require more intensive prophylaxis and monitoring to reduce the risk of TLS when initiating treatment with VENCLEXTA [see Dosage and Administration (2.2, 2.3) and Warnings and Precautions (5.1)].

No dose adjustment is recommended for patients with mild or moderate renal impairment (CLcr ≥ 30 mL/min [see Clinical Pharmacology (12.3)]. A recommended dose has not been determined for patients with severe renal impairment (CLcr < 30 mL/min) or patients on dialysis.

12.1 Mechanism of Action

Venetoclax is a selective and orally bioavailable small-molecule inhibitor of BCL-2, an anti-apoptotic protein. Overexpression of BCL-2 has been demonstrated in CLL and AML 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. In nonclinical studies, venetoclax has demonstrated cytotoxic activity in tumor cells that overexpress BCL-2.

12.2 Pharmacodynamics

Based on the exposure response analyses for efficacy, a relationship between drug exposure and a greater likelihood of response was observed in clinical studies in patients with CLL/SLL, and in patients with AML. Based on the exposure response analyses for safety, a relationship between drug exposure and a greater likelihood of some safety events was observed in clinical studies in patients with AML. No exposure-safety relationship was observed in patients with CLL/SLL at doses up to 1200 mg given as monotherapy and up to 600 mg given in combination with rituximab.

Cardiac Electrophysiology

The effect of multiple doses of VENCLEXTA up to 1200 mg once daily (2 times the maximum approved recommended dosage) on the QTc interval was evaluated in an open-label, single-arm study in 176 patients with previously treated hematologic malignancies. VENCLEXTA had no large effect on QTc interval (i.e., > 20 ms) and there was no relationship between venetoclax exposure and change in QTc interval.

12.3 Pharmacokinetics

Venetoclax mean (± standard deviation) steady state Cmax was 2.1 ± 1.1 mcg/mL and AUC0-24 was32.8 ± 16.9 mcg•h/mL following administration of 400 mg once daily with a low-fat meal. Venetoclax steady state AUC increased proportionally over the dose range of 150 to 800 mg (0.25 to 1.33 times the maximum approved recommended dosage). The pharmacokinetics of venetoclax does not change over time.

Absorption

Maximum plasma concentration of venetoclax was reached 5 to 8 hours following multiple oral administration under fed conditions.

Effect of Food

Administration with a low-fat meal (approximately 512 kilocalories, 25% fat calories, 60% carbohydrate calories, and 15% protein calories) increased venetoclax exposure by approximately 3.4-fold and administration with a high-fat meal (approximately 753 kilocalories, 55% fat calories, 28% carbohydrate calories, and 17% protein calories) increased venetoclax exposure by 5.1- to 5.3-fold compared with fasting conditions.

Distribution

Venetoclax is highly bound to human plasma protein with unbound fraction in plasma <0.01 across a concentration range of 1-30 micromolar (0.87-26 mcg/mL). The mean blood-to-plasma ratio was 0.57. The apparent volume of distribution (Vdss/F) of venetoclax ranged from 256-321 L in patients.

Elimination

The terminal elimination half-life of venetoclax was approximately 26 hours.

Metabolism

Venetoclax is predominantly metabolized by CYP3A in vitro. The major metabolite identified in plasma, M27, has an inhibitory activity against BCL-2 that is at least 58-fold lower than venetoclax in vitro and its AUC represented 80% of the parent AUC.

Excretion

After single oral dose of radiolabeled [14C]-venetoclax 200 mg to healthy subjects, > 99.9% of the dose was recovered in feces (20.8% as unchanged) and < 0.1% in urine within 9 days.

Specific Populations

No clinically significant differences in the pharmacokinetics of venetoclax were observed based on age (19 to 90 years), sex, race (White, Black, Asians, and Others), weight, mild to moderate renal impairment (CLcr 30 to 89 mL/min, calculated by Cockcroft-Gault), or mild to moderate hepatic impairment (normal total bilirubin and aspartate transaminase (AST) > upper limit of normal (ULN) or total bilirubin 1 to 3 times ULN). The effect of severe renal impairment (CLcr < 30 mL/min), dialysis, or severe hepatic impairment (total bilirubin > 3 times ULN) on venetoclax pharmacokinetics is unknown.

Drug Interactions Studies

Clinical Studies

No clinically significant differences in venetoclax pharmacokinetics were observed when co-administered with azacitidine, azithromycin, cytarabine, decitabine, gastric acid reducing agents, obinutuzumab, or rituximab.

Ketoconazole

Concomitant use of ketoconazole (a strong CYP3A, P-gp and BCRP inhibitor) 400 mg once daily for 7 days increased venetoclax Cmax by 130% and AUCinf by 540% [see Drug Interactions (7.1)].

Ritonavir

Concomitant use of ritonavir (a strong CYP3A, P-gp and OATP1B1/B3 inhibitor) 50 mg once daily for 14 days increased venetoclax Cmax by 140% and AUC by 690% [see Drug Interactions (7.1)].

Posaconazole

Concomitant use of posaconazole (a strong CYP3A and P-gp inhibitor) 300 mg with venetoclax 50 mg and 100 mg for 7 days resulted in 61% and 86% higher venetoclax Cmax, respectively, compared with venetoclax 400 mg administered alone. The venetoclax AUC24 was 90% and 144% higher, respectively.

Rifampin

Concomitant use of a single dose of rifampin(an OATP1B1/1B3 and P-gp inhibitor) 600 mg increased venetoclax Cmax by 106% and AUCinf by 78%. Concomitant use of multiple doses of rifampin (as a strong CYP3A inducer) 600 mg once daily for 13 days decreased venetoclax Cmax by 42% and AUCinf by 71% [see Drug Interactions (7.1)].

Warfarin

Concomitant use of a single 400 mg dose of venetoclax with 5 mg warfarin resulted in 18% to 28% increase in Cmax and AUC∞ of R-warfarin and S-warfarin [see Drug Interactions (7.2)].

Digoxin

Concomitant use of a single dose of venetoclax 100 mg with digoxin (a P-gp substrate) 0.5 mg increased digoxin Cmax by 35% and AUCinf by 9% [see Drug Interactions (7.2)].

In Vitro Studies

Venetoclax is not an inhibitor or inducer of CYP1A2, CYP2B6, CYP2C19, CYP2D6 or CYP3A4. Venetoclax is a weak inhibitor of CYP2C8, CYP2C9, and UGT1A1.

Venetoclax is not an inhibitor of UGT1A4, UGT1A6, UGT1A9, or UGT2B7.

Venetoclax is an inhibitor and substrate of P-gp and BCRP and weak inhibitor of OATP1B1.

Venetoclax is not an inhibitor of OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, or MATE2K.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been conducted with venetoclax.

Venetoclax was not mutagenic in an in vitro bacterial mutagenicity (Ames) assay, did not induce numerical or structural aberrations in an in vitro chromosome aberration assay using human peripheral blood lymphocytes, and was not clastogenic in an in vivo mouse bone marrow micronucleus assay at doses up to 835 mg/kg. The M27 metabolite was negative for genotoxic activity in in vitro Ames and chromosome aberration assays.

Fertility and early embryonic development studies were conducted in male and female mice. These studies evaluate mating, fertilization, and embryonic development through implantation. There were no effects of venetoclax on estrous cycles, mating, fertility, corpora lutea, uterine implants or live embryos per litter at dosages up to 600 mg/kg/day. However, a risk to human male fertility exists based on testicular toxicity (germ cell loss) observed in dogs at exposures as low as 0.5 times the human AUC exposure at a dose of 400 mg.

13.2 Animal Toxicology and/or Pharmacology

In dogs, venetoclax caused single-cell necrosis in various tissues, including the gallbladder, exocrine pancreas, and stomach with no evidence of disruption of tissue integrity or organ dysfunction; these findings were minimal to mild in magnitude. Following a 4-week dosing period and subsequent 4-week recovery period, minimal single-cell necrosis was still present in some tissues and reversibility has not been assessed following longer periods of dosing or recovery.

In addition, after approximately 3 months of daily dosing in dogs, venetoclax caused progressive white discoloration of the hair coat, due to loss of melanin pigment.

14.1 Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Combination Therapy

CLL14

CLL14 (BO25323) was a randomized (1:1), multicenter, open label, actively controlled, phase 3 trial (NCT02242942) that evaluated the efficacy and safety of VENCLEXTA in combination with obinutuzumab (VEN+G) versus obinutuzumab in combination with chlorambucil (GClb) for patients with previously untreated CLL with coexisting medical conditions (total Cumulative Illness Rating Scale [CIRS] score > 6 or CLcr < 70 mL/min). The trial required hepatic transaminases and total bilirubin ≤2 times upper limit of normal and excluded patients with Richter’s transformation or any individual organ/system impairment score of 4 by CIRS except eye, ear, nose, and throat organ system.

All patients received obinutuzumab 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, and on Day 1 of each subsequent cycle, for a total of 6 cycles. Patients in the VEN+G arm began the 5-week VENCLEXTA ramp-up schedule [see Dosage and Administration (2.1, 2.2)] on Day 22 of Cycle 1, and received VENCLEXTA 400 mg once daily from Cycle 3 Day 1 until the last day of Cycle 12. Patients randomized to the GClb arm received 0.5 mg/kg oral chlorambucil on Day 1 and Day 15 of Cycles 1 to 12. Each cycle was 28 days.

A total of 432 patients were randomized, 216 to each study arm. Baseline demographic and disease characteristics were similar between the study arms. The median age was 72 years (range: 41 to 89 years), 89% were white, 67% were male; 36% and 43% were Binet stage B and C, respectively, and 88% had ECOG performance status <2. The median CIRS score was 8.0 (range: 0 to 28) and 58% of patients had CLcr <70 mL/min. A 17p deletion was detected in 8% of patients, TP53 mutations in 7%, 11q deletion in 19%, and unmutated IgVH in 57%.

The major efficacy outcome was progression-free survival (PFS) as assessed by an Independent Review Committee (IRC). The median duration of follow-up for PFS was 28 months (range: 0.1 to 36 months).

Efficacy results for CLL14 are shown in Table 19. The Kaplan-Meier curve for PFS is shown in Figure 1.

Figure 1: Kaplan-Meier Curve of IRC-Assessed Progression-free Survival in CLL14

At the time of analysis, median overall survival (OS) had not been reached, with fewer than 10% of patients experiencing an event. The median duration of follow-up for OS was 28 months.

Minimal residual disease (MRD) was evaluated using allele-specific oligonucleotide polymerase chain reaction (ASO-PCR). The definition of negative status was less than one CLL cell per 104 leukocytes. Rates of MRD negativity 3 months after the completion of treatment regardless of response and in patients who achieved CR are shown in Table 20. At this assessment, 134 patients in the VEN+G arm who were MRD negative in peripheral blood had matched bone marrow specimens; of these, 122 patients (91%) were MRD negative in both peripheral blood and bone marrow.

Twelve months after the completion of treatment, MRD negativity rates in peripheral blood were 58% (126/216) in patients treated with VEN+G and 9% (20/216) in patients treated with GClb.

MURANO

MURANO was a randomized (1:1), multicenter, open label study (NCT02005471) that evaluated the efficacy and safety of VENCLEXTA in combination with rituximab (VEN+R) versus bendamustine in combination with rituximab (B+R) in patients with CLL who had received at least one line of prior therapy. Patients in the VEN+R arm completed the 5-week ramp-up schedule [see Dosage and Administration (2.1, 2.2)] and received VENCLEXTA 400 mg once daily for 24 months from Cycle 1 Day 1 of rituximab in the absence of disease progression or unacceptable toxicity. Rituximab was initiated intravenously after the 5-week dose ramp-up at 375 mg/m2 on Day 1 of Cycle 1 and 500 mg/m2 on Day 1 of Cycles 2-6. Each cycle was 28 days. Patients randomized to B+R 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.

A total of 389 patients were randomized: 194 to the VEN+R arm and 195 to the B+R arm. Baseline demographic and disease characteristics were similar between the VEN+R and B+R arms. The median age was 65 years (range: 22-85 years), 97% were white, 74% were male, and 99% had ECOG performance status <2. Median prior lines of therapy was 1 (range: 1-5); 59% had received 1 prior therapy, 26% had received 2 prior therapies, and 16% had received 3 or more prior therapies. Prior therapies included alkylating agents (94%), anti-CD20 antibodies (77%), B-cell receptor pathway inhibitors (2%), and prior purine analogs (81%, including fludarabine/cyclophosphamide/rituximab in 55%). A 17p deletion was detected in 24% of patients, TP53 mutations in 25%, 11q deletion in 32%, and unmutated IgVH in 63%.

Efficacy was based on progression-free survival (PFS) as assessed by an Independent Review Committee (IRC). The median follow-up for PFS was 23.4 months (range: 0 to 37.4+ months).

Efficacy results for MURANO are shown in Table 21. The Kaplan-Meier curve for PFS is shown in Figure 2.

Figure 2. Kaplan-Meier Curve of IRC-Assessed Progression-free Survival in MURANO

At the time of analysis, median overall survival had not been reached in either arm after a median follow-up of 22.9 months.

At 3 months after the last dose of rituximab, the MRD negativity rate in peripheral blood in patients who achieved PR or better was 53% (103/194) in the VEN+R arm and 12% (23/195) in the B+R arm. The MRD-negative CR/CRi rate at this timepoint was 3% (6/194) in the VEN+R arm and 2% (3/195) in the B+R arm.

Monotherapy

The efficacy of VENCLEXTA monotherapy in previously-treated CLL or SLL is based on three single-arm studies.

Study M13-982

The efficacy of VENCLEXTA was established in study M13-982 (NCT01889186), an open-label, single-arm, multicenter clinical trial of 106 patients with CLL with 17p deletion who had received at least one prior therapy. In the study, 17p deletion was confirmed in peripheral blood specimens from patients using Vysis CLL FISH Probe Kit, which is FDA approved for selection of patients for VENCLEXTA treatment. 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.

Efficacy was based on overall response rate (ORR) as assessed by an Independent Review Committee (IRC).  

Table 22 summarizes the baseline demographic and disease characteristics of the study population.

The median time on treatment at the time of evaluation was 12.1 months (range: 0 to 21.5 months). Efficacy results are shown in Table 23.

The median time to first response was 0.8 months (range: 0.1 to 8.1 months).

Based on a later data cutoff date and investigator-assessed efficacy, the duration of response (DOR) ranged from 2.9 to 32.8+ months. The median DOR has not been reached with median follow-up of 22 months.

MRD was evaluated in peripheral blood and bone marrow for patients who achieved CR or CRi, following treatment with VENCLEXTA. Three percent (3/106) achieved MRD negativity in the peripheral blood and bone marrow (less than one CLL cell per 104 leukocytes).

Study M12-175

Study M12-175 (NCT01328626) was a multicenter, open-label trial that enrolled previously treated patients with CLL or SLL, including those with 17p deletion. Efficacy was evaluated in 67 patients (59 with CLL, 8 with SLL) who had received a 400 mg daily dose of VENCLEXTA. Patients continued this dose until disease progression or unacceptable toxicity. The median duration of treatment at the time of evaluation was 22.1 months (range: 0.5 to 50.1 months).

The median age was 66 years (range: 42 to 84 years), 78% were male and 87% were white. The median number of prior treatments was 3 (range: 1 to 11). At baseline, 67% of patients had one or more nodes ≥5 cm, 30% of patients had ALC ≥25 x 109/L, 33% had documented unmutated IgVH, and 21% had documented 17p deletion.

Efficacy in CLL was evaluated according to 2008 IWCLL guidelines. As assessed by an IRC, the ORR was 71% (95% CI: 58%, 82%), CR + CRi rate was 7%, and PR rate was 64%.

Based on investigator assessments, the ORR in patients with CLL was 80% (14% CR+ CRi, 66% PR + nPR). With an estimated median follow-up of 25.2 months, the DOR ranged from 2.3+ to 48.6+ months. Of the 47 responders, 83% had a DOR of at least 12 months.

For the 8 patients with SLL, the investigator-assessed ORR was 100%.

Study M14-032

Study M14-032 (NCT02141282) was an open-label, multicenter, study that evaluated the efficacy of VENCLEXTA in patients with CLL who had been previously treated with and progressed on or after ibrutinib or idelalisib. Patients received a daily dose of 400 mg of VENCLEXTA following the ramp-up schedule. Patients continued to receive VENCLEXTA 400 mg once daily until disease progression or unacceptable toxicity. At the time of analysis, the median duration of treatment was 14.3 months (range: 0.1 to 31.4 months).

Of the 127 patients treated (91 with prior ibrutinib, 36 with prior idelalisib), the median age was 66 years (range: 28 to 85 years), 70% were male and 92% were white. The median number of prior treatments was 4 (range: 1 to 15). At baseline, 41% of patients had one or more nodes ≥5 cm, 31% had an absolute lymphocyte count ≥25 x 109/L, 57% had documented unmutated IgVH, and 39% had documented 17p deletion.

Efficacy was based on 2008 IWCLL guidelines. Based on IRC assessment, the ORR was 70% (95% CI: 61%, 78%), with a CR + CRi rate of 1%, and PR rate of 69%.

Based on investigator assessment, the ORR was 65% (95% CI: 56%, 74%). The median DOR per investigator has not been reached with an estimated median follow-up of 14.6 months.

14.2 Acute Myeloid Leukemia

VENCLEXTA was studied in two open-label non-randomized trials in patients with newly-diagnosed AML who were ≥75 years of age, or had comorbidities that precluded the use of intensive induction chemotherapy based on at least one of the following criteria: baseline Eastern Cooperative Oncology Group (ECOG) performance status of 2-3, severe cardiac or pulmonary comorbidity, moderate hepatic impairment, or CLcr <45 mL/min or other comorbidity. Efficacy was established based on the rate of complete remission (CR) and the duration of CR.

Study M14-358

VENCLEXTA was studied in a non-randomized, open-label clinical trial (NCT02203773) of VENCLEXTA in combination with azacitidine (N=84) or decitabine (N=31) in patients with newly-diagnosed AML. Of those patients, 67 who received azacitidine combination and 13 who received decitabine combination were age 75 or older or had comorbidities that precluded the use of intensive induction chemotherapy.

Patients received VENCLEXTA via a daily ramp-up to a final 400 mg once daily dose [see Dosage and Administration (2.1)]. During the ramp-up, patients received TLS prophylaxis and were hospitalized for monitoring. Azacitidine at 75 mg/m2 was administered either intravenously or subcutaneously on Days 1-7 of each 28-day cycle beginning on Cycle 1 Day 1. Decitabine at 20 mg/m2 was administered intravenously on Days 1-5 of each 28-day cycle beginning on Cycle 1 Day 1. Patients continued to receive treatment cycles until disease progression or unacceptable toxicity. Azacitidine dose reduction was implemented in the clinical trial for management of hematologic toxicity, see azacitidine full prescribing information. Dose reductions for decitabine were not implemented in the clinical trial.

Table 24 summarizes the baseline demographic and disease characteristics of the study population.

The efficacy results are shown in Table 25.

The median follow-up was 7.9 months (range: 0.4 to 36 months) for VENCLEXTA in combination with azacitidine. At the time of analysis, for patients who achieved a CR, the median observed time in remission was 5.5 months (range: 0.4 to 30 months). The observed time in remission is the time from the start of CR to the time of data cut-off date or relapse from CR.

The median follow-up was 11 months (range: 0.7 to 21 months) for VENCLEXTA in combination with decitabine. At the time of analysis, for patients who achieved a CR, the median observed time in remission was 4.7 months (range: 1.0 to 18 months). The observed time in remission is the time from the start of CR to the time of data cut-off date or relapse from CR.

Median time to first CR or CRh for patients treated with VENCLEXTA in combination with azacitidine was 1.0 month (range: 0.7 to 8.9 months).

Median time to first CR or CRh for patients treated with VENCLEXTA in combination with decitabine was 1.9 months (range: 0.8 to 4.2 months).

Of patients treated with VENCLEXTA in combination with azacitidine, 7.5% (5/67) subsequently received stem cell transplant.

The study enrolled 35 additional patients (age range: 65 to 74 years) who did not have known comorbidities that preclude the use of intensive induction chemotherapy and were treated with VENCLEXTA in combination with azacitidine (N=17) or decitabine (N=18).

For the 17 patients treated with VENCLEXTA in combination with azacitidine, the CR rate was 35% (95% CI: 14%, 62%). The CRh rate was 41% (95% CI: 18%, 67%). Seven (41%) patients subsequently received stem cell transplant.

For the 18 patients treated with VENCLEXTA in combination with decitabine, the CR rate was 56% (95% CI: 31%, 79%). The CRh rate was 22% (95% CI: 6.4%, 48%). Three (17%) patients subsequently received stem cell transplant. 

Study M14-387

VENCLEXTA was studied in a non-randomized, open-label clinical trial (NCT02287233) of VENCLEXTA in combination with low dose cytarabine (N=82) in patients with newly-diagnosed AML, including patients with previous exposure to a hypomethylating agent for an antecedent hematologic disorder. Of those patients, 61 were age 75 or older or had comorbidities that precluded the use of intensive induction chemotherapy based on at least one of the criterion: baseline Eastern Cooperative Oncology Group (ECOG) performance status of 2-3, severe cardiac or pulmonary comorbidity, moderate hepatic impairment, or CLcr ≥30 to <45 mL/min or other comorbidity.

Patients initiated VENCLEXTA via daily ramp-up to a final 600 mg once daily dose [see Dosage and Administration (2.1)]. During the ramp-up, patients received TLS prophylaxis and were hospitalized for monitoring. Cytarabine at a dose of 20 mg/m2 was administered subcutaneously once daily on Days 1-10 of each 28-day cycle beginning on Cycle 1 Day 1. Patients continued to receive treatment cycles until disease progression or unacceptable toxicity. Dose reduction for low-dose cytarabine was not implemented in the clinical trial.

Table 26 summarizes the baseline demographic and disease characteristics of the study population.

Efficacy results are shown in Table 27.

The median follow-up was 6.5 months (range: 0.3 to 34 months). At the time of analysis, for patients who achieved a CR, the median observed time in remission was 6.0 months (range: 0.03 to 25 months). The observed time in remission is the time from the start of CR to the time of data cut-off date or relapse from CR.

Median time to first CR or CRh for patients treated with VENCLEXTA in combination with low-dose cytarabine was 1.0 month (range: 0.8 to 9.4 months).

The study enrolled 21 additional patients (age range: 67 to 74 years) who did not have known comorbidities that preclude the use of intensive induction chemotherapy and were treated with VENCLEXTA in combination with low-dose cytarabine. The CR rate was 33% (95% CI:15%, 57%). The CRh rate was 24% (95% CI: 8.2%, 47%). One patient (4.8%) subsequently received stem cell transplant.