Results from a clinical trial using VENCLEXTA™ (venetoclax) oral monotherapy

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The efficacy of VENCLEXTA™ was established in 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 until disease progression or unacceptable toxicity.¹

CLL=chronic lymphocytic leukemia.

Patients treated with VENCLEXTA monotherapy achieved over 80% ORR—including complete remissions¹

ORR=overall response rate; CR=complete remission; CRi=CR with incomplete marrow recovery; nPR=nodular partial response; PR=partial response.

Median DoR not yet reached with ~12-month follow-up for patients treated with VENCLEXTA¹

Rapid response in patients who responded to VENCLEXTA¹

*	Per IRC assessment (n=85). Time to first response: The number of days from the date of the first dose to the date of the first sign of response (CR, CRi, nPR, or PR).²

MRD negativity was achieved with VENCLEXTA in the peripheral blood and bone marrow of select previously treated CLL patients with 17p deletion¹

	MRD=minimal residual disease.
^†	MRD was evaluated in peripheral blood and bone marrow for patients who achieved CR or CRi, following treatment with VENCLEXTA.

•	VENCLEXTA is the only oral monotherapy approved for previously treated patients with 17p deletion CLL based on a data set that included MRD negativity¹
•	MRD negativity was evaluated using flow cytometry and defined as having achieved <1 CLL cell in 10,000 leukocytes²

Summary of safety information with VENCLEXTA™¹

•	The safety of single agent VENCLEXTA at the 400-mg recommended daily dose following a dose ramp-up schedule is based on pooled data of 240 patients with previously treated CLL in two phase 2 trials and one phase 1 trial

	RTI=respiratory tract infection.
	Adverse reactions graded using NCI Common Terminology Criteria for Adverse Events version 4.0.
*	Neutropenia/neutrophil count decreased.
^†	Anemia/hemoglobin decreased.
^‡	Thrombocytopenia/platelet count decreased.

•	The median duration of treatment at the time of data analysis was approximately 10.3 months (range: 0 to 34.1 months); approximately 46% of patients received VENCLEXTA for more than 48 weeks
•	Serious ARs were reported in 43.8% of patients. The most frequent serious ARs (≥2%) were pneumonia (5%), febrile neutropenia (4.6%), pyrexia (3.3%), autoimmune hemolytic anemia (AIHA) (2.9%), anemia (2.1%), and TLS (2.1%)^1,3
•	The most common ARs (≥20%, any grade) were neutropenia (45%), diarrhea (35%), nausea (33%), anemia (29%), upper respiratory tract infection (22%), thrombocytopenia (22%), and fatigue (21%)¹
•	Discontinuations due to ARs occurred in 8.3% of patients. The most frequent adverse reactions leading to drug discontinuation were thrombocytopenia and AIHA¹
•	Dosage adjustments due to ARs occurred in 9.6% of patients. The most frequent adverse reactions leading to dosage adjustments were neutropenia, febrile neutropenia, and thrombocytopenia¹
•	A trend for increased adverse events was observed in patients with moderate hepatic impairment; monitor these patients more closely for signs of toxicity during the initiation and dose ramp-up phase¹

Please see full Prescribing Information.

References: 1. Venclexta Prescribing Information. 2. U.S. Food and Drug Administration website. U.S. Department of Health and Human Services. Center for Drug Evaluation and Research: Medical Review(s)/Statistical Review(s). http://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208573Orig1s000MedR.pdf. Review completion date, March 14, 2016. Accessed July 22, 2016. 3. Data on file. ABVRRTI62926.

INDICATION AND IMPORTANT SAFETY INFORMATION

Indication

•	VENCLEXTA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion, as detected by an FDA-approved test, who have received at least one prior therapy.^a
•	This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Important Safety Information

Contraindication

•	Concomitant use of VENCLEXTA with strong CYP3A inhibitors at initiation and during ramp-up phase is contraindicated.

Tumor Lysis Syndrome

•	Tumor lysis syndrome (TLS), including fatal events and renal failure requiring dialysis, has occurred in previously treated CLL patients with high tumor burden treated with VENCLEXTA.

•	VENCLEXTA 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.

•

Patients should be assessed for TLS risk, including evaluation of tumor burden and comorbidities, and should receive appropriate prophylaxis for TLS, including hydration and anti-hyperuricemics. Reduced renal function (CrCl <80 mL/min) further increases the risk. Monitor blood chemistries and manage abnormalities promptly. Interrupt dosing if needed. Employ more intensive measures (IV hydration, frequent monitoring, hospitalization) as overall risk increases.

•	Concomitant use of VENCLEXTA with strong or moderate CYP3A inhibitors and P-gp inhibitors may increase the risk of TLS at initiation and during the ramp-up phase, and may require dose adjustment due to increases in VENCLEXTA exposure.

Neutropenia

•

Grade 3 or 4 neutropenia occurred in 41% (98/240) of patients treated with VENCLEXTA. Monitor complete blood counts throughout treatment. 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).

Immunization

•	Do not administer live attenuated vaccines prior to, during, or after treatment with VENCLEXTA until B-cell recovery. Advise patients that vaccinations may be less effective.

Embryo-Fetal Toxicity

•	VENCLEXTA may cause embryo-fetal harm when administered to a pregnant woman. Advise females of reproductive potential to avoid pregnancy during treatment.

Adverse Reactions

•	Serious adverse reactions were reported in 43.8% of patients. The most frequent serious adverse reactions (≥2%) were pneumonia (5%), febrile neutropenia (4.6%), pyrexia (3.3%), autoimmune hemolytic anemia (2.9%), anemia (2.1%), and TLS (2.1%).^b
•	The most common adverse reactions (≥20%) of any grade were neutropenia (45%), diarrhea (35%), nausea (33%), anemia (29%), upper respiratory tract infection (22%), thrombocytopenia (22%), and fatigue (21%).^a

Drug Interactions

•

For patients who have completed the ramp-up phase and are on a steady daily dose of VENCLEXTA, reduce the dose by at least 75% when used concomitantly with strong CYP3A inhibitors. Resume the VENCLEXTA dose that was used prior to initiating the CYP3A inhibitor 2 to 3 days after discontinuation of the inhibitor.

•	Avoid concomitant use of moderate CYP3A inhibitors or P-gp inhibitors. If an inhibitor must be used, reduce the VENCLEXTA dose by at least 50%. Monitor patients more closely for signs of VENCLEXTA toxicities. Resume the VENCLEXTA dose that was used prior to initiating the CYP3A inhibitor or P-gp inhibitor 2 to 3 days after discontinuation of the inhibitor.
•	Patients should avoid grapefruit products, Seville oranges, and starfruit during treatment as they contain inhibitors of CYP3A.
•	Avoid concomitant use of strong or moderate CYP3A inducers.
•	Avoid concomitant use of narrow therapeutic index P-gp substrates. If these substrates must be used, they should be taken at least 6 hours before VENCLEXTA.
•	Monitor international normalized ratio (INR) closely in patients receiving warfarin.

Lactation

•	Advise nursing women to discontinue breastfeeding during treatment with VENCLEXTA.

Females and Males of Reproductive Potential

•	Advise females of reproductive potential to use effective contraception during treatment with VENCLEXTA and for at least 30 days after the last dose.
•	Based on findings in animals, male fertility may be compromised by treatment with VENCLEXTA.

^a	VENCLEXTA [package insert]. North Chicago, IL: AbbVie Inc.
^b	Data on file, AbbVie Inc. ABVRRTI62926.

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750-1902316/March 2017

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