AbbVie Announces Positive Results from CLL14, a Phase 3 Trial Evaluating a Venetoclax Combination as First-Line Therapy with a Fixed Duration of Treatment in Patients with Chronic Lymphocytic Leukemia

NORTH CHICAGO, Ill., Oct. 31, 2018 /PRNewswire/ -- AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, today announced positive results from CLL14, a Phase 3, randomized clinical trial evaluating venetoclax plus obinutuzumab versus obinutuzumab plus chlorambucil, a standard of care, in patients with chronic lymphocytic leukemia (CLL) and coexisting medical conditions who have not received a prior treatment. The study met its primary endpoint of investigator-assessed progression-free survival (PFS; the time on treatment without disease progression or death¹) with a 12-month fixed duration of treatment. Preliminary analysis suggests the safety profile observed in the combination of venetoclax plus obinutuzumab is consistent with the known safety profile of each medicine alone.

Results from the CLL14 trial will be presented at a future medical meeting.

"Patients with chronic lymphocytic leukemia generally face a lifetime of continuous treatment to keep their disease from recurring or relapsing. The positive results from the CLL14 trial further demonstrate the potential of venetoclax as a treatment with a fixed duration for patients with chronic lymphocytic leukemia, and may serve as the basis to expand into first-line treatment," said Michael Severino, M.D., executive vice president, research and development and chief scientific officer, AbbVie. "We look forward to sharing full results from the CLL14 trial, and to advancing other clinical development programs in our pipeline that have the potential to continue transforming the standards of care for patients with blood cancers."

Venetoclax is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S.

About the Phase 3 CLL14 Trial
The prospective, multicenter, open-label, randomized Phase 3 CLL14 trial is being conducted in close collaboration with the German CLL Study Group (DCLLSG) and was designed to evaluate the efficacy and safety of a combined regimen of venetoclax and obinutuzumab versus obinutuzumab and chlorambucil in previously-untreated patients with CLL and coexisting medical conditions. The therapies were administered for a fixed duration of 12 months for venetoclax in combination with six cycles of obinutuzumab. The trial enrolled 445 patients, all of whom were previously-untreated according to the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria. The primary endpoint was PFS based on investigator assessment, using iwCLL criteria.²

About VENCLEXTA^®/VENCLYXTO^® (venetoclax)   
VENCLEXTA^®/VENCLYXTO^® (venetoclax) is a first-in-class medicine that selectively binds and inhibits the B-cell lymphoma-2 (BCL-2) protein. In some blood cancers and other cancerous tumors, BCL-2 builds up and prevents cancer cells from undergoing their natural death or self-destruction process, which is called apoptosis. VENCLEXTA targets the BCL-2 protein and works to restore the process of apoptosis.

VENCLEXTA/VENCLYXTO is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S. Together, the companies are committed to BCL-2 research and to studying venetoclax in clinical trials across several blood and other cancers. 

VENCLEXTA/VENCLYXTO is approved in more than 50 countries, including the U.S. AbbVie and Roche are currently working with regulatory agencies around the world to bring this medicine to additional eligible patients in need.

Important VENCLEXTA^® (venetoclax) US Safety Information³

What is the most important information I should know about VENCLEXTA? 

VENCLEXTA can cause serious side effects, including:
Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure, the need for dialysis treatment, and may lead to death. Your health care provider will do tests to check your risk of getting TLS before starting and during treatment with VENCLEXTA to help reduce your risk of TLS. You may also need to receive intravenous (IV) fluids into your vein. Your health care provider will do blood tests in your first 5 weeks of treatment to check you for TLS during treatment with VENCLEXTA. It is important to keep your appointments for blood tests. Tell your health care provider right away if you have any symptoms of TLS during treatment with VENCLEXTA, including fever, chills, nausea, vomiting, confusion, shortness of breath, seizures, irregular heartbeat, dark or cloudy urine, unusual tiredness, or muscle or joint pain.

Drink plenty of water when taking VENCLEXTA to help reduce your risk of getting TLS. Drink 6 to 8 glasses (about 56 ounces total) of water each day, starting 2 days before your first dose, on the day of your first dose of VENCLEXTA, and each time your dose is increased.

Who should not take VENCLEXTA?

Certain medicines must not be taken when you first start taking VENCLEXTA and while your dose is being slowly increased because of the risk of increased tumor lysis syndrome.

• Tell your health care provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. VENCLEXTA and other medicines may affect each other, causing serious side effects.
• Do not start new medicines during treatment with VENCLEXTA without first talking with your health care provider.

Before taking VENCLEXTA, tell your health care provider about all of your medical conditions, including if you:

• Have kidney or liver problems.
• Have problems with your body salts or electrolytes, such as potassium, phosphorus, or calcium.
• Have a history of high uric acid levels in your blood or gout.
• Are scheduled to receive a vaccine. You should not receive a "live vaccine" before, during or after treatment with VENCLEXTA until your health care provider tells you it is okay. If you are not sure about the type of immunization or vaccine, ask your health care provider. These vaccines may not be safe or may not work as well during treatment with VENCLEXTA.
• Are pregnant or plan to become pregnant. VENCLEXTA may harm your unborn baby. If you are able to become pregnant, your health care provider should do a pregnancy test before you start treatment with VENCLEXTA, and you should use effective birth control during treatment and for 30 days after the last dose of VENCLEXTA. If you become pregnant or think you are pregnant, tell your health care provider right away.
• Are breastfeeding or plan to breastfeed. It is not known if VENCLEXTA passes into your breast milk. Do not breastfeed during treatment with VENCLEXTA.

What should I avoid while taking VENCLEXTA?
You should not drink grapefruit juice, eat grapefruit, Seville oranges (often used in marmalades), or starfruit while you are taking VENCLEXTA. These products may increase the amount of VENCLEXTA in your blood.

What are the possible side effects of VENCLEXTA?
VENCLEXTA can cause serious side effects, including:

• Low white blood cell count (neutropenia). Low white blood cell counts are common with VENCLEXTA, but can also be severe. Your health care provider will do blood tests to check your blood counts during treatment with VENCLEXTA. Tell your health care provider right away if you have a fever or any signs of an infection while taking VENCLEXTA.

The most common side effects of VENCLEXTA when used in combination with rituximab include low white blood cell count, diarrhea, upper respiratory tract infection, cough, tiredness, and nausea.

The most common side effects of VENCLEXTA when used alone include low white blood cell count, diarrhea, nausea, upper respiratory tract infection, low red blood cell count, tiredness, low platelet count, muscle and joint pain, swelling of your arms, legs, hands, and feet, and cough.

VENCLEXTA may cause fertility problems in males. This may affect your ability to father a child. Talk to your health care provider if you have concerns about fertility.

These are not all the possible side effects of VENCLEXTA. Tell your health care provider if you have any side effect that bothers you or that does not go away.

People are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

The full U.S. prescribing information, including Medication Guide, for VENCLEXTA can be found here. Globally, prescribing information varies; refer to the individual country product label for complete information.

Important VENCLYXTO (venetoclax) EU Safety Information⁴

Contraindications
Hypersensitivity to the active substance or to any of the excipients is contraindicated. Concomitant use of strong CYP3A inhibitors at initiation and during the dose-titration phase due to increased risk for tumor lysis syndrome (TLS). Concomitant use of preparations containing St. John's wort as VENCLYXTO efficacy may be reduced.

Special Warnings & Precautions for Use
Tumor lysis syndrome (TLS), including fatal events, has occurred in patients with previously treated CLL with high tumor burden when treated with VENCLYXTO. VENCLYXTO poses a risk for TLS in the initial 5-week dose-titration phase. Changes in electrolytes consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of VENCLYXTO and at each dose increase. Patients should be assessed for risk and should receive appropriate prophylaxis, monitoring, and management for TLS.

Neutropenia (grade 3 or 4) has been reported and complete blood counts should be monitored throughout the treatment period. Serious infections including events of sepsis with fatal outcome have been reported. Supportive measures including antimicrobials for any signs of infection should be considered.      

Live vaccines should not be administered during treatment or thereafter until B-cell recovery.

Drug Interactions
CYP3A inhibitors may increase VENCLYXTO plasma concentrations. At initiation and dose-titration phase: Strong CYP3A inhibitors are contraindicated due to increased risk for TLS and moderate CYP3A inhibitors should be avoided. If moderate CYP3A inhibitors must be used, physicians should refer to the SmPC for dose adjustment recommendations. At steady daily dose: If moderate or strong CYP3A inhibitors must be used, physicians should refer to the SmPC for dose adjustment recommendations.

Avoid concomitant use of P-gp and BCRP inhibitors at initiation and during the dose-titration phase.

CYP3A4 inducers may decrease VENCLYXTO plasma concentrations. Avoid coadministration with strong or moderate CYP3A inducers. These agents may decrease venetoclax plasma concentrations.

Co-administration of bile acid sequestrants with VENCLYXTO is not recommended as this may reduce the absorption of VENCLYXTO.

Adverse Reactions
The most commonly occurring adverse reactions (>=20%) of any grade in patients receiving venetoclax in the combination study with rituximab were neutropenia, diarrhea, and upper respiratory tract infection. In the monotherapy studies, the most common adverse reactions were neutropenia/neutrophil count decreased, diarrhea, nausea, anemia, fatigue, and upper respiratory tract infection.

The most frequently occurring serious adverse reactions (>=2%) in patients receiving venetoclax in combination with rituximab or as monotherapy were pneumonia, febrile neutropenia and TLS.

Discontinuation due to adverse reactions occurred in 16% of patients receiving venetoclax plus rituximab and 9% receiving venetoclax monotherapy. Dosage adjustments due to adverse reactions occurred in 15% of patients receiving venetoclax plus rituximab and 2% receiving venetoclax monotherapy. Dose interruptions occurred in 71% of patients treated with the combination of venetoclax and rituximab. 

Specific Populations
Patients with reduced renal function (CrCl <80 mL/min) may require more intensive prophylaxis and monitoring to reduce the risk of TLS. Safety in patients with severe renal impairment (CrCl <30 mL/min) or on dialysis has not been established, and a recommended dose for these patients has not been determined. VENCLYXTO should be administered to patients with severe renal impairment only if the benefit outweighs the risk and patients should be monitored closely for signs of toxicity due to increased risk of TLS.

VENCLYXTO may cause embryo-fetal harm when administered to a pregnant woman. Advise nursing women to discontinue breastfeeding during treatment.

This is not a complete summary of all safety information. See VENCLYXTO full summary of product characteristics (SmPC) at www.ema.europa.eu. Globally, prescribing information varies; refer to the individual country product label for complete information.

About Obinutuzumab
Obinutuzumab is an engineered monoclonal antibody designed to attach to CD20, a protein expressed on certain B cells, but not on stem cells or plasma cells. Obinutuzumab is designed to attack and destroy targeted B cells both directly and together with the body's immune system.

Obinutuzumab is currently approved in more than 90 countries in combination with chlorambucil for people with previously-untreated chronic lymphocytic leukemia (CLL), in more than 80 countries in combination with bendamustine for people with certain types of previously-treated follicular lymphoma, and in more than 60 countries in combination with chemotherapy for previously-untreated, follicular lymphoma.

Additional combination studies investigating obinutuzumab with other approved or investigational medicines, including cancer immunotherapies and small molecule inhibitors, are underway across a range of blood cancers.

About the German CLL Study Group (DCLLSG)
Founded in 1996 and headed by Dr. Michael Hallek, the DCLLSG has been running various Phase 3, Phase 2 and Phase 1 trials in CLL with the goal of providing optimal treatment to patients suffering from this disease. Among those were landmark trials, including the CLL8 and CLL11 trials, which led to the current standard of care in CLL. For many years, DCLLSG has been aiming to improve not just the treatment of younger and physically fit patients, but also that of elderly and less fit patients. These patients are generally underrepresented in clinical trials although they constitute the majority of CLL patients treated by doctors in daily practice. The DCLLSG is an independent non-profit research organization supported by German Cancer Aid (Deutsche Krebshilfe). For more information, visit www.dcllsg.de.

About AbbVie in Oncology
At AbbVie, we strive to discover and develop medicines that deliver transformational improvements in cancer treatment by uniquely combining our deep knowledge in core areas of biology with cutting-edge technologies, and by working together with our partners – scientists, clinical experts, industry peers, advocates, and patients. We remain focused on delivering these transformative advances in treatment across some of the most debilitating and widespread cancers. We are also committed to exploring solutions to help patients obtain access to our cancer medicines. With the acquisitions of Pharmacyclics in 2015 and Stemcentrx in 2016, our research and development efforts, and through collaborations, AbbVie's oncology portfolio now consists of marketed medicines and a pipeline containing multiple new molecules being evaluated worldwide in more than 200 clinical trials and more than 20 different tumor types. For more information, please visit http://www.abbvie.com/oncology.

About AbbVie
AbbVie is a global, research and development-based biopharmaceutical company committed to developing innovative advanced therapies for some of the world's most complex and critical conditions. The company's mission is to use its expertise, dedicated people and unique approach to innovation to markedly improve treatments across four primary therapeutic areas: immunology, oncology, virology and neuroscience. In more than 75 countries, AbbVie employees are working every day to advance health solutions for people around the world. For more information about AbbVie, please visit us at www.abbvie.com. Follow @abbvie on Twitter, Facebook, LinkedIn or Instagram.

Forward-Looking Statements
Some statements in this news release are, or may be considered, forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. The words "believe," "expect," "anticipate," "project" and similar expressions, among others, generally identify forward-looking statements. AbbVie cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements. Such risks and uncertainties include, but are not limited to, challenges to intellectual property, competition from other products, difficulties inherent in the research and development process, adverse litigation or government action, and changes to laws and regulations applicable to our industry. Additional information about the economic, competitive, governmental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, "Risk Factors," of AbbVie's 2017 Annual Report on Form 10-K, which has been filed with the Securities and Exchange Commission. AbbVie undertakes no obligation to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law.

¹ Hallek M, et al. Guidelines for diagnosis, indications for treatment, response assessment and supportive management of chronic lymphocytic leukemia. Blood. 2018;131(25):2745-2760.
² Clinicaltrials.gov (2018). NCT02242942: A Prospective, Open-Label, Multicenter Randomized Phase III Trial to Compare The Efficacy and Safety of A Combined Regimen of Obinutuzumab and Venetoclax (GDC-0199/ABT-199) Versus Obinutuzumab and Chlorambucil in Previously Untreated Patients With CLL and Coexisting Medical Conditions. Accessed October 2018.
³ VENCLEXTA (venetoclax) [Package Insert]. North Chicago, Ill.: AbbVie Inc.
⁴ Summary of Product Characteristics for VENCLYXTO. Ludwigshafen, Germany: AbbVie Deutschland GmbH & Co. KG.

SOURCE AbbVie

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