CALQUENCE (acalabrutinib) Granted US Breakthrough Therapy Designation for Chronic Lymphocytic Leukemia

Business Wire 14-Aug-2019 8:00 AM

Designation based on positive results from two Phase III trials

AstraZeneca today announced that the US Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation (BTD) for CALQUENCE® (acalabrutinib) as a monotherapy treatment for adult patients with chronic lymphocytic leukemia (CLL), one of the most common types of leukemia in adults.

José Baselga, Executive Vice President, Oncology R&D, said: "This is an important regulatory milestone for our work in hematology and for patients living with chronic lymphocytic leukemia, a life-threatening disease. The Breakthrough Therapy Designation acknowledges the growing body of evidence that supports CALQUENCE as a highly-selective Bruton tyrosine kinase inhibitor with the potential to offer patients a new, differentiated, chemotherapy-free treatment option with a favorable safety profile."

The FDA granted the BTD based on positive results from the interim analyses of the ELEVATE-TN and ASCEND Phase III clinical trials. Together the trials showed that CALQUENCE alone, or in combination with obinutuzumab, significantly increased the time patients lived without disease progression or death, with safety and tolerability that was consistent with its established profile.

This is the 10th BTD that AstraZeneca has received from the FDA since 2014. An FDA BTD is designed to accelerate the development and regulatory review of new medicines that are intended to treat a serious condition and that have shown encouraging early clinical results which may demonstrate substantial improvement on a clinically-significant endpoint over currently-available medicines.

CALQUENCE is currently approved for the treatment of adults with relapsed or refractory mantle cell lymphoma (MCL) in the US, Brazil, Qatar, the United Arab Emirates, Mexico, Argentina and recently Singapore and is being developed for the treatment of CLL and other blood cancers. In the US, 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 confirmatory trials. The positive results from both the ELEVATE-TN and ASCEND trials will serve as the foundation for regulatory submissions later this year.

IMPORTANT SAFETY INFORMATION ABOUT CALQUENCE® (acalabrutinib)

Hemorrhage

Serious hemorrhagic events, including fatal events, have occurred in the combined safety database of 612 patients with hematologic malignancies treated with CALQUENCE monotherapy. Grade 3 or higher bleeding events, including gastrointestinal, intracranial, and epistaxis, have been reported in 2% of patients. Overall, bleeding events, including bruising and petechiae of any grade, occurred in approximately 50% of patients with hematological malignancies.

The mechanism for the bleeding events is not well understood.

CALQUENCE may further increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies, and patients should be monitored for signs of bleeding.

Consider the benefit-risk of withholding CALQUENCE for 3 to 7 days pre- and post-surgery, depending upon the type of surgery and the risk of bleeding.

Infection

Serious infections (bacterial, viral, or fungal), including fatal events and opportunistic infections, have occurred in the combined safety database of 612 patients with hematologic malignancies treated with CALQUENCE monotherapy. Grade 3 or higher infections occurred in 18% of these patients. The most frequently reported Grade 3 or 4 infection was pneumonia. Infections due to hepatitis B virus (HBV) reactivation and progressive multifocal leukoencephalopathy (PML) have occurred.

Monitor patients for signs and symptoms of infection and treat as medically appropriate. Consider prophylaxis in patients who are at increased risk for opportunistic infections.

Cytopenias

In the combined safety database of 612 patients with hematologic malignancies, patients treated with CALQUENCE monotherapy experienced Grade 3 or 4 cytopenias, including neutropenia (23%), anemia (11%), and thrombocytopenia (8%), based on laboratory measurements. Monitor complete blood counts monthly during treatment.

Second Primary Malignancies

Second primary malignancies, including non-skin carcinomas, have occurred in 11% of patients with hematologic malignancies treated with CALQUENCE monotherapy in the combined safety database of 612 patients. The most frequent second primary malignancy was skin cancer, reported in 7% of patients. Advise protection from sun exposure.

Atrial Fibrillation and Flutter

In the combined safety database of 612 patients with hematologic malignancies treated with CALQUENCE monotherapy, atrial fibrillation and atrial flutter of any grade occurred in 3% of patients, and Grade 3 in 1% of patients. Monitor for atrial fibrillation and atrial flutter and manage as appropriate.

ADVERSE REACTIONS

The most common adverse reactions (=20%) of any grade were anemia,* thrombocytopenia,* headache (39%), neutropenia,* diarrhea (31%), fatigue (28%), myalgia (21%), and bruising (21%).

*Treatment-emergent decreases (all grades) of hemoglobin (46%), platelets (44%), and neutrophils (36%) were based on laboratory measurements and adverse reactions.

The most common Grade = 3 non-hematological adverse reaction (reported in at least 2% of patients) was diarrhea (3.2%).

Dosage reductions or discontinuations due to any adverse reaction were reported in 1.6% and 6.5% of patients, respectively.

Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 4.8% of patients.

DRUG INTERACTIONS

Strong CYP3A Inhibitors: Avoid co-administration with a strong CYP3A inhibitor. If a strong CYP3A inhibitor will be used short-term, interrupt CALQUENCE.

Moderate CYP3A Inhibitors: When CALQUENCE is co-administered with a moderate CYP3A inhibitor, reduce CALQUENCE dose to 100 mg once daily.

Strong CYP3A Inducers: Avoid co-administration with a strong CYP3A inducer. If a strong CYP3A inducer cannot be avoided, increase the CALQUENCE dose to 200 mg twice daily.

Gastric Acid Reducing Agents: If treatment with a gastric acid reducing agent is required, consider using an H2-receptor antagonist or an antacid. Take CALQUENCE 2 hours before taking an H2-receptor antagonist. Separate dosing with an antacid by at least 2 hours.

Avoid co-administration with proton pump inhibitors. Due to the long-lasting effect of proton pump inhibitors, separation of doses may not eliminate the interaction with CALQUENCE.

SPECIFIC POPULATIONS

There is insufficient clinical data on CALQUENCE use in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. Advise women of the potential risk to a fetus.

It is not known if CALQUENCE is present in human milk. Advise lactating women not to breastfeed while taking CALQUENCE and for at least 2 weeks after the final dose.

Please see complete Prescribing Information including Patient Information.

NOTES TO EDITORS

About ELEVATE-TN

ELEVATE-TN (ACE-CL-007) is a randomized, multicenter, open-label Phase III trial evaluating the safety and efficacy of CALQUENCE alone or in combination with obinutuzumab vs. chlorambucil in combination with obinutuzumab in previously-untreated patients with CLL. In the trial, 535 patients were randomized (1:1:1) into three arms. Patients in the first arm received chlorambucil in combination with obinutuzumab. Patients in the second arm received CALQUENCE (100mg twice daily until disease progression or unacceptable toxicity) in combination with obinutuzumab. Patients in the third arm received CALQUENCE monotherapy (100mg twice daily until disease progression or unacceptable toxicity).

The primary endpoint is progression-free survival (PFS) in the CALQUENCE and obinutuzumab arm compared to the chlorambucil and obinutuzumab arm, assessed by an independent review committee (IRC), and a key secondary endpoint is IRC-assessed PFS in the CALQUENCE monotherapy arm compared to the chlorambucil and obinutuzumab arm. Other secondary endpoints include objective response rate, time to next treatment and overall survival.

About ASCEND

ASCEND (ACE-CL-309) is a global, randomized, multicenter, open-label Phase III trial evaluating the efficacy of CALQUENCE in previously-treated patients with CLL. In the trial, 310 patients were randomized (1:1) into two arms. Patients in the first arm received CALQUENCE monotherapy (100mg twice daily until disease progression or unacceptable toxicity). Patients in the second arm received investigator's choice of either rituximab in combination with idelalisib or rituximab in combination with bendamustine.

The primary endpoint is PFS assessed by an IRC, and key secondary endpoints include investigator-assessed PFS, IRC- and investigator-assessed overall response rate and duration of response, as well as overall survival, patient reported outcomes and time to next treatment.

About CALQUENCE

CALQUENCE® (acalabrutinib) was granted accelerated approval by the US Food and Drug Administration (FDA) in October 2017 for the treatment of adult patients with MCL who have received at least one prior therapy. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

CALQUENCE is an inhibitor of Bruton tyrosine kinase (BTK). CALQUENCE binds covalently to BTK, thereby inhibiting its activity. In B-cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.

As part of an extensive clinical development program, AstraZeneca and Acerta Pharma are currently evaluating CALQUENCE in 26 company-sponsored clinical trials. CALQUENCE is being developed for the treatment of multiple B-cell blood cancers including CLL, MCL, diffuse large B-cell lymphoma, Waldenstrom macroglobulinemia, follicular lymphoma, and multiple myeloma and other hematologic malignancies. Several Phase III clinical trials are ongoing, including ASCEND, ELEVATE-TN, ELEVATE-RR (ACE-CL-006) evaluating acalabrutinib vs. ibrutinib in patients with previously treated high-risk CLL, and ACE-CL-311 evaluating acalabrutinib in combination with venetoclax and with/without obinutuzumab in patients with previously-untreated CLL without 17p deletion or TP53 mutation.

About chronic lymphocytic leukemia (CLL)

Chronic lymphocytic leukemia (CLL) is one of the most common types of leukemia in adults, with an estimated 191,000 new cases globally and 20,720 new cases in the US annually, and prevalence that is expected to grow with improved treatment. In CLL, too many blood stem cells in the bone marrow become abnormal lymphocytes and these abnormal cells have difficulty fighting infections. As the number of abnormal cells grows there is less room for healthy white blood cells, red blood cells and platelets. This could result in anemia, infection and bleeding. B-cell receptor signaling through BTK is one of the essential growth pathways for CLL.

About AstraZeneca in hematology

Leveraging its strength in oncology, AstraZeneca has established hematology as one of four key oncology disease areas of focus. The Company's hematology franchise includes two US FDA-approved medicines and a robust global development program for a broad portfolio of potential blood cancer treatments. Acerta Pharma serves as AstraZeneca's hematology research and development arm. AstraZeneca partners with like-minded science-led companies to advance the discovery and development of therapies to address unmet need.

In October 2018, AstraZeneca and Innate Pharma announced a global strategic collaboration that included Innate Pharma licensing the US commercial rights of LUMOXITI™ (moxetumomab pasudotox-tdfk), and with support from AstraZeneca, will continue EU development and commercialization, pending regulatory submission and approval.

About AstraZeneca in oncology

AstraZeneca has a deep-rooted heritage in Oncology and offers a quickly-growing portfolio of new medicines that has the potential to transform patients' lives and the Company's future. With at least six new medicines to be launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, we are committed to advance Oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to our core capabilities, we actively pursue innovative partnerships and investments that accelerate the delivery of our strategy as illustrated by our investment in Acerta Pharma in hematology.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumor Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates – and by championing the development of personalized combinations, AstraZeneca has the vision to redefine cancer treatment and one day eliminate cancer as a cause of death.

About AstraZeneca

AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines, primarily for the treatment of diseases in three therapy areas - Oncology, Cardiovascular, Renal & Metabolism and Respiratory. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information, please visit www.astrazeneca-us.com and follow us on Twitter @AstraZenecaUS.

US-31998 Last Updated 8/19

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