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AstraZeneca’s CALQUENCE® (acalabrutinib) Shows Potential in Chronic Lymphocytic Leukemia Trials

AZN | December 10, 2017

AstraZeneca’s CALQUENCE ^® (acalabrutinib) Shows Potential in Chronic Lymphocytic Leukemia Trials

Data from two Phase I/II trials presented at American Society of Hematology Annual Meeting on efficacy and safety profile of acalabrutinib as monotherapy and combination treatment

Findings highlight overall response rates and emerging safety profile of acalabrutinib, a Bruton tyrosine kinase (BTK) inhibitor

AstraZeneca and Acerta Pharma, its hematology research and development center of excellence, today presented results from the Phase Ib/II ACE-CL-003 clinical trial (Abstract #432) and updated results from the Phase I/II ACE-CL-001 (Abstract #498) clinical trial that are evaluating acalabrutinib alone and in combination for the treatment of chronic lymphocytic leukemia (CLL) in multiple treatment settings. The findings were presented during two oral sessions at the 59th American Society of Hematology (ASH) Annual Meeting & Exhibition in Atlanta.

Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said: “These data add to the growing body of evidence that supports the potential of acalabrutinib in the treatment of chronic lymphocytic leukemia, a life-threatening disease that affects tens of thousands of people around the world. These emerging clinical data underscore AstraZeneca’s commitment to advancing the science of blood cancer treatments.”

Jennifer Woyach, MD, Associate Professor of Internal Medicine, Division of Hematology, The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, said: “Despite treatment advances for chronic lymphocytic leukemia in recent years, the urgent need for additional treatment options remains. The overall response rates observed in the acalabrutinib trials and presented at ASH highlight the potential impact that this investigational treatment could have on the management of CLL.”

New, early acalabrutinib data from ACE-CL-003 combination therapy trial

Data on two patient cohorts treated with acalabrutinib and obinutuzumab from the Phase Ib/II ACE-CL-003 trial were presented. The primary endpoint of overall response rate was 95% (95% CI: 74,100) for the 19 patients in the treatment-naïve cohort and 92% (95% CI: 75,99) in the 26 patients with relapsed or refractory CLL. Additionally, the complete response rate was 16% for treatment-naïve patients and 8% for previously-treated patients. At approximately 2 years median study follow-up, the secondary endpoints of duration of response and median progression-free survival had not yet been reached in either patient cohort.

Across both cohorts in the trial, the most common adverse reactions (≥25%) of any grade were upper respiratory tract infection (69%), maculopapular rash (64%), increased weight (64%), diarrhea (62%), cough (58%), nausea (51%), headache (47%), infusion-related reaction (42%), contusion (42%), dizziness (42%), arthralgia (40%), vomiting (40%), constipation (38%), hypertension (38%), skin lesion (38%), fatigue (36%), peripheral edema (36%), decreased appetite (33%), sinusitis (33%), fall (31%), myalgia (31%), oral pain (31%), dyspepsia (27%) and paraesthesia (27%). One patient with relapsed or refractory CLL who had a history of atrial fibrillation experienced intermittent atrial fibrillation (Grade 3), which was not considered treatment related and did not lead to treatment discontinuation.

Updated acalabrutinib monotherapy safety and efficacy data from ACE-CL-001 trial

In a separate oral session, investigators presented new longer-term follow-up safety (primary endpoint) and efficacy (secondary endpoint) data evaluating acalabrutinib as a monotherapy in the full-study cohort of 134 patients with relapsed or refractory CLL at median time on study and follow-up of 24.5 months. These data expand on previously reported findings in 61 patients at median follow-up of 14.3 months.

These latest findings from the trial highlight the overall response rate and duration of response in this patient population. With a median follow-up of 24.5 months, the overall response rate was 87% (95% CI: 80,92) and the overall response including partial response with lymphocytosis (increase in number of lymphocytes in the blood) was 93% (95% CI: 88,97). The complete response was 4% (3 patients). The median progression-free survival, a secondary endpoint in the trial, was not yet reached; however, the 18-month progression-free survival rate was 90% (95% CI: 83,94).

In this trial, the most common adverse reactions (≥20%) of any grade were diarrhea (48%), headache (47%), upper respiratory tract infection (31%), fatigue (28%), nausea (26%), cough (24%), arthralgia (25%), pyrexia (23%), contusion (23%), weight increased (21%), petechiae (21%) and constipation (20%). Grade ≥3 adverse reactions (≥5% of patients) were neutropenia (12%) and pneumonia (11%). 22% of patients discontinued treatment.

The Phase I/II CLL clinical trial (ACE-CL-003 and ACE-CL-001) findings are part of an extensive development program for acalabrutinib in a range of blood cancers, which includes three ongoing Phase III clinical trials (ACE-CL-006, ACE-CL-007 and ACE-CL-309) in patients with CLL.

INDICATION AND IMPORTANT SAFETY INFORMATION ABOUT CALQUENCE (acalabrutinib)

CALQUENCE was granted accelerated approval by the US Food and Drug Administration (FDA) in October 2017 for the treatment of adult patients with mantle cell lymphoma (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 not approved for use outside of its labeled indication in the US.

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 CALQUENCE (acalabrutinib)

CALQUENCE^® (acalabrutinib, previously known as ACP-196 is an inhibitor of Bruton tyrosine kinase (BTK). Acalabrutinib 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.

CALQUENCE was granted accelerated approval by the US Food and Drug Administration (FDA) in October 2017 for the treatment of adult patients with mantle cell lymphoma (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 not approved for use outside of its labelled indication in the US.

Acalabrutinib is in development for the treatment of multiple B-cell malignancies and other cancers including CLL, MCL, Waldenström macroglobulinemia (WM), follicular lymphoma, diffuse large B-cell lymphoma, and multiple myeloma. It is also being studied as a monotherapy and in combination trials for the treatment of solid tumors. More than 35 clinical trials across 40 countries with more than 2,500 patients are underway or have completed.

Acalabrutinib was granted Orphan Drug Designation by the US FDA in 2015 for the treatment of patients with CLL, MCL and WM.

About Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults and accounts for approximately one in four cases of leukemia. The average age at the time of diagnosis is approximately 71 years of age. 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 uncontrolled bleeding. B cell receptor signaling through BTK is one of the essential growth pathways for CLL.

About Acerta Pharma

Acerta Pharma, a member of the AstraZeneca Group, is creating novel therapies intended for the treatment of cancer and autoimmune diseases. AstraZeneca acquired a majority stake interest in Acerta Pharma, which serves as AstraZeneca’s hematology research and development center of excellence. For more information, please visit www.acerta-pharma.com.

About AstraZeneca in Oncology

AstraZeneca has a deep-rooted heritage in Oncology and offers a quickly growing portfolio of new medicines that have the potential to transform patients’ lives and the Company’s future. With at least six new medicines aimed to be launched between 2014 and 2020 and a broad pipeline of small molecules and biologics in development, we are committed to advance New Oncology as one of AstraZeneca’s five Growth Platforms 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 main therapy areas – Oncology, Cardiovascular & Metabolic Diseases and Respiratory. The Company also is selectively active in the areas of autoimmunity, neuroscience and infection. 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-16400 Last Updated 12/17