AstraZeneca's CALQUENCE® (acalabrutinib) Demonstrates Activity In Relapsed Or Refractory Mantle Cell Lymphoma Trial

AstraZeneca and Acerta Pharma, its hematology research and development center of excellence, today presented results from the open-label, single-arm Phase II ACE-LY-004 clinical trial, which served as the basis for the recent US Food and Drug Administration (FDA) accelerated approval of CALQUENCE ® (acalabrutinib). The findings were presented for the first time during an oral session at the 59th American Society of Hematology (ASH) Annual Meeting & Exhibition in Atlanta and demonstrate the safety profile and efficacy of CALQUENCE in the management of previously-treated mantle cell lymphoma (MCL).

CALQUENCE 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. This indication is approved based on overall response rate, and continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said: "These results presented for the first time to the medical community highlight the potential of CALQUENCE as a treatment for people with relapsed or refractory mantle cell lymphoma, a life-threatening form of blood cancer. These data reinforce the important progress of our clinical development program as well as our commitment to advancing the treatment of patients with blood cancers."

Michael L. Wang, MD, Professor, Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, and Principal Investigator of the ACE-LY-004 MCL clinical trial, said: "Most people living with mantle cell lymphoma will unfortunately relapse, and new treatment options are greatly needed. As shown by the consistent overall response rates observed in this trial across several pre-specified subgroups, acalabrutinib is a welcome new treatment option for certain patients with this aggressive blood cancer."

Summary of key investigator-assessed efficacy results from ACE-LY-004, a Phase II open-label, single-arm clinical trial in 124 adult patients with relapsed or refractory MCL (15.2 months median follow-up):
         
Efficacy measure       Patients (percent response)

Overall response rate(Complete response + partial response)

Complete response

Partial response
      81% (95% CI: 73,87)

 

40% (95% CI: 31,49)

41% (95% CI: 32,50)
Stable disease       9% (95% CI: 5,15)
Progressive disease       8% (95% CI: 4,14)
Not evaluable       2% (95% CI: 1,7)

Per 2014 Lugano classification response criteria for non-Hodgkin lymphoma; high concordance was observed between investigator-assessed and independent review committee assessed overall response and complete response rates, respectively.

The overall response rate was consistent across multiple subgroups including age, tumor burden and number or type of prior treatments. The secondary endpoint of median duration of response had not yet been reached at 15.2 months median follow-up. The median time-to-response, an exploratory endpoint, was 1.9 months. After 12 months of treatment, 72% (95% CI: 62,80) of patients were still responding to acalabrutinib treatment. The secondary endpoints of progression-free survival and overall survival had not yet been reached; at 12 months, the progression-free survival and overall survival rates were 67% (95% CI: 58,75) and 87% (95% CI: 79,92), respectively.

In this trial, the most common non-hematological adverse reactions (reported in =20% of patients at a median follow-up time of 15.2 months) were headache (38%), diarrhea (30%), fatigue (26%) and myalgia (21%), per investigator assessment. Grade 3 or 4 adverse reactions (=5%) included anemia (12%), neutropenia (11%), and pneumonia (6%). Please refer to the Important Safety Information about CALQUENCE (acalabrutinib) below for the adverse reaction rates as shown in the FDA-approved product label.

A Grade 3 gastrointestinal hemorrhage occurred in 1 patient (1%) with a history of a gastrointestinal ulcer. Tumor lysis syndrome was reported in 2 patients (2%). A Grade 5 adverse reaction of aortic stenosis was reported in 1 patient with previous history and was not considered related to study treatment.

Treatment discontinuation was primarily due to progressive disease (31%) or adverse reaction (6%).

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.

- ENDS -

NOTES TO EDITORS

About CALQUENCE (acalabrutinib)

CALQUENCE ® (acalabrutinib; previously known as ACP-196) 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.

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.

The recommended dose of CALQUENCE is one 100mg capsule taken orally approximately every twelve hours until disease progression or unacceptable toxicity. CALQUENCE may be taken with or without food.

CALQUENCE is also in development for the treatment of multiple B-cell malignancies and other cancers including 1st line MCL, chronic lymphocytic leukemia (CLL), Waldenström macroglobulinemia (WM), follicular lymphoma, diffuse large B-cell lymphoma, and multiple myeloma. It is also being developed as a monotherapy and in combination trials for solid tumors. More than 35 clinical trials across 40 countries with more than 2,500 patients are underway or have been completed.

CALQUENCE was granted Orphan Drug Designation for the treatment of patients with CLL, MCL and WM in 2015, and Breakthrough Therapy Designation in August 2017 by the US FDA for the treatment of patients with MCL who have received at least one prior therapy.

About Mantle Cell Lymphoma (MCL)

MCL is an aggressive B-cell non-Hodgkin lymphoma (NHL) with poor prognosis. MCL accounts for approximately 3% of new NHL cases in the US, with approximately 3,300 new cases of MCL diagnosed each year. The median age at diagnosis is 68 years, with a 3:1 male predominance. While MCL patients initially respond to treatment, there is a high relapse rate.

About the ACE-LY-004 Trial

ACE-LY-004 is a Phase II open-label, single-arm clinical trial in 124 adult patients with relapsed or refractory MCL. The trial showed that 81% (95% CI: 73,87) of patients treated with CALQUENCE achieved an overall response; 40% (95% CI: 31,49) achieved a complete response and 41% (95% CI: 32,50) achieved a partial response, per 2014 Lugano classification as assessed by investigator.

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 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

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 & 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-16401 Last Updated 12/17

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