Study Design

The efficacy of CALQUENCE was based upon Trial LY-004, a Phase 2, open-label, single-arm trial in patients (≥18 years) with MCL who had received ≥1 prior therapy (N=124).1,2

Patients received CALQUENCE 100 mg twice daily until disease progression or unacceptable toxicity.

Clinical trial for mantle cell lymphoma included patients who had received prior cancer therapy.Clinical trial for mantle cell lymphoma included patients who had received prior cancer therapy.

These study design details are important to consider:

  • Tumor response was assessed according to the Lugano Classification for Non-Hodgkin lymphoma (NHL).

  • The major efficacy outcome of Trial LY-004 was overall response rate (ORR) and the median follow-up was 15.2 months.

  • Patients who received prior treatment with BTK inhibitors were excluded.

  • Primary endpoint:

    • Overall response rate (ORR) per 2014 Lugano Classification response criteria1

      • Defined as the proportion of subjects who achieve a complete response (CR) or partial response (PR)*2

  • Secondary endpoints2:

    • Duration of Response (DoR)

    • Progression Free Survival (PFS)

    • Overall Survival (OS)

  • Key inclusion criteria1,2:

    • Documented failure to achieve at least PR with, or documented disease progression after, the most recent treatment regimen

    • Presence of radiographically measurable lymphadenopathy or extranodal lymphoid malignancy

    • Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

  • Key exclusion criteria2:

    • Prior treatment with a BTK inhibitor

    • Significant cardiovascular disease

    • Anticoagulation with warfarin or equivalent vitamin K antagonists within 7 days of first dose of study drug

*CR (complete response) is defined as the disappearance of all evidence of disease including extranodal disease if present at baseline, by radiographic imaging. PR (partial response) is defined as the regression of measurable disease and no new sites. Efficacy endpoints were assessed by the investigator and an Independent Review Committee.2 Significant cardiovascular disease included uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification.2

Baseline Patient Characteristics1,2

The baseline characteristics of the patients (≥18 years) with MCL who had received ≥1 prior therapy in the Phase 2 open-label, single-arm trial of CALQUENCE monotherapy include:

 

Chart showing baseline characteristics of patients who had received at least one prior therapy and took CALQUENCE as a monotherapy.Chart showing baseline characteristics of patients who had received at least one prior therapy and took CALQUENCE as a monotherapy.

MIPI=Mantle Cell Lymphoma International Prognostic Index. ARA-C=cytarabine; CHOP=cyclophosphamide/doxorubicin/vincristine/prednisone; hyper-CVAD=cyclophosphamide/vincristine/doxorubicin/dexamethasone.

Overall Response Rate (ORR)

CALQUENCE received accelerated approval from the Food and Drug Administration for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy based on overall response rate.1 Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials.

LY-004 Study Design Criteria1:

  • Phase 2, open label, single-arm trial of CALQUENCE monotherapy

  • 124 patients with MCL 18 years of age or older who had received ≥1 prior therapy

  • Primary endpoint:

    • Overall response rate (ORR) - defined as the proportion of patients who achieve a complete response (CR) or partial response (PR)*2

*CR (complete response) is defined as the disappearance of all evidence of disease including extranodal disease if present at baseline; PR (partial response) is defined as the regression of measurable disease and no new sites. Efficacy endpoints were assessed by the investigator and by an Independent Review Committee.

For adult patients with MCL who have received at least one prior therapy,1 CALQUENCE focused on efficacy

80% ORR was achieved with CALQUENCE1

Graph showing response rates for acalabrutinib in patients with relapsed or refractory mantle cell lymphoma.Graph showing response rates for acalabrutinib in patients with relapsed or refractory mantle cell lymphoma.

§Independent Review Committee-assessed per 2014 Lugano Classification response criteria.1 Investigator-assessed response rates were ORR: 81%; CR 40%; PR 41%.1 CR=complete response; ORR=overall response rate; PR=partial response.CI=confidence interval

  • Median time to best response was 1.9 months1

Complete Response (CR)

Complete response (CR) is defined, based on radiographic and PET scans, as the disappearance of all detectable evidence of disease including extranodal disease if present at baseline.2

Graph showing response rates for acalabrutinib in patients with relapsed or refractory mantle cell lymphoma.Graph showing response rates for acalabrutinib in patients with relapsed or refractory mantle cell lymphoma.

§Independent Review Committee-assessed per 2014 Lugano Classification response criteria.1 Investigator-assessed response rates were ORR: 81%; CR 40%; PR 41%.1 CR=complete response; ORR=overall response rate; PR=partial response.CI=confidence interval

CALQUENCE: focused on efficacy, 40% (CR) was achieved1

In patients who responded to CALQUENCE (99/124):

  • 49% (49/99) achieved a complete response1,2

Partial Response (PR)

Partial response (PR) is defined, based on radiographic and PET scans, as the regression of measurable disease and no new sites.2

40% of patients with refractory/relapsed MCL had a PR with CALQUENCE.1,2

Graph showing response rates for acalabrutinib in patients with relapsed or refractory mantle cell lymphoma.Graph showing response rates for acalabrutinib in patients with relapsed or refractory mantle cell lymphoma.

§Independent Review Committee-assessed per 2014 Lugano Classification response criteria.1 Investigator-assessed response rates were ORR: 81%; CR 40%; PR 41%.1 CR=complete response; ORR=overall response rate; PR=partial response.CI=confidence interval

Duration of Response (DoR)

In LY-004, a Phase 2, open-label, single-arm trial of CALQUENCE monotherapy, one of the secondary endpoints was duration of response (DoR).2

DoR was measured as the interval from documentation of CR or PR to documentation of disease progression or death, whichever occurred earlier.2

Median DoR not reached at a median follow-up of 15.2 months (range: 0.3-23.7 months).1,2

Duration of response in relapsed/refractory MCL.Duration of response in relapsed/refractory MCL.

§Independent Review Committee-assessed per 2014 Lugano Classification response criteria.1

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Important Safety Information

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 discontinuation 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.

Indication and Usage

CALQUENCE is a Bruton tyrosine kinase (BTK) inhibitor indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

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.

Please see complete Prescribing Information including Patient Information.

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

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References:

  1. CALQUENCE [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017.
  2. Cheah CY, Seymour JF, Wang ML. Mantle cell lymphoma. J Clin Oncol. 2016;34:1256-1269.
  3. Hoster E, Klapper W, Hermine O, et al. Confirmation of the mantle-cell lymphoma International Prognostic Index in randomized trials of the European Mantle-Cell Lymphoma Network. J Clin Oncol. 2014;32:1338-1346.
  4. Zhou Y, Wang H, Fang W, et al. Incidence trends of mantle cell lymphoma in the United States between 1992 and 2004. Cancer. 2008;113:791-798.
  5. Teras LR, DeSantis CE, Cerhan JR, et al. 2016 US lymphoid malignancy statistics by World Health Organization subtypes. CA Cancer J Clin. 2016;66:443-459.
  6. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). B-cell lymphomas. Version 3.2017. https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf.Accessed June 28, 2017.
  7. Hendriks RW, Yuvaraj S, Kil LP. Targeting Bruton’s tyrosine kinase in B cell malignancies. Nat Rev Cancer. 2014;14(4):219-232.

References:

  1. CALQUENCE [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017.
  2. Data on File, 18540, AstraZeneca Pharmaceuticals LP.

References:

  1. CALQUENCE [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017.
  2. Data on File, 18540, AstraZeneca Pharmaceuticals LP.

Reference:

  1. CALQUENCE [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017.