CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`210259Orig1s000
`
`RISK ASSESSMENT and RISK MITIGATION
`REVIEW(S)
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`Application Type
`Application Number
`PDUFA Goal Date
`OSE RCM #
`
`Division of Risk Management (DRISK)
`Office of Medication Error Prevention and Risk Management (OMEPRM)
`Office of Surveillance and Epidemiology (OSE)
`Center for Drug Evaluation and Research (CDER)
`
`NDA
`210259
`February 17, 2018
`2017-1196
`2017-1199
`
`Ingrid N. Chapman, Pharm.D.
`Elizabeth Everhart, MSN, ACNP
`Cynthia LaCivita, Pharm.D.
`September 29, 2017
`Evaluation of Need for a REMS
`
`Acalabrutinib
`Calquence
`Acerta Pharma BV
`Bruton Tyrosine Kinase Inhibitor
`Capsule for oral use: 100 mg
`100 mg by mouth twice daily
`
`
`Reviewer Name(s)
`Team Leader
`Division Director
`Review Completion Date
`Subject
`
`Established Name
`Trade Name
`Name of Applicant
`Therapeutic Class
`Formulation(s)
`Dosing Regimen
`
`
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`Reference ID: 4161021
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`Table of Contents
`
`EXECUTIVE SUMMARY ......................................................................................................................................................... 3
`1
`Introduction ..................................................................................................................................................................... 3
`2 Background ...................................................................................................................................................................... 3
`2.1
`Product Information ........................................................................................................................................... 3
`2.2
`Regulatory History............................................................................................................................................... 4
`3
`Therapeutic Context and Treatment Options .................................................................................................... 4
`3.1
`Description of the Medical Condition .......................................................................................................... 4
`3.2
`Description of Current Treatment Options ............................................................................................... 4
`4 Benefit Assessment ....................................................................................................................................................... 5
`5 Risk Assessment & Safe-Use Conditions .............................................................................................................. 6
`5.1
`Hemorrhage ............................................................................................................................................................ 7
`5.2
`Infections ................................................................................................................................................................. 7
`5.3
`Cytopenias ............................................................................................................................................................... 7
`5.4
`Second Primary Malignancies ......................................................................................................................... 7
`5.5
`Atrial Fibrillation .................................................................................................................................................. 7
`5.6
`Tumor Lysis Syndrome ...................................................................................................................................... 8
`5.7
`Deaths ....................................................................................................................................................................... 8
`6
`Expected Postmarket Use ........................................................................................................................................... 8
`7 Risk Management Activities Proposed by the Applicant ............................................................................... 8
`8 Discussion of Need for a REMS ................................................................................................................................. 8
`9
`Conclusion & Recommendations ............................................................................................................................. 9
`10
`Appendices .................................................................................................................................................................. 9
`10.1 References ............................................................................................................................................................... 9
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`Reference ID: 4161021
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`EXECUTIVE SUMMARY
`This review by the Division of Risk Management (DRISK) evaluates whether a risk evaluation and
`mitigation strategy (REMS) for the new molecular entity Calquence (acalabrutinib) is necessary to ensure
`the benefits outweigh its risks. Acerta Pharma BV submitted a New Drug Application (NDA) # 210259 for
`acalabrutinib with the proposed indication for the treatment of patients with mantle cell lymphoma
`(MCL) who have received at least one prior therapy. The risks associated with acalabrutinib include
`hemorrhage, infections, cytopenias, second primary malignancies, atrial fibrillation tumor lysis
`syndrome. The applicant did not submit a REMS with this application but proposed routine
`pharmacovigilance activities to identify and characterize safety concerns for acalabrutinib.
`
`If approved, the labeling will communicate the risks of acalabrutinib with Warning and Precautions
`specifically highlighting the risks of hemorrhage, infections, cytopenias, second primary malignancies,
`atrial fibrillation and tumor lysis syndrome. DRISK and the Division of Hematology Products (DHP) agree
`that a REMS is not needed to ensure the benefits of acalabrutinib outweigh its risks for the proposed
`indication: for the treatment of patients with mantle cell lymphoma (MCL) who have received at least
`one prior therapy.
`
`1 Introduction
`This review by the Division of Risk Management (DRISK) evaluates whether a risk evaluation and
`mitigation strategy (REMS) for the new molecular entity (NME) Calquence (acalabrutinib) is necessary to
`ensure the benefits outweigh its risks. Acerta Pharma BV submitted a New Drug Application (NDA) #
`210259 for acalabrutinib with the proposed indication for the treatment of patients with mantle cell
`lymphoma (MCL) who have received at least one prior therapy. This application is under review in the
`Division of Hematology Products (DHP). The applicant did not submit a REMS with this application but
`proposed routine pharmacovigilance activities to address the risks of hemorrhage, infections,
`cytopenias, second primary malignancies, atrial fibrillation and tumor lysis syndrome.
`
`2 Background
`2.1 PRODUCT INFORMATION
`Calquence (acalabrutinib), a new molecular entity,a is a bruton tyrosine kinase (BTK) inhibitor proposed
`for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior
`therapy. Acalabrutinib, if approved, will be the second drug in the pharmacologic class of bruton
`tyrosine kinase inhibitors. Acalabrutinib is proposed as a 100 mg capsule for oral administration. The
`recommended dose is 100 mg by mouth twice daily until disease progression or unacceptable toxicity.b
`Acalabrutinib is not currently approved in any jurisdiction.
`
`
`
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`a Section 505-1 (a) of the FD&C Act: FDAAA factor (F): Whether the drug is a new molecular entity.
`b Section 505-1 (a) of the FD&C Act: FDAAA factor (D): The expected or actual duration of treatment with the drug.
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`Reference ID: 4161021
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`2.2 REGULATORY HISTORY
`The following is a summary of the regulatory history for NDA 210259 relevant to this review:
`
`• 11/27/2013: IND 118717 submission received for acalabrutinib
`
`• 06/13/2017: NDA 210259 submission for the treatment of patients with MCL who received at
`least one prior therapy
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`• 07/31/2017: Breakthrough designation granted
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`• 09/01/2017: Midcycle telecommunication with the applicant; the FDA stated there were no
`safety issues that require a REMS for acalabrutinib
`
`3 Therapeutic Context and Treatment Options
`3.1 DESCRIPTION OF THE MEDICAL CONDITION
`Mantle Cell Lymphoma (MCL) is one of 70 different subtypes of Non-Hodgkin Lymphoma (NHL). It’s
`estimated that MCL represents 2-10% of all non-Hodgkin lymphomas.1 NHL represents approximately
`4% of all cancer diagnoses and is the seventh most common cancer.c In 2017, the estimated number of
`new cases of NHL is 72,240 and the estimated number of deaths is 20,140.2,d MCL carries a poor
`prognosis with the median time to treatment failure being less than 18 months and 10-year survival rate
`being low at 5-10%.1
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`3.2 DESCRIPTION OF CURRENT TREATMENT OPTIONS
`MCL has an aggressive clinical course and patients usually present with extensive disease, including
`widespread lymphadenopathy, bone marrow involvement, splenomegaly, circulating tumor cells, and
`bowel infiltration.3 Treatment is non-curative and is based upon patient specific factors such as prior
`treatment, comorbidities and performance status, the regimens’ expected toxicities and the clinicians
`experience.4 Non-pharmacologic treatment of MCL consists of non-myeloablative allogenic
`hematopoietic cell transplantation (HCT) in certain patient populations or radiation therapy for
`chemotherapy refractory disease. In the relapsed or refractory setting, combination chemotherapy with
`or without rituximab and single agent therapy with bortezomib, lenalidomide, or ibrutinib are
`considered salvage therapy.
`
`Combination chemotherapy regimens are associated with many toxicities, which are often intolerable.
`Examples used as salvage therapy in relapsed/refractory MCL include RICE (rituximab, ifosfamide,
`carboplatin and etoposide) and ESHAP (etoposide, methylprednisolone, high-dose cytarabine and
`
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`c Section 505-1 (a) of the FD&C Act: FDAAA factor (B): The seriousness of the disease or condition that is to be
`treated with the drug.
`d Section 505-1 (a) of the FD&C Act: FDAAA factor (A): The estimated size of the population likely to use the drug
`involved.
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`cisplatin). Single agent therapy avoids the toxicities while providing at least a partial response with
`subsequent progression free survival.
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`Table 1:5 Monotherapy Treatment for Relapsed/Refractory Mantle Cell Lymphoma
`Product Trade Name
`Dosing and
`Important Safety and Tolerability Issues
`Risk
`(Generic)
`Administration
`Management
`Year Approved
`Approaches
`Revlimid
`REMS
`(Lenalidomide)
`Program*
`2005
`
`Labeling -
`Immunomodulator
`Boxed Warning
`Labeling –
`Warning and
`Precautions
`
`Velcade
`(Bortezomib)
`2003
`Proteasome Inhibitor
`
`25 mg by mouth
`once daily on
`days 1 – 21 of
`repeated 28-day
`cycles
`1.3 mg/m2
`subcutaneously
`or IV twice
`weekly for 2
`weeks followed
`by a 10 day rest
`period
`
`Risk of embryo-fetal exposure
`Fetal Risk – birth defects or embryo-fetal
`death
`Neutropenia and thrombocytopenia
`Venous and arterial thromboembolism
`Peripheral neuropathy
`Cardiac effects
`Pulmonary effects
`Neutropenia and thrombocytopenia
`Liver failure
`Diabetes
`GI effects
`Tumor lysis syndrome
`Hemorrhage
`Infections
`Hematologic effects
`Cardiovascular effects
`Hypertension
`GI toxicity
`Renal toxicity
`Secondary primary malignancies
`Tumor lysis syndrome
`Waldenstrom macroglobulinemia
`Hyperuricemia
`*REMS is to mitigate embryo-fetal exposure
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`420 mg by
`mouth daily
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`Imbruvica
`(Ibrutinib)
`2013
`Bruton Tyrosine
`Kinase Inhibitor
`
`
`Labeling –
`Warning and
`Precautions
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`4 Benefit Assessmente
`The pivotal trial (ACE-LY-004) supporting the application for acalabrutinib consisted of a Phase 2,
`multicenter, open-label, single-arm study that is ongoing. Through January 5, 2016, the study enrolled
`124 patients who were ≥ 18 years with histologically confirmed MCL. The patients were required to
`have no previous BTK inhibitor exposure, have disease that relapsed after or been refractory to ≥ 1 prior
`therapy for MCL and required further treatment. The primary endpoint of study ACE-LY-004 was overall
`response rate (ORR). The secondary endpoints were duration of response (DOR) and progression free
`survival (PFS) based on investigator assessment and ORR, DOR and PFS based on an independent review
`committee (IRC) assessment. All of the endpoints studied were assessed according to the Lugano
`
`e Section 505-1 (a) of the FD&C Act: FDAAA factor (C): The expected benefit of the drug with respect to such disease
`or condition.
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`classification. The primary endpoint, investigator assessment of ORR, resulted as 80.6% (95% CI: 72.6%,
`87.2%). The primary and secondary endpoints are shown in Table 2 below.
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`
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`Table 26: Acalabrutinib (ACE-LY004) Primary and Secondary Endpoints
`
`
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`Investigator Assessment
`N = 124
`
`95% CIa
`
`Overall response rate
`
`80.6%
`
`(72.6%, 87.2%)
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`IRC Assessment
`N= 124
`79.8%
`
`95% CIa
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`(71.7%, 86.5%)
`
`13.5 months
`
`15.2 months
`
`NE
`
`NE
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`Duration of response
`(median)
`Progression-free
`survival (median)
`a 95% exact binomial confidence interval
`Abbreviations: CI = confidence interval; IRC = Independent Review Committee; NE = not estimable
`
`The clinical reviewer recommends accelerated approval of acalabrutinib for the treatment of mantle cell
`lymphoma in patients who have failed at least one therapy. This recommendation is based on the ORR
`(80.6%) showing a clinically meaningful benefit and the durable overall response (DOR) of 13.5 months.7
`
`14.8 months
`
`15.2 months
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`NE
`
`NE
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`5 Risk Assessment & Safe-Use Conditions
`The safety profile of acalabrutinib was derived from the pivotal Phase 2 study ACE-LY-004 and an
`integrated analysis of 7 pooled studies in patients with hematological malignancies treated with
`acalabrutinib monotherapy that support the proposed indication. These studies were analyzed in 3
`analysis pools based on the underlying hematologic malignancy and dosing regimen.8 Overall, 319/612
`(52.1%) patients experienced an adverse event ≥ CTCAE (Common Terminology Criteria for Adverse
`Events, Version 4) Grade 3 with 122/612 (19.9%) being deemed related to acalabrutinib by the
`applicant.
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`•
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`•
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`•
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`ISS-LY004 (N=124): This population consists of all subjects in the pivotal study treated with
`acalabrutinib monotherapy at 100 mg by mouth twice daily.
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`ISS-100 (N=443): This population consists of subjects treated with acalabrutinib monotherapy
`with 100 mg by mouth twice daily as the starting dose.
`
`ISS-All (N=612): This population consists of all subjects treated with acalabrutinib monotherapy
`at any dose and frequency.
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`The serious adverse events (referred to as risks) determined to be associated with acalabrutinib are
`hemorrhage, infections, cytopenias, second primary malignancies, atrial fibrillation and tumor lysis
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`Reference ID: 4161021
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`syndrome.f The Warnings and Precautions section of the acalabrutinib proposed label includes these
`risks and will be discussed below along with the deaths that occurred.
`
`5.1 HEMORRHAGE
`Overall, hemorrhage of all grades was reported in 316/612 patients (51.6%). Major hemorrhage
`occurred in 1/124 (0.8%) patients in the ISS-LY004 population, 10/443 (2.3%) in the ISS-100 population
`and 17/612 (2.8%) in the ISS-All population. One death (CTCAE Grade 5 adverse event) occurred in ISS-
`100 which was an intracranial hematoma. The proposed label advises healthcare providers to monitor
`for bleeding and manage appropriately.
`
`INFECTIONS
`5.2
`Infections ≥ CTCAE Grade 3 occurred in 17/124 (13.7%) in ISS-LY004, 67/443 (15.1%) in ISS-100 and
`109/612 (17.8%) in ISS-All. The most frequently reported infection, CTCAE Grade 3 or higher, was
`pneumonia. The proposed label advises healthcare providers to monitor patients for signs and
`symptoms of infection and treat as medically appropriate
`
`5.3 CYTOPENIAS
`Cytopenias including anemia, thrombocytopenia, and neutropenia occurred in patients receiving
`acalabrutinib. Anemia ≥ CTCAE Grade 3 occurred in 11/124 (8.9%) in ISS-LY004, 33/443 (7.4%) in ISS-100
`and 45/612 (7.4%) in ISS-All. Thrombocytopenia ≥ CTCAE Grade 3 occurred in 6/124 (4.8%) in ISS-LY004,
`21/443 (4.7%) in ISS-100 and 29/612 (4.7%) in ISS-All. Neutropenia ≥ CTCAE Grade 3 occurred in 16/124
`(12.9%) in ISS-LY004, 60/443 (13.5%) in ISS-100 and 82/612 (13.4%) in ISS-All. The proposed label
`advises healthcare providers to monitor complete blood counts monthly during treatment.
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`5.4 SECOND PRIMARY MALIGNANCIES
`Second primary malignancies of CTCAE Grade 3 or higher occurred in 4/124 patients (3.2%) in ISS-LY004,
`17/443 patients (3.8%) in ISS-100 and 25/612 patients (4.1%) in ISS-All. The most frequently reported
`malignancy type were skin malignances (basal cell carcinoma, squamous cell carcinoma and squamous
`cell carcinoma of the skin). The proposed label recommends healthcare providers advise patients to use
`sun protection.
`
`5.5 ATRIAL FIBRILLATION
`Atrial fibrillation, all CTCAE Grades, was reported in the ISS-All population in 82/612 (13.4%) patients
`with 18/612 patients (2.9%) ≥ CTCAE Grade 3. One patient discontinued study treatment due to the
`atrial fibrillation adverse event. There were no cases of atrial fibrillation reported in the ISS-LY004
`
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`f Any adverse drug experience occurring at any dose that results in any of the following outcomes: Death, a life-
`threatening adverse drug experience, inpatient hospitalization or prolongation of existing hospitalization, a
`persistent or significant disability/incapacity, or a congenital anomaly/birth defect. Important medical events that
`may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse drug
`experience when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may
`require medical or surgical intervention to prevent one of the outcomes listed in this definition.
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`Reference ID: 4161021
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`population. The proposed label advises healthcare providers to monitor for atrial fibrillation and
`manage as appropriate.
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`5.6 TUMOR LYSIS SYNDROME
`Tumor lysis syndrome occurred in 3/124 patients (2.4%) in ISS-LY004, and 4/612 patients (0.7%) in ISS-
`All. All of the events in IS-LY004 were ≥ CTCAE Grade 3. The proposed label advises healthcare
`providers to assess baseline risk and take precaution and to monitor and treat for tumor lysis syndrome.
`
`5.7 DEATHS
`Overall, 79/612 (12.9%) patients died during treatment and 36/612 (5.9%) died within 30 days of
`discontinuing acalabrutinib. On treatment, disease progression was the most common cause of death
`amongst all analysis groups (ISS-LY004, 25/30; ISS-100, 33/56; ISS-All 47/79). Fatal adverse events
`(CTCAE Grade 5) occurred in 25/612 (4.1%) of patients in the ISS-All population. The most frequently
`reported fatal adverse event was pneumonia (6/25, 24%). Of the fatal adverse events, 2/124 (1.6%)
`occurred in the ISS-LY004 population and the applicant attributed the deaths to aortic stenosis and non-
`small cell lung cancer.
`
`6 Expected Postmarket Use
`
`Acalabrutinib will be primarily prescribed in the outpatient setting by hematologists and oncologists
`who should be familiar with the management of adverse reactions associated with bruton tyrosine
`kinase inhibitors. The draft prescribing information currently addresses the associated serious risks and
`management of hemorrhage, infections, cytopenias, second primary malignancies, atrial fibrillation and
`tumor lysis syndrome.
`
`7 Risk Management Activities Proposed by the Applicant
`The Applicant did not propose any risk management activities for acalabrutinib beyond routine
`pharmacovigilance and labeling.
`
`8 Discussion of Need for a REMS
`The Clinical Reviewer recommends approval of acalabrutinib on the basis of the efficacy and safety
`information currently available. Mantle cell lymphoma is a serious disease that represents
`approximately 2-10% of all non-Hodgkin lymphomas. Based on this data, an estimated 1,400 to 7,200
`new cases of MCL and up to 2,000 deaths will occur in 2017. The standard treatment of
`relapsed/refractory MCL with combination chemotherapy is associated with significant toxicities.
`Treatment with acalabrutinib provides a monotherapy option with a durable overall response and less
`toxicity.
`
`The serious risks associated with acalabrutinib are hemorrhage, infections, cytopenias, second primary
`malignancies, atrial fibrillation and tumor lysis syndrome. The hematologists and oncologists prescribing
`acalabrutinib should be familiar with managing these risks as they are well known in this specialty. The
`labeling will be used to communicate these risks. DRISK recommends that, should acalabrutinib be
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`Reference ID: 4161021
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`approved, a REMS is not necessary to ensure its benefits outweigh its risks for the treatment of mantle
`cell lymphoma.
`
`9 Conclusion & Recommendations
`Based on the clinical review, the benefit-risk profile is favorable for the treatment of mantle cell
`lymphoma and therefore, a REMS is not necessary for acalabrutinib to ensure the benefits outweigh the
`risks. At the time of this review, evaluation of safety information and labeling was ongoing. Please
`notify DRISK if new safety information becomes available that changes the benefit-risk profile; this
`recommendation can be reevaluated.
`
`2.
`
`10 Appendices
`10.1 REFERENCES
`Abbasi MR, Sparano JA. Mantle Cell Lymphoma. Medscape. July 31, 2015.
`1.
`http://emedicine.medscape.com/article/203085-overview. Accessed July 6, 2017.
`Adult Non-Hodgkin Lymphoma Treatment (PDQ®)–Health Professional Version. May 12, 2017;
`National Cancer Institute. Available at: https://www.cancer.gov/types/lymphoma/hp/adult-nhl-
`treatment-pdq#cit/section 1.2. Accessed July 6, 2017.
`Acerta Pharma BV. Acalabrutinib. Module 2.5 - Clinical Overview. June 13, 2017.
`Freedman AS, Friedberg JW. Treatment of relapsed or refractory mantle cell lymphoma.
`UpToDate. 2017. Accessed June 10, 2017.
`Drugs@FDA: FDA Approved Drug Products. https://www.accessdata.fda.gov/scripts/cder/daf/.
`Accessed August 1, 2017.
`Acerta Pharma. Calquence (acalabrutinib). Module 2.5 - Clinical Overview. May 24, 2017.
`Merino M. Division of Hematology Products (DHP). Acalabrutinib (Calquence) Mid-Cycle
`Meeting, Clinical Reviewer Slides
`August 18, 2017.
`Acerta Pharma. Calquence (acalabrutinib). Module 2.7.4 - Summary of Clinical Safety: 90-Day
`Safety Update. September 6, 2017.
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`3.
`4.
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`5.
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`6.
`7.
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`8.
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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`INGRID N CHAPMAN
`09/29/2017
`
`CYNTHIA L LACIVITA
`09/30/2017
`Concur
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`Reference ID: 4161021
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