CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
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`205552Orig2s000
`
`SUMMARY REVIEW
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`
`

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`205552-02
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`Action/Recommended Action for
`
`140 mg hard gelatin capsules
`Indicated for the treatment ofpatients with chronic
`lymphocytic lymphoma whohavereceived prior
`therapy
`Accelerated Approval
`
`Material Reviewed/Consulted
`
`OND Action Package, including:
`Medical Officer Review
`
`Nicole Verdun, M.D./ Angelo DeClaro, M.D.
`
`Pharmacology Toxicology Review|Shwu-Luan Lee, Ph.D., Haw-Jyh (Brian) Chiu,
`Ph.D., George Ching-Jey Chang, Ph.D.,
`Margaret E. Brower, Ph.D. / Haleh Saber, Ph.D. / John
`Leighton, Ph.D.
`Donghao Lu, Ph.D./Xiao Chen, Ph.D./Janice Brown,
`M.S./Ali Al-Hakim, Ph.D./Ramesh K. Sood, Ph.D./John
`Z. Duan, Ph.D./Angelica Dorantes, Ph.D.
`
`CMCReview/OBP Review
`
`(electronic stamp)
`Date
`Ann.T.Farrell, M.D., Division Director
`From
`
`Subject
`Summary Review
`NDA/BLA #
`Supplement #
`Pharmacyclics and Janssen Research and Development
`Applicant Name
`Date of Submission
`June 28, 2013
`PDUFAGoalDate
`February 28, 2014
`Proprietary Name/
`Imbruvica/ibrutinib/PCI-32765
`Name
`Established
`(USAN)
`Dosage Forms/ Strength
`Proposed Indication(s)
`
`
`
`Clinical Pharmacology Review
`
`OSI
`
`CDTL Review
`OSE/DMEPA
`
`OSE/DPV
`OSE/DRISK
`
`Reference ID: 3452394
`
`Elimika Pfuma, Pharm.D., Ph.D./Julie Bullock,
`Pharm.D./Rosane Charlab Orbach, Ph.D./Bahru
`Habtemariam, Ph.D./Yuzhuo Pao, Ph.D./Anshu
`Marathe, Ph.D./Ping Zhao, Ph.D.
`Nisha Patel/Karen Rulli
`Anthony Orenica, M.D./Janice Pohlman, M.D./Kassa
`Ayalew, M.D.
`Angelo DeClaro, M.D.
`Kevin Wright, Pharm.D./Yelena Maslov, Pharm. D./
`Carol Holquist, R. Ph.
`Katherine Coyle, Pharm.D. / Tracy Salaam, Pharm.D.
`Joyce Weaver, Pharm.D. / Cynthia LaCivita, Pharm.D.
`
`

`

`Karen Dowdy, RN, BSN/Nisha Patel, Pharm.D./
`LaShawn Griffiths,MSHS-PH, BSN,RN/ Barbara
`Fuller, RN, MSN, CWOCN
`Kevin M. Krudys, Pharm.D./Qianyu Dang/Monica L.
`Fiszman/Norman Stockbridge,M.D.
`
`Signatory Authority Review Template
`
`Other -OMP
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`Other-IRT
`
`
`
`
`
`
`
`
`
`1. Introduction
`
`
`On June 28, 2013, Pharmacyclics, Inc. filed a new drug application (NDA) for ibrutinib.
`Ibrutinib (PCI-32765) is an irreversible inhibitor of Bruton’s tyrosine kinase (Btk).
`
`The FDA therapeutic class designation is a kinase inhibitor.
`
`The original application had two indications and was administratively split into the
`mantle cell indication (original 01) and the chronic lymphocytic lymphoma indication
`(original 02). This summary review concerns the chronic lymphocytic lymphoma
`indication.
`
`The clinical support for the proposed indication is from clinical trial PCYC-1102-CA,
`an ongoing, an open-label, single-arm trial of ibrutinib monotherapy in 48 patients with
`CLL who have received at least one prior therapy.
`
`The applicant proposes an oral dosing regimen of 420 mg once daily for patients with
`CLL. This proposed dosing is lower than the dose approved for the treatment of
`mantle cell lymphoma.
`
`The application was filed as a priority review. The PDUFA goal date for the current
`submission is February 28, 2014.
`
`Imbruvica/ibrutinib is marketed in the United States but not for the treatment of CLL.
`
`
`2. Background
`
`
`The following text is from Dr. DeClaro’s review. I concur with his statements.
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`Reference ID: 3452394
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`

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`Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in
`adulthood. The National Cancer Institute estimates that 15,680 men and women
`(9,720 men and 5,960 women) will be diagnosed with CLL in 2013. CLL is a
`lymphoproliferative neoplasm characterized by an accumulation of monoclonal mature
`B-cells (CD5+CD23+) in the blood, bone marrow, and secondary lymphatic organs.
`
`Current treatments for CLL are not curative, and relapse, toxicity, and resistance to
`therapy provide for an unmet medical need. Among patients who relapse or who are
`refractory to first line treatment, the choice of subsequent therapy depends on age,
`duration of response to prior therapy, ability to tolerate treatment, disease related
`manifestations, and the presence of molecular poor-risk features.
`
`The following treatments are FDA-approved for the treatment of CLL: Chlorambucil
`(1957), Cyclophosphamide (1959), Fludarabine (1991), Alemtuzumab (2007),
`Bendamustine (2008), Ofatumumab (2009, accelerated approval), Rituximab (2010),
`and Obinituzumab (2013).
`
`
`3. CMC/Device
`
`
`From the primary review for the original 01 submission:
`
`From a CMC perspective, this application is recommended for Approval.
`EES has an overall “Acceptable” recommendation for this NDA. …
`
`Based on the available stability data an 24-month expiry dating is granted for
`Imbruvica® ibrutinib capsules stored at temperature of 20°C to 25°C (68°F to 77°F)
`with excursions permitted between 15°C and 30°C (between 59°F and 86°F).
`
`The biopharmaceutics review recommends a post-marketing commitment to collect
`additional dissolution profile data (release and stability).
`4. Nonclinical Pharmacology/Toxicology
`
`
`No issues that would preclude approval were identified.
`From the primary review for the original 01 submission:
`
`Ibrutinib (PCI-32765) is an irreversible inhibitor of Bruton’s tyrosine kinase (Btk); it
`binds covalently to a cysteine in the active site of Btk….
`
`The general toxicology studies in rats and dogs identified GI tract, lymphoid tissues,
`bone and skin as the main target of toxicities…
`
`Ibrutinib was not mutagenic in bacterial Ames test or clastogenic in a chromosome
`aberration test in Chinese Hamster Ovary cells (CHO). Ibrutinib did not increase
`
`Reference ID: 3452394
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`

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`micronucleus formation in mice after oral doses up to 2000 mg/kg. The mutagenicity
`of impurities was assessed through Ames test or by 2 computational SAR analyses
`(DEREK Nexus and MultiCase). The impurities tested were not mutagenic.
`
`Reproductive and developmental toxicities of ibrutinib were investigated in rats and
`rabbits….
`Ibrutinib was administered orally to pregnant rats during the period of organogenesis
`at doses of 10, 40 and 80 mg/kg/day. Increased post-implantation loss and increased
`resorption occurred at the high dose of 80 mg/kg. Fetal toxicities (visceral
`malformations and variations, and skeletal variations) were observed at the high dose
`of 80 mg/kg. Reduced fetal weight was seen at ibrutinib doses at 40 mg/kg and 80
`mg/kg. The dose of 80 mg/kg resulted in maternal toxicities. The dose of 80
`mg/kg/day in animals resulted in exposures (total AUC) approximately 14 times the
`AUC in patients with MCL (ibrutinib dose of 560 mg/day) and 20 times the AUC in
`patients with CLL (ibrutinib dose of 420 mg/day). The exposure at 40 mg/kg/day was
`approximately 6 times the AUC in patients with MCL and 8 times the AUC in patients
`with CLL.
`
`In a non-GLP study conducted in rabbits, ibrutinib was administered orally to pregnant
`animals during the period of organogenesis at doses of 10, 30, and 100 mg/kg/day. At
`the ibrutinib dose of 100 mg/kg, which is greater than the maternally-toxic dose (≥30
`mg/kg/day), there were embryo-fetal toxicities. Findings included increases in
`resorption and implantation loss, decreases in viable fetuses and fetal body weights,
`as well as spontaneous abortions.
`
`Ibrutinib did not cause adverse findings in male or female reproductive organs in
`general toxicology studies.
`5. Clinical Pharmacology/Biopharmaceutics
`From the Clin Pharm review for the original 01 submission:
`
`Ibrutinib is primarily metabolized by CYP3A4. No dose reduction is recommended for
`weak CYP3A4 inhibitors, but a dose reduction to 140 mg is recommended for
`concomitant use of a moderate CYP3A4 inhibitor. A dose recommendation could not
`be made for strong CYP3A4 inhibitors due to the 24-fold increase in exposure.
`Therefore, it is recommended that concomitant use be avoided for chronic CYP3A4
`inhibitors and the dose of ibrutinib can be temporarily interrupted during the use of a
`short-term CYP3A4 inhibitor (≤ 7 days). A 7 day interruption of ibrutinib dosing was
`supported by data from the pivotal trial where patients responded to therapy
`even when they required short term dose interruption during therapy. The concomitant
`use of strong CYP3A4 inducers should be avoided. There is insufficient data to
`recommend a dose of ibrutinib in patients with hepatic impairment. A PMR will be
`issued for the submission of the study report for the ongoing hepatic impairment trial.
`
`
`The following are the proposed PMRs from the Clin Pharm review team’s review:
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`Reference ID: 3452394
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`

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`1. Submit the final study report for trial PCI-32765CLL1006entitled, “An Open-Label,
`Multicenter, Pharmacokinetic Study of PCI-32765 in Subjects with Varying Degrees of
`Hepatic Impairment”.
`2. Submit the final study report for trial PCI-32765CLL1010 entitled, “An Open-Label,
`Sequential Design Study to Assess the Effect of Rifampin on the Pharmacokinetics of
`PCI-32765 in Healthy Subjects”.
`
`(b) (4)
`
`The food effect study demonstrated a two-fold increase in exposure whenibrutinib
`wasadministered with a high-fat meal compared to overnightfast.
`
`No issues that would preclude approval wereidentified.
`
`6. Microbiology
`No issues that would preclude approval wereidentified in the review of original 01.
`
`7. Clinical/Statistical-Efficacy
`Theclinical team reviewed the application. The following text is from the CDTL
`review:
`
`Efficacy Summary
`The safety and efficacy of Imbruvica in patients with CLL who have received at
`least one prior therapy were evaluated in an open-label, multi-center trial of 48
`previously treated patients. The median age was 67 years (range, 37 to 82 years),
`71% were male, and 94% were Caucasian. All patients had a baseline ECOG
`performancestatus of 0 or 1. The median time since diagnosis was 80 months and
`the median number of prior treatments was 4 (range, 1 to 12 treatments). At
`baseline, 46% of subjects had at least one tumor 2 5 cm.
`
`Imbruvica was administered orally at 420 mg once daily until disease progression
`or unacceptable toxicity. Overall response (ORR) and duration of response (DOR)
`were assessed using a modified version of the International Working Group CLL
`Criteria by an Independent Review Committee. he ORR was 58.3% (95% Cl:
`43.2%, 72.4%), all partial responses. None of the patients achieved a complete
`response. The DOR rangedfrom 5.6 to 24.2+ months. The median DOR was not
`reached.
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`Reference ID: 3452394
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`

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`I agree with the conclusions of the clinical and statistical review team recommending
`approval for this application under the accelerated approval regulations. I recommend
`that the labeling provide a range for the duration of response.
`
` concur with the recommendations of the primary reviewer and CDTL regarding the
`recommendation for accelerated approval.
`8. Safety
`No new safety issues were identified during the review of this portion of the
`application. The following text is from the CDTL review:
`
`Safety Summary
`• The ibrutinib dose was 420 mg once daily. The median exposure duration was
`15.6 months.
`
`• All treated subjects experienced at least 1 treatment-emergent adverse event.
`
`• Fifty-eight percent of patients had at least one bleeding event, characterized as
`bruising (54%), epistaxis (6%), eye related hemorrhage (6%), rectal
`hemorrhage (4%), or subdural hematoma (4%). Seventeen percent of patients
`experienced petechiae during the clinical trial.
`
` I
`
`
`
`• The most common non-hematological adverse events (occurring in ≥ 20% of
`patients) were diarrhea (63%), upper respiratory tract infection (39%), fatigue
`(33%), pyrexia (25%), peripheral edema (23%), arthralgia (23%), constipation
`(22%), stomatitis (21%), sinusitis (21%), nausea (21%), and dizziness (21%).
`
`• The most common Grade 3 or 4 adverse events (occurring in ≥ 5% of patients)
`were neutropenia, pneumonia, thrombocytopenia, hypertension, dehydration,
`and sinusitis.
`
`• Forty-two percent of patients required a dose modification or interruption due to
`an adverse event. The most common adverse events leading to a modification
`or interruption were infections (19%).
`
`This summary highlights what has been observed in a limited number of patients.
`Based on the potential for serious adverse reactions – bleeding/bruising risk,
`myelosuppression, and infection are identified as the most serious. Peripheral
`lymphocytosis has been observed with this agent.
`
` I
`
` have read the primary review and secondary review and concur with their
`recommendation.
`
`Reference ID: 3452394
`
`

`

`9. Advisory Committee Meeting
`This application is the second indication under the original NDA submission. The
`application for the treatment of mantle cell was approved in 2013. This is the fourth
`application within the past several years for an indication to treat chronic lymphocytic
`leukemia. This application was not taken to an Oncologic Drugs Advisory Committee
`meeting because there were no issues with the trial design, conduct, endpoint or data
`analysis. In addition the trial results demonstrated a positive risk benefit and no safety
`issues arose during the review of the application requiring an expert committee
`meeting.
`
`
`Pediatrics
`10.
`This product has orphan designation therefore is exempt from the requirement to
`conduct studies in pediatric patients.
`
`
`Other Relevant Regulatory Issues
`11.
`Financial Disclosure information was provided and reviewed. The information
`provided did not suggest any integrity issue. In addition an independent review
`committee reviewed the clinical response data.
`
`From the Office of Scientific Investigation review:
`The study data collected appear generally reliable in support of the requested
`indication.
`Labeling
`12.
`All disciplines made recommendations for labeling. The recommendations were
`discussed during internal labeling negotiations.
`13.
`Decision/Action/Risk Benefit Assessment
`• Recommended regulatory action
`Approval under 21 CFR 314.500 -- Accelerated Approval with requirements for
`trials to confirm clinical benefit.
`
`The clinical trial database for the accelerated approval is admittedly small.
`However the during the review the Applicant notified the Agency regarding
`early stopping of the RESONATE trial (PCYC-1112-CA), a Phase 3,
`randomized controlled trial of ibrutinib or ofatumumab in patients with
`previously treated CLL. The Applicant decided to stop the trial early due to
`significant improvements in progression-free survival and overall survival in the
`ibrutinib arm. The Applicant shared the top-line results with the Agency and
`although the top-line results have not been verified by the Agency, this news
`suggests the Applicant will be able to submit a supplement relatively soon
`allowing fulfillment of accelerated approval requirements.
`
`Reference ID: 3452394
`
`

`

`
`
`
`
` •
`
` Risk Benefit Assessment
`CLL remains an incurable disease at this time. Ibrutinib has demonstrated a
`durable response rate in a small single arm trial. Safety issues include
`bleeding/bruising risk, myelosuppression, infection, gastrointestinal
`disturbance, rash, musculoskeletal pain, and peripheral edema. Based on the
`submitted data the risk-benefit profile appears favorable.
`
`
` •
`
` Recommendation for Post marketing Risk Management Activities
`See original 01 approval letter for information regarding enhanced
`pharmacovigilance.
`Please see approval letter for exact wording.
`
` •
`
` Recommendation for other Post marketing Study Requirements/
`Commitments
`
`
`
`The PMRs/PMCs will address the following issues:
`
`
`Accelerated approval – For fulfillment of accelerated approval (Subpart H)
`requirements, the Applicant has agreed to the following postmarketing
`requirements:
`
`PMR-1: Submit the results of the completed randomized, open-label Phase 3
`clinical trial (PCYC-1112-CA) of ibrutinib versus ofatumumab in patients with
`relapsed or refractory chronic lymphocytic leukemia or relapsed or refractory
`small lymphocytic lymphoma. Enrollment of 391 patients was completed. The
`primary endpoint is progression-free survival as assessed by an Independent
`Review Committee.
`
`PMR-2: Complete and submit the results of the ongoing randomized, double-
`blind, placebo-controlled Phase 3 clinical trial (PCI-32765CLL3001) of ibrutinib
`in combination with bendamustine and rituximab in patients with relapsed or
`refractory chronic lymphocytic leukemia or relapsed or refractory small
`lymphocytic lymphoma. Enrollment of 578 patients was completed. The
`primary endpoint is progression-free survival as assessed by an Independent
`Review Committee.
`
`
`Successful completion of either PMR-1 or PMR-2 could verify clinical benefit
`and fulfill accelerated approval requirements for the Chronic Lymphocytic
`Leukemia (CLL) indication.
`
`
`Reference ID: 3452394
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`

`

`
`Please refer to action letter for final wording of the post-marketing requirements
`and commitments.
`
`
`In addition, the Applicant has several PMRs/PMCs that are described in the original
`01 approval letter.
`
`
`
`
`
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`Reference ID: 3452394
`
`

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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/
`----------------------------------------------------
`
`ANN T FARRELL
`02/11/2014
`
`Reference ID: 3452394
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`