CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`205552Orig1s000
`
`SUMMARY REVIEW
`
`
`
`
`

`

`Ann.T.Farrell, M.D., Division Director
`
`Division Director Summary Review
`Subject
`NDA/BLA #
`205552
`
`140 mg hardgelatin capsules
`Indicated for the treatment ofpatients with mantle cell
`lymphoma
`Action/Recommended Action for|Accelerated Approval
`NME:
`
`Supplement #
`
`Applicant Name
`Pharmacyclics and Janssen Research and Development
`Date of Submission
`June 28, 2013
`PDUFAGoal Date
`February
`28, 2014
`Proprietary Name/
`Imbruvica/ibrutinib/PCI-32765
`Name
`Established
`(USAN)
`Dosage Forms/ Strength
`Proposed Indication(s)
`
`LaShawn Griffiths,MSHS-PH, BSN,RN/Barbara
`
`Material Reviewed/Consulted
`OND Action Package, including:
`Medical Officer Review
`
`CMCReview/OBP Review
`
`Clinical Pharmacology Review
`
`Karen McGinn, M.S.N. C.R.N.P./ Angelo DeClaro,
`M.D.
`Yun Wang, Ph.D./Lei Nie, Ph.D.
`
`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
`.
`,
`Ph.D.
`gelica Dorantes, Ph.D.
`
`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.
`
`Anthony Orenica, M.D./Janice Pohlman, M.D./Kassa
`Ayalew, 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/NishaPatel, Pharm.D./
`
`OSE/DMEPA
`
`OSE/DPV
`OSE/DRISK
`Other -OMP
`
`Reference ID: 3404122
`
`

`

`
`
` Other-IRT
`
`Fuller, RN, MSN, CWOCN
`Kevin M. Krudys, Pharm.D./Qianyu Dang/MonicaL.
`Fiszman/Norman Stockbridge,M.D.
`
`Signatory Authority Review Template
`
`1. Introduction
`
`On June 28, 2013, Pharmacyclics, Inc. filed a new drug application (NDA)foribrutinib.
`Ibrutinib (PCI-32765) is an irreversible inhibitor of Bruton’s tyrosine kinase (Btk).
`
`The FDAtherapeutic class designation is a kinase inhibitor.
`
`The applicant submitted a request to be designated as a Breakthrough Therapy and
`the designation was granted. The applicant has proposed the following indication: “for
`the treatment of patients with mantle cell lymphoma’.
`
`(b) (4)
`
`This
`
`summary review concerns the mantle cell indication.
`
`Theclinical support for the proposedindication is from clinical trial PCYC-1104-CA,
`an ongoing, open-label, single-arm trial of ibrutinib monotherapy in 111 patients with
`MCL who havereceivedat least oneprior therapy.
`
`The applicant proposes an oral dosing regimen of 560 mg oncedaily for patients with
`MCL.
`
`The application wasfiled as a priority review. The PDUFA goal date for the current
`submission is February 28, 2014.
`
`Imburivca/ibrutinib is not marketed in any country.
`
`2. Background
`
`Mantle cell lymphoma (MCL)is a relatively rare form of Non-Hodgkin Lymphoma
`(NHL) and represents approximately 5-9 % of all new NHL cases per year. Several
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`subtypes of MCL exist: centrocytic, small cell type and blastoid variant. The
`chromosomal translocation t(11;14) is the hallmark of MCL and this translocation
`results in the overexpression of cyclin D1. MCL has a male predominance, with an
`incidence rate 2.5 times higher than that of females. The median age at diagnosis is
`68 years. Patients typically present with generalized lymphadenopathy, and
`extranodal involvement is common particularly the gastrointestinal tract, blood, bone
`marrow and spleen.
`
`There is no curative therapy for MCL except for those patients who undergo an
`allogeneic stem cell transplantation. However the median age at diagnosis means
`that an allogeneic stem cell transplant is not an option for many patients. The median
`overall survival in patients with newly-diagnosed MCL is 3 to 5 years. First-line
`treatment regimens include multi-agent chemotherapy regimens, however, almost all
`patients will eventually relapse.
`
`FDA approved agents for the treatment of MCL include Velcade and Revlimid. Both
`were approved for patients with MCL who had received at least 1 prior therapy. The
`Velcade approval was based on demonstration of an overall response rate (ORR) of
`31%, complete response (CR) rate of 8%, and a median duration of response (DOR)
`of 9.3 months. The Revlimid approval was based on demonstration of an ORR 26%,
`CR 7%, and median DOR of 16.6 months.
`
`
`3. CMC/Device
`
`
`From the primary review:
`
`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:
`
`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….
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`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
`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)
`
` The exposure at 40 mg/kg/day was
`approximately 6 times the AUC in patients with MCL
`
`
`
`
`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:
`
`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
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`Reference ID: 3404122
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`(b) (4)
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`(b) (4)
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`recommenda doseofibrutinib in patients with hepatic impairment. A PMRwill be
`issued for the submission of the study report for the ongoing hepatic impairmenttrial.
`
`Thefollowing are the proposed PMRsfrom the Clin Pharm review team’s review:
`
`1. Submit the final study report for trial PCI-32765CLL1006 entitled, “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
`N/A
`
`7. Clinical/Statistical-Efficacy
`The clinical team reviewed the application. The following text is from the CDTL
`review:
`
`Efficacy Summary
`Theefficacy of ibrutinib was primarily evaluated in 111 patients with previously treated
`MCLenrolled in PCYC-1104-CA, a single-arm Phase2clinical trial. The median age
`was 68 years (range, 40 to 84 years), 77% were male, and 92% were Caucasian. At
`baseline, 89% of patients had a baseline ECOG performance status of 0 or 1. The
`median time since diagnosis was 42 months, and median numberof prior treatments
`was 3 (range, 1 to 5 treatments), including 11% with prior stem cell transplant. At
`baseline, 39% of subjects had at least one tumor 25 cm, 49% had bone marrow
`involvement, and 54% had extranodal involvementat screening.
`
`Ibrutinib was administered orally at 560 mg once daily until disease progression or
`unacceptable toxicity. Tumor response was assessed according to the revised
`International Working Group (IWG) for non-Hodgkin’s lymphoma (NHL) criteria. The
`primary endpointin this clinical trial was investigator-assessed overall response rate
`(ORR). Responsesto ibrutinib are shownin Table 2.
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`Table 2: Overall Response Rate (ORR) and Duration of Response (DOR)
`Based on Investigator Assessment in Patients with Mantle Cell Lymphoma
`
`Total (N =111)
`65.8
`ORR (%)
`95% CI (%)
`(56.2, 74.5)
`17.1
`CR (%)
`48.6
`PR (%)
`17.5 (15.8, NR)
`Median DOR months 95% CI
`CI = confidence interval; CR = complete response, PR = partial response, NR =
`not reached.
`
`An Independent Review Committee (IRC) performed independent reading and
`interpretation of imaging scans. The IRC review demonstrated an ORR of 69%.
`
`From the statistical review:
`In Study PCYC-1104-CA, the overall response rate (ORR) was 65.8% (95% CI
`[56.2%, 74.5%]) with median duration of response (DOR) of 17.5 months (lower 95%
`confidence limit (CI) of 15.8 months, and upper 95% CI not evaluable).
`
`Study PCYC-1104-CA was designed as a nonrandomized study. Therefore, all
`statistical analyses were descriptive and no formal statistical comparisons were
`performed.
`
`The response data from PCYC-1104-CA demonstrate durable treatment effect of
`ibrutinib for relapsed and refractory mantle cell lymphoma patients.
`I agree with the conclusions of the clinical and statistical review team. I also agree
`with the recommendations for accelerated approval based on the submitted data. In
`particular this applicant has chosen to use a revision of response criteria that has
`been used for prior Velcade and Revlimid applications. The following text from the
`primary reviewer and CDTL reviews discuss the issue:
`
`
` The ibrutinib NDA represents the first regulatory application of the 2007
`Response Criteria for a MCL indication. The MCL approvals for Revlimid
`and Velcade were based on the 1999 Response Criteria. A new feature in
`the 2007 Response Criteria is the integration of FDG-PET scans in the
`response assessments. Patients were not followed long enough to correlate
`FDG-PET scan determination of response with long-term outcomes.
`Whether the FDG-PET-negative complete responses confer the same
`benefit as CT-based complete response is unknown. There is also limited
`information in the published literature on the long-term outcomes of patients
`with MCL assessed using the 2007 Response Criteria, and even less
`information on patients with MCL treated with targeted therapy, such as
`ibrutinib.
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`o FDG-PET scans were considered exploratory in the Revlimid trial, and
`were conducted in 25% of the patients. FDG-PET scans were not
`mentioned in the Velcade trial. In contrast, 100% of patients had FDG-
`PET scans at baseline in the ibrutinib trial, and the protocol required
`mandatory FDG-PET scans for documentation of complete responses.
`
`
`
`Eight of the 19 patients who achieved a CR based on the 2007 criteria
`would not be considered a CR based on the 1999 criteria. A longer
`duration of follow-up is needed to further characterize the correlation of
`on-treatment FDG-PET scans with long-term outcomes.
`
` The MCL indication for ibrutinib is not supported by efficacy in any other
`indications.
`o At the time of regular approval for a MCL indication, both Revlimid and
`Velcade had received regular approval based on data from large
`randomized, controlled trials (RCTs). Prior to approval for MCL,
`Velcade had received regular approval for previously treated multiple
`myeloma based on a RCT (N=669) that showed a significant effect on
`time to progression (TTP) (HR 0.55, P<0.001) and OS (HR 0.57,
`P<0.05). Prior to approval for MCL, Revlimid had received approval for
`the treatment of patients with previously treated multiple myeloma based
`on the results of 2 large RCTs (N=353 and N=351), and both trials
`showed significant improvements in TTP [hazard ratio (HR) 0.285 and
`0.324, P<0.001 for both trials].
`
`
`Because multiple therapies are now approved for mantle cell lymphoma, it is
`important to comprehensively characterize the efficacy of antineoplastic agents and
`the disease course and to determine adequacy of long-term follow-up. Therefore, this
`reviewer does not recommend the use of the same approval standard for Revlimid
`and Velcade for future approvals for mantle cell lymphoma. Important questions for
`mantle cell lymphoma treatment remain, such as, optimal use of combination
`treatment regimens, comprehensive characterization of the disease course (nodal and
`extranodal sites), and evaluation of the treatment effect on time-to-event endpoints
`including progression-free survival and overall survival.
`
`The regular approval of Revlimid and Velcade occurred at a time when there was
`limited available therapy. Standards for approval for drugs used in the treatment of
`mantle cell lymphoma may need to be reconsidered. This approach would be
`consistent with the regulatory history for approvals for cutaneous T-cell lymphoma
`(CTCL). The initial regular approvals for CTCL (Zolinza and Istodax) were based on
`single-arm trials. With the availability of these therapies, FDA now recommends
`randomized controlled trials for future approvals for CTCL, and this approach was
`also supported by ODAC. The most recent regular approval for CTCL, Valchlor
`(topical nitrogen mustard), was based on the results of a randomized controlled trial.
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` I
`
` 
`
` concur with the recommendations of the primary reviewer and CDTL regarding the
`recommendation for accelerated approval.
`8. Safety
`The following text is from the CDTL review:
`
`Safety Summary
`The safety profile of ibrutinib was primarily evaluated in 111 patients with previously
`treated MCL enrolled in PCYC-1104-CA, a single-arm Phase 2 clinical trial. A
`summary of the key safety findings based on the data cut-off date of December 26,
`2013 is listed below:
`
` The starting ibrutinib dose was 560 mg once daily. The median duration of
`ibrutinib treatment with ibrutinib was 8.3 months (range 0.7 to 21.4+ months). At
`the time of data cut-off, 46 patients remained on therapy.
`
` There were 16 deaths within 30 days of treatment with ibrutinib (8 deaths due to
`disease progression, and 8 deaths due to treatment-emergent adverse events).
`The deaths due to adverse events include 2 cases of pneumonia and 1 case each
`of sepsis, respiratory failure, acute renal failure, paralytic ileus, cardiac arrest, and
`dyspnea.
`
` There were 62 patients (55.8%) who experienced serious adverse events (SAEs).
`Infection was the most common SAE.
`
` Discontinuations due to TEAEs occurred in 9 patients (8.1%).
`
` Almost three quarters of subjects (74%) experienced a Grade 3 or Grade 4
`treatment- emergent adverse event (TEAE). Neutropenia,
`thrombocytopenia, anemia, and pneumonia were the most common Grade 3
`and 4 TEAEs.
`
` TEAEs that occurred in ≥ 20% of patients include thrombocytopenia,
`diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, peripheral
`edema, upper respiratory tract infection, nausea, bruising, dyspnea,
`constipation, rash, abdominal pain, vomiting and decreased appetite.
`
` No new safety signals were detected in the analysis of 120-day safety update
`data.
`
` Review of the adverse events of special interest revealed the following:
`o Hemorrhagic events (MedDRA 15.1 SMQ Hemorrhage terms [excluding laboratory
`terms]) occurred in 48% of the patients. Major bleeding events occurred in 7
`patients (6.3%). Two subjects had grade 3 subdural hematoma, one had grade
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`2 and one had grade 1 subdural hematoma. Two subjects had grade 3
`hematuria and one had grade 3 lower gastrointestinal hemorrhage. The
`majority of the hemorrhagic events were grade 2 or less, with bruising and
`ecchymoses as the most common hemorrhagic events.
`
`The mechanism for the bleeding events is not well understood. There was no
`correlation between thrombocytopenia and the occurrence of bleeding events.
`o Second primary malignancies occurred in 5% of patients with MCL, including
`skin cancers (4%) and other carcinomas (1%).
`o Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients.
`These included neutropenia (29%), thrombocytopenia (17%) and anemia (9%).
`
`o
`
`Infections occurred in 82 (74%) patients. At least 25% of patients with MCL
`had CTCAE Grade 3 or greater infections.
`o Treatment-emergent increases in creatinine levels up to 1.5 times the upper
`limit of normal occurred in 67% of patients and from 1.5 to 3 times the upper
`limit of normal in 9% of patients.
`o Patients with MCL who develop lymphocytosis greater than 400,000/mcL have
`developed intracranial hemorrhage, lethargy, gait instability, and headache.
`However, some of these cases were in the setting of disease progression.
`
`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.
`
`From the IRT review for the potential for QT prolongation:
`
`For the objective of a dedicated QTc assessment following treatment with ibrutinib, we
`conclude that the current QTc study is inconclusive due to the following limitations in
`trial design:
`Baseline ECGs were not adequately collected. The Sponsor used screening
`ECGs that were collected at any time point up to two weeks before the drug
`was administered.
`Single on-treatment ECGs were collected in this study. Triplicate ECGs should
`be collected to reduce variability in QT measurements.
`
`
`In a previous review (1/30/13), QT-IRT recommended that a thorough QT study be
`conducted for ibrutinib and the results be submitted as a post-marketing requirement.
`After reviewing the current study we reaffirm our previous recommendation.
`
` I
`
` concur with their recommendation.
`
`Reference ID: 3404122
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`9. Advisory Committee Meeting
`This application is the third submitted within the past 10 years for an indication to treat
`mantle cell lymphoma. 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 – in section 7 above see discussion of reasons
`for accelerated approval.
` Risk Benefit Assessment
`MCL remains an incurable disease at this time with few available treatment
`options. 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
`Enhanced pharmacovigilance in order to characterize bleeding risks in patients
`treated with Imbruvica including their potential association with concomitant
`use of anti-platelet and/or anticoagulant drugs
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`Reference ID: 3404122
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`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 – The first requirement will involve the submission of longer
`term follow-up from the single arm trial (PCYC-1104-CA) and the second requirement
`will involve the submission of the final results of the ongoing randomized, double-
`blind, placebo-controlled Phase 3 clinical trial (PCI-32765MCL3002) of ibrutinib in
`combination with bendamustine and rituximab in patients with newly diagnosed
`mantle cell lymphoma.
`
`There will be additional PMRs that involve the following:
`1. Determination of the effect of a broad range of concentrations of ibrutinib on
`platelet function by in vitro studies
`2. Submission of the final study report for the hepatic impairment trial PCI-
`32765CLL1006
`3. Submission of the final study report for trial PCI-32765CLL1010 to assess the
`effect of Rifampin on the Pharmacokinetics of ibrutinib.
`
`
`There will be a PMC that addresses the dissolution profile of ibrutinib under various
`conditions.
`
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`Reference ID: 3404122
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`(b) (4)
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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
`11/08/2013
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`Reference ID: 3404122
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