`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`205552Orig2s000
`
`
`CROSS DISCIPLINE TEAM LEADER REVIEW
`
`

`

`Cross Discipline Team Leader Review
`
`Cross-Discipline Team Leader Review
`
`
`“amp “‘6
`R. An elo de Claro, M.D.
`From
`m__—
`
`Proprietary Name /
`Established
`S ‘
`
`names
`
`Imbruvica
`
`Dosa _e forms / Stren_ h
`Proposed Indication(s)
`
`Ca sules, 140 m-
`Treatment of patients with chronic lymphocytic leukemia
`CLL who have received at least one rior therau
`
`Material Reviewed/Consulted
`
`Clinical Review
`
`Nicole Verdun, MD. / R. An elo de Claro, MD.
`
`Pharmacology Toxicology
`Review
`
`Shwu-Luan Lee, Ph.D., Haw-Jyh (Brian) Chiu,
`Ph.D., George Ching-Jey Chang, Ph.D.,
`
`Yun Wang, PhD. /Lei Nie, PhD.
`
`
`
`ONDQA—CMC and
`Biopharmaceutic Reviews
`
`Clinical Pharmacology Review
`
`Xiao—Hong Chen, Ph.D. (Drug product)/
`Biopharm: John Duan, PhD. /Angelica Dorantes, Ph.D.
`Microbiology: Bryan Riley, PhD.
`ONDQA: Ramesh Sood, PhD. (Tertiary Review)
`Elimika Pfuma, PharmD, Ph.D., Julie Bullock, PhamlD,
`Rosane Charlab Orbach, PhD, Bahru Habtemariam,
`PhannD, Yuzhuo Pan, PhD, Anshu Marathe, PhD, Ping
`Zhao PhD
`
`Anthon Orencia, M.D. / Janice Pohhnan, M.D., M.P.H.
`
`Patient Labelin- Team DMPP
`
`Kevin Wri -
`
`t, PharmD. / Yelena Maslov, PharmD.
`
`Katherine Coyle, PhannD. / Tracy Salaam, PharmD.
`Karen Dowd , RN, BSN / Barbara Fuller RN, MSN
`
`Page 1 of 8
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`Reference ID: 3452369
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`Cross Discipline Team Leader Review
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`1. Introduction
`
`On June 28, 2013, Pharmacyclics Inc. (Applicant) submitted NDA 205552 Original-2
`proposed for the treatment of patients with chronic lymphocytic leukemia (CLL) who have
`received at least one prior therapy. The Applicant had submitted a concurrent application
`(NDA 205552 Original-1) for the treatment of patients with mantle cell lymphoma (MCL)
`who have received at least one prior therapy also on June 28, 2013, and received
`accelerated approval for the treatment of patients with MCL who have received at least one
`prior therapy on November 13, 2013.
`
`Imbruvica (ibrutinib) is a first-in-class Bruton’s tyrosine kinase inhibitor, which targets the
`B-cell antigen receptor (BCR) signaling pathway.
`
`The primary basis for the application is the result from clinical trial PCYC-1102-CA, an
`open-label, single-arm trial of Imbruvica monotherapy in 48 patients with CLL who have
`received at least one prior therapy.
`2. Background
`
`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
`Obinutuzumab (2013).
`
`3. CMC/Device
`
`CMC sections were addressed in the NDA 205552 (Original-1) review. There are no
`major labeling changes proposed for the CMC sections with NDA 205552 (Original-2).
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`Cross Discipline Team Leader Review
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`4. Nonclinical Pharmacology/Toxicology
`
`Nonclinical Pharmacology and Toxicology sections were addressed in the NDA 205552
`(Original-1) review. There are no major labeling changes proposed for the Nonclinical
`Pharmacology and Toxicology sections with NDA 205552 (Original-2).
`
`5. Clinical Pharmacology/Biopharmaceutics
`
`Clinical Pharmacology reviewed the MCL and CLL indications together in the NDA
`205552 (Original-1) review, and issued a brief addendum for NDA 205552 Original-2.
`There are no major labeling changes proposed for the Clinical Pharmacology sections with
`NDA 205552 (Original-2).
`
`6. Clinical Microbiology
`
`The application did not include clinical microbiology information. Refer to Section 3 of
`NDA 205552 (Original-1) review for product quality microbiology information.
`
`7. Clinical/Statistical- Efficacy
`
`I agree with the conclusions of the statistical and clinical reviewers for the efficacy of
`Imbruvica for patients with CLL who have received at least one prior therapy.
`
`The following summarizes the key milestones in the regulatory history. The Applicant
`submitted the IND for ibrutinib (PCI-32765) on September 8, 2008. Protocol PCYC-1102-
`CA (single-arm trial in patients with CLL/SLL) was initiated on March 11, 2010. End of
`Phase 2 (EOP2) meetings to discuss the CLL clinical development program including
`registrational approach occurred on December 5, 2011, April 30, 2012, July 26, 2012, and
`September 26, 2012. Fast Track was granted on October 29, 2012 for the treatment of
`patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL)
`who have relapsed or have refractory disease and have previously received at least one
`prior therapy. On March 18, 2013, Breakthrough Therapy designation was granted by the
`FDA for the treatment of patients with chronic lymphocytic leukemia or small lymphocytic
`lymphoma with deletion of the short arm of chromosome 17 (del 17p). Pre-NDA meeting
`occurred on April 9, 2013.
`
`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 performance status of 0 or 1. The
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`Cross Discipline Team Leader Review
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`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
`≥ 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. The ORR was 58.3% (95% CI: 43.2%, 72.4%), all partial
`responses. None of the patients achieved a complete response. The DOR ranged from 5.6
`to 24.2+ months. The median DOR was not reached.
`
`Primary Reviewer Conclusions
`The statistical reviewer concluded that Imbruvica provided durable treatment effect for
`patients with relapsed or refractory chronic lymphocytic leukemia in Study PCYC-1102-
`CA.
`
`CDTL Comment: The statistical review was finalized prior to agreement with the
`Applicant on the ORR results. The ORR of 58.3% (28/48) is acceptable to both the clinical
`and statistical teams, and differs from the final ORR (56.3%, 27/48) reported in the
`statistical review based on clarification provided by the Applicant regarding the response
`profile of 1 patient.
`
`The clinical reviewer concluded that the Applicant has demonstrated the efficacy of
`Imbruvica in patients with chronic lymphocytic leukemia who have been previously
`treated.
`
`CDTL Comment: At the time of application submission, the clinical and statistical teams
`noted lack of independent review committee (IRC) verification of the efficacy results.
`During the review cycle, the Applicant submitted the requested IRC assessments for the
`efficacy endpoints.
`8. Safety
`
`I concur with the clinical reviewer’s conclusions regarding the safety of Imbruvica for the
`proposed CLL indication.
`
`Safety Summary
`The safety profile of Imbruvica was primarily evaluated in 48 patients with previously
`treated CLL enrolled in PCYC-1102-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 Imbruvica 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.
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`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.
`
`The most common non-hematological adverse events (occurring in 2 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 diuiness (21%).
`
`The most common Grade 3 or 4 adverse events (occurring in 2 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%).
`
`9.
`
`Advisory Committee Meeting
`
`The NDA for this new molecular entity was not presented to the Oncologic Drugs
`Advisory Committee because the application did not raise significant efficacy or safety
`issues for the proposed indication.
`
`10.
`
`Pediatrics
`
`Imbruvica is exempt from the pediatric study requirements in 21 CFR 314.55. FDA Office of
`Orphan Products Development granted Orphan Drug Designation for ibrutinib for the
`treatment of CLL on April 6. 2012. Imbruvica has not been evaluated in pediatric patients.
`
`11.
`
`Other Relevant Regulatory Issues
`
`Application Integrity Policy (AIP): No issues.
`
`Exclusivity or Patent Issues of Concern: No issues. Refer to exclusivity review.
`
`Financial Disclosures: A concern with respect to possible bias arose from the large
`monetary donations to the two sites with the largest enrollment into Trial
`one)
`which enrolled 22 (46% of total) patients and
`(bus) which enrolled 15 (31% of total) patients. Both sites were inspected by the
`Office of Scientific Integrity (OSI), and the inspectors verified that the conduct of the
`trial complied with US. laws and regulations covering good clinical practices. In
`addition, the implementation of an IRC review for verification of efficacy mitigates
`this concern.
`
`Other GCP Issues: None
`
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` Office of Scientific Investigation (OSI) Audits: The following is from the executive
`summary of the findings:
`For Protocol PCYC-1102-CA, two U.S. clinical investigation sites were inspected in
`support of the application (MD Anderson and Ohio State University). The clinical site
`inspections reviewed the records of 45 subjects were screened and 42 subjects were
`enrolled. Thirty-two subjects were rolled over into a long-term extension study, under
`Protocol 1103. A complete audit of 16 subjects’ records including verification of the
`informed consent documents of 16 enrolled subjects was performed.
`Source documents for randomized subjects whose records were reviewed were
`verified against the case report forms and NDA subject line listings. Specific records
`were reviewed for study participants’ inclusion or exclusion criteria, drug
`accountability, adverse events, monitoring, IRB approval, financial disclosure forms,
`and overall protocol compliance. There was no evidence of under-reporting of
`significant adverse events.
`No significant regulatory violations were noted during the FDA inspection and a Form
`FDA 483 was not issued.
`The study appears to have been conducted adequately and the data generated by this
`site appear acceptable in support of the respective indication.
` Other discipline consults: None
` Other outstanding regulatory issues: None
`12.
`Labeling
`
` Proprietary name. On 16 August 2013, OSE/DMEPA concluded that the proposed
`proprietary name, Imbruvica is acceptable.
`
` OSE/DPV. There were no new OSE/DPV concerns with NDA 205552 Original-2.
`Action letter will include reminder for PMR 2060-4, pharmacovigilance plan for
`serious hemorrhagic events. Refer to OSE/DPV review for NDA 205552 Original-1.
`
` OSE/DRISK. There were no new OSE/DRISK concerns with NDA 205552
`Original-2. Refer to OSE/DRISK review for NDA 205552 Original-1. Based on the
`currently available information, REMS is not recommended.
`
` OSE/DMEPA. There were no new OSE/DMEPA concerns with NDA 205552
`Original-2. Refer to OSE/DMEPA review for NDA 205552 Original-1.
`
` Patient Labeling Team. The patient labeling group participated in the labeling
`discussions.
`
` OPDP. OPDP attended labeling meetings and provided input. Refer to OPDP review
`in DARRTS for OPDP labeling recommendations.
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`13.
`
`Recommendations/Risk Benefit Assessment
`
` Recommended Regulatory Action: Approval
`
` Risk Benefit Assessment
`
`Relapsed CLL is a serious and life-threatening illness. The efficacy and safety results
`in clinical trial PCYC-1102-CA demonstrate an acceptable benefit-risk profile for
`Imbruvica for the treatment of patients with previously treated CLL. All review team
`members recommend approval.
`
`The response rate of 58.3% (95%CI: 43.2%, 72.4%) in a patient population with
`relapsed CLL, with a duration of response ranging from 5.6 to 24.2+ months support
`approval. However, multiple uncertainties remain regarding the clinical benefit of
`Imbruvica in the CLL population.
`
`Section 21 CFR 314.510 addresses approval based on a clinical endpoint other than
`survival or irreversible morbidity. Accelerated approval is subject to the requirement
`that the applicant study the drug further, to verify and describe its clinical benefit,
`where there is uncertainty as to the relation of the surrogate endpoint to clinical benefit,
`or of the observed clinical benefit to ultimate outcome.
`
` The small number of patients (N=48) treated at the proposed dosing regimen (420
`mg per day) raises uncertainty on the magnitude of effect on response rate as
`evidenced by the confidence interval spanning 43% to 72%.
`
` None of the patients achieved a complete response.
`
` Time-to-event endpoints such as progression-free survival or overall survival
`cannot be adequately interpreted in single-arm trials due to confounding effects of
`the disease course.
`
`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 due to significant
`improvements in progression-free survival and overall survival in the ibrutinib arm.
`Although the results have not been verified by the Agency, this news is encouraging
`regarding fulfillment of accelerated approval requirements.
`
`CDTL Recommendation: Accelerated approval
`
` Recommendation for Postmarketing Risk Evaluation and Management Strategies
`
`The Applicant did not propose a REMS and the review teams did not identify the need
`for a REMS at this time to ensure the safe use of Imbruvica.
`
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` Recommendation for other Postmarketing Requirements and Commitments
`
`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.
`
`Refer to action letter for final wording of the post-marketing requirements and
`commitments.
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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/
`----------------------------------------------------
`
`ROMEO A DE CLARO
`02/11/2014
`
`Reference ID: 3452369
`
`