CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`205552Orig2s000
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`
`
`
`
`
`
`

`

`OFFICE OF CLINICAL PHARMACOLOGY:
`PHARMACOMETRIC MEMO
`NDA 205552
`Original-2 (06/28/2013)
`Ibrutinib
`420 mg QD (Chronic Lymphocytic Leukemia)
`DHP
`Bahru A Habtemariam, Pharm.D.
`Julie M. Bullock, Pharm. D.
`Anshu Marathe, Ph.D.
`
`Application Number
`Submission Number (Date)
`Compound
`Dosing regimen
`Clinical Division
`Primary PM Reviewer
`Clinical Pharmacology Team Leader
`Secondary PM Reviewer
`
`Background ............................................................................................................................. 2
`Summary of Findings:............................................................................................................. 2
`Is there exposure-response relationship for effectiveness endpoint in CLL patients?............ 2
`Is the proposed dose of 420 mg QD in CLL patients appropriate?......................................... 4
`Recommendation .................................................................................................................... 4
`Appendix 1: IRC Efficacy Analysis Details ........................................................................... 5
`
`Reference ID: 3442944
`
`

`

`Background
`
`The original NDA for Ibrutinib (submitted on 6/28/13) proposed the treatment of patients with:
`mantle cell lymphoma (MCL; Original-1) and chronic lymphocytic leukemia (CLL; Original-2).
`The applicant submitted two pivotal clinical trials: a phase 2 trial (study 1104) in patients with
`MCL and a phase 1b/2 trial (study 1102) in patients with CLL.
`
`The Original-1 NDA was approved on 11/13/2013 for patients with MCL. Exposure-efficacy
`analysis for patients with MCL and exposure-safety analysis for all patients which included both
`patients with MCL and CLL was conducted as part of the Pharmacometric review (for details see
`review in DARRTS dated 11/01/2013). At the time of the Original-1 NDA review, several issues
`with regards to interpretation of the efficacy data were identified by the Clinical Reviewers for
`patients enrolled in the CLL study 1102. Thus the approval for the CLL indication was deferred
`until data interpretation issues were resolved. Consequently the exposure-efficacy analysis for
`CLL patients was also deferred until updated data/analysis was submitted.
`
`The initial treatment-response analysis in study 1102 was based on investigator assessment. On
`12/17/2013, the sponsor submitted updated data, reports and analysis for CLL patients enrolled in
`study 1102 based on response assessment conducted by an independent review committee (IRC).
`The sponsor’s IRC efficacy analysis found that the overall response rate (ORR) was 67.4% for all
`treated subjects (N=132). Details of the IRC efficacy analysis results are provided in appendix 1.
`Study design and treatment and dosing details are provided in Table 1.
`
`Table 1. Study design details for trial 1102
`Study Number
`Study Description
`Treatment Arms
`
`PCYC-1102-CA
`
`Phase 1b/2 open-
`label trial in treatment
`naïve (N=47) or
`relapsed/ refractory
`(N=85) CLL/SLL
`
`High-Risk RR 420 mg (N=23)
`RR 420 mg (=27)
`RR 840 mg (N=31)
`RR Food Effect 420 mg (16)
`TN 420 mg (N=26)
`TN 840 mg (N=3)
`RR= Relapsed/Refractory, TN=Treatment-Naive
`
`Primary Study
`Endpoint
`Overall Response Rate
`(ORR)
`
`Summary of Findings: The purpose of this memo is to address the following key questions.
`
`Is there exposure-response relationship for effectiveness endpoint in CLL patients?
`There is no evidence of an exposure-response for overall response rate (ORR) in the range of
`exposures observed following ibrutinib doses of 420 mg or 840 mg in patients with CLL. Steady
`state trough plasma concentrations were available from a total of 132 patients who were enrolled
`in study 1102. Trough concentrations were obtained on days 1, 8, and 15. Trough concentrations
`collected on days 8 or later were used to calculate mean steady state trough concentrations.
`
`Reference ID: 3442944
`
`2
`
`

`

`Figure 1 below shows that there is no increase in proportion of patients with ORR with
`increasing trough concentrations of ibrutinib. Because the proposed dose is 420 mg for patients
`with at least one prior treatment, a separate exposure-efficacy analysis was conducted for those
`with refractory disease treated at 420 mg once daily. Figure 2 below shows that the proportion of
`patients with ORR is not influenced by trough concentration in refractory CLL patients treated
`with ibrutinib dose of 420 mg once daily. However, the data was limited with only 45 subjects
`included in this analysis.
`
`Figure 1. The proportion of patients with ORR versus steady trough concentrations in CLL
`patients treated with 420 or 840 mg once daily.
`
`30
`
`30/31
`
`26/31
`
`30/32
`
`|
`
`|
`
`0
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`Proportion of Patients With ORR (%)
`
`|
`
`26/32
`
`|
`25
`20
`15
`10
`5
`Mean Steady State Ctrough (ug/mL)
`
`Reference ID: 3442944
`
`3
`
`

`

`Figure 2. The proportion of patients ORR is not influenced by increasing steady trough
`concentrations in refractory CLL patients treated with 420 mg once daily.
`
`30
`
`11/13 12/12
`|
`
`|
`
`0
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`Proportion of Patients With ORR (%)
`
`|
`|
`25
`20
`15
`10
`5
`Mean Steady State Ctrough (ug/mL)
`
`10/12
`
`|
`
`12/13
`
`Is the proposed dose of 420 mg QD in CLL patients appropriate?
`
`The proposed dose of 420 mg QD in CLL patients appears acceptable based on reasonable safety
`profile and a response rate of 67.4% that was achieved in the phase 1b/2 trial. Additionally, no
`meaningful exposure-response relationship is identified for Grade 3 or 4 neutropenia and Grade 3
`or 4 infections and infestations (see Pharmacometrics review in DARRTS dated 11/01/2013).
`Thus based on available effectiveness and safety data, the proposed dose appears acceptable.
`
`However, the proposed dose is 2.4-fold higher than the lowest dose that resulted in maximum
`BTK occupancy and maximum clinical response. Dose-response relationship for ORR and BTK
`occupancy from Phase 1 study suggested that maximum ORR and maximum occupancy was
`achieved at doses of ≥ 2.5 mg/kg (≥ 175 mg for average weight of 70 kg) [see Pharmacometrics
`review in DARRTS dated 11/01/2013. The sponsor should thus consider exploring lower doses
`in future development programs.
`
`Recommendation: Division of Pharmacometrics finds NDA 205552 acceptable from a clinical
`pharmacology perspective.
`
`Reference ID: 3442944
`
`4
`
`

`

`Appendix 1: IRC Efficacy Analysis Details
`
`Source: Table 2 of sponsor’s CSR
`
`Reference ID: 3442944
`
`5
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`BAHRU A HABTEMARIAM
`01/28/2014
`
`JULIE M BULLOCK
`01/28/2014
`
`ANSHU MARATHE
`01/28/2014
`
`Reference ID: 3442944
`
`

`

`205552 Clinical Pharmacology Review
`205552
`NDA
`28th June 2013
`Submission Date:
`ImbruvicaTM
`Brand Name:
`ibrutinib
`Generic Name:
`140 mg Capsules
`Formulation:
`Elimika Pfuma, PharmD, PhD
`OCP and Genomics Reviewer:
`Julie Bullock, PharmD
`OCP Team Leader:
`Rosane Charlab Orbach, PhD
`Genomics Team Leader
`Bahru Habtemariam, PharmD and Yuzhuo Pan, PhD
`Pharmacometrics Reviewers:
`Pharmacometrics Team Leaders: Anshu Marathe, PhD and Ping Zhao, PhD
`Division of Clinical Pharmacology V
`OCP Division:
`
`Division of Hematology Products
`OND Division:
`Pharmacyclics
`Applicant:
`Submission Type; Code:
`0000/1
`MCL: 560 mg (4 x 140 mg capsules) once daily
`Proposed Dosing regimen:
`CLL/SLL: 420 mg (3 x 140 mg capsules) once daily
`Original 1: Mantle cell lymphoma (MCL)
`Original 2: Chronic lymphocytic leukemia (CLL)
`
`
`
`
`
`Proposed Indication:
`
`
`Table of Contents
`
` 1
`
` Executive Summary ......................................................................................................2
`1.1
`Recommendations ...........................................................................................3
`1.2
`Post Marketing Requirements .........................................................................3
`1.3
`Comments to the Applicant .............................................................................4
`1.4
`Summary of Clinical Pharmacology Findings .................................................4
`
`2 Question Based Review ................................................................................................6
`2.1
`General Attributes ...........................................................................................6
`2.2
`General Clinical Pharmacology .......................................................................7
`2.3
`Intrinsic Factors .............................................................................................24
`2.4
`Extrinsic Factors ............................................................................................29
`2.5
`General Biopharmaceutics.............................................................................36
`2.6
`Analytical Section .........................................................................................40
`
`3 Appendices ...................................................................................................................45
`3.1
`Pharmacometrics Review ..............................................................................45
`3.2
`PBPK Review ................................................................................................55
`
`
`
`
`Reference ID: 3400137
`
`1
`
`
`
`

`

`EXECUTIVE SUMMARY
`
`1
`
`Ibrutinib is an irreversible Bruton’s tyrosine kinase (BTK) inhibitor that binds to a cysteine
`residue (Cys-481) in the BTK active site. It is proposed for the treatment of patients with mantle
`cell lymphoma (MCL; Original NDA 1) and chronic lymphocytic leukemia (CLL; Original NDA
`2). The applicant proposes oral dosing regimens of 560 mg once daily in MCL and 420 mg once
`daily in CLL.
`
`To support the approval of ibrutinib, the applicant submitted two pivotal clinical trials: a phase 2
`trial (PCYC-1104-CA) in patients with MCL and a phase 1b/2 trial (PCYC-1102-CA) in patients
`with CLL. PCYC-1102-CA was an open-label trial in elderly treatment naïve (N=31) or relapsed/
`refractory (N=82) CLL that evaluated ibrutinib at daily doses of 420 mg or 840 mg. Trial PCYC-
`1104-CA was an open label, non-randomized trial in patients with relapsed or refractory MCL
`(N=111) that evaluated ibrutinib at 560 mg daily. Original NDA 1 is for the MCL indication and
`the CLL indication will be reviewed under Original NDA 2. Treatment with ibrutinib resulted in
`an ORR of 65.8% (95% CI: 56.2, 74.5) and a CR rate of 17.1% in the overall MCL study
`population. The safety database is small and does not include long term data. The median
`duration of treatment with ibrutinib was 8.3 months and the median dose intensity was 550
`mg/day.
`
`Pharmacokinetic data to support the clinical pharmacology program were submitted for the two
`pivotal trials and three additional trials (mass balance trial, CYP3A4 inhibitor trial and a dose-
`escalation trial). No exposure-response relationship was observed for effectiveness at the dose of
`560 mg in MCL. No exposure-response relationship was observed for Grade 3 or 4 infection and
`infestation and Grade 3 or 4 neutropenia in the dose range of 420 - 840 mg in the pivotal phase 2
`trials. The dose-response relationship for BTK occupancy and clinical response in the phase 1
`dose escalation trial showed that maximum BTK occupancy and maximum response were
`achieved at doses of ≥ 2.5 mg/kg (≥ 175 mg for average weight of 70 kg).
`
`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.
`
`
`Reference ID: 3400137
`
`2
`
`
`
`

`

`1.1 RECOMMENDATIONS
`
`The Office of Clinical Pharmacology Divisions of Clinical Pharmacology V, Pharmacometrics
`and Genomics have reviewed the information contained in NDA 205-552. This NDA is
`acceptable from a clinical pharmacology perspective. The adequacy of specific drug information
`is provided below:
`
`
`Decision
`Evidence of
`Effectiveness
`Proposed dose
`for general
`population
`
`Sufficiently Supported?
` Yes
` No
` NA
`
`Recommendations and Comments
`Pivotal trials
`
` Yes
`
` No
`
` NA
`
`The proposed doses are effective and appear to be safe
`given the limited data available. However, given what is
`known about the in vitro IC50, and the flat-exposure
`response seen between 2.5 mg/kg and 12.5 mg/kg a lower
`dose would likely be efficacious. See Section 2.2.4.4 for
`more information.
`Comment:
`1. Evaluate lower doses of ibrutinib in future clinical
`development as data from the Phase 1 trial showed
`that maximum BTK occupancy and maximum response
`were achieved at doses of ≥ 2.5 mg/kg.
`Labeling Recommendations:
`1. A dose reduction to 140 mg is recommended for
`concomitant use of a moderate CYP3A4 inhibitor
`PMR studies:
`1. Submit final study report for trial evaluating the effect of
`a strong CYP3A4 inducer (rifampin) on ibrutinib
`exposure
`2. Submit final study report for trial evaluating the effect of
`hepatic impairment on ibrutinib exposure
`A formal bioequivalence trial was not performed to evaluate
`differences between the two clinical trial formulations used
`across studies. The to-be-marketed formulation (one of the
`clinical trial formulations) was used in >70% of the
`treatment cycles in the two pivotal trials.
`
`
` Yes
`
` No
`
` NA
`
`Proposed dose
`adjustment in
`specific patients
`or patients with
`comedications
`
`Pivotal
`bioequivalence
`studies
`
` Yes
`
` No
`
` NA
`
`Labeling
`
` Yes
`
` No
`
` NA
`
`
`1.2 POST MARKETING REQUIREMENTS
`
`
`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”.
`
`3.
`
`Reference ID: 3400137
`
`3
`
`
`
`(b) (4)
`
`

`

`
`1.3 COMMENTS TO THE APPLICANT
`
`1. Submit the final study report for trial PCI-32765CLL1001 entitled, “An Open-Label,
`Randomized, 4-Way Crossover Study to Determine the Effect of Food on the
`Pharmacokinetics of PCI-32765”.
`2. We recommend you evaluate lower doses of ibrutinib in future clinical development as
`data from the Phase 1 trial PCYC-04753 showed that maximum BTK occupancy and
`maximum response were achieved at doses of ≥ 2.5 mg/kg.
`3. The potential for ibrutinib to inhibit transporters has not been evaluated. We recommend
`that you evaluate, in vitro, the potential for ibrutinib to inhibit transporters such as BCRP,
`OATP1B1/OATP1B3, OCT2, OAT1 and OAT3.
`
`
`1.4 SUMMARY OF CLINICAL PHARMACOLOGY FINDINGS
`
`Ibrutinib is an irreversible Bruton’s tyrosine kinase (BTK) inhibitor that binds to a cysteine
`residue (Cys-481) in the BTK active site. It is proposed for the treatment of patients with mantle
`cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). The applicant proposes oral
`dosing regimens of 560 mg once daily in MCL and 420 mg once daily in CLL.
`
`Two pivotal clinical trials (a phase 1b/2 trial for CLL and a phase 2 trial for MCL) were
`submitted to support the proposed indication and dosing regimen. Pharmacokinetic data to
`support the clinical pharmacology program were submitted from the two pivotal trials and three
`additional trials (mass balance trial, CYP3A4 inhibitor trial and a dose-escalation trial).
`
`Ibrutinib exposure increases with dose up to 840 mg. The median ibrutinib Tmax ranged from 1
`to 2 hours and the mean elimination half-life ranged from 4 to 6 hours. The mean accumulation
`ratio observed at steady state ranged from 1 – 1.6. In a food effect cohort (sub-study) of trial
`1102-CA, a high-fat meal increased ibrutinib exposure approximately 2-fold compared to when
`ibrutinib was administered after an overnight fast. In an oral mass balance trial, radioactivity
`recoveries in feces and urine were 81% (<1% unchanged ibrutinib) and 8%, respectively. The
`absolute bioavailability of ibrutinib has not been determined.
`
`Ibrutinib is extensively metabolized and is primarily metabolized by CYP3A4. In a dedicated
`drug-interaction trial, concomitant ketoconazole (strong CYP3A4 inhibitor) increased ibrutinib
`Cmax 29-fold and AUC 24-fold. Based on preliminary clinical trial data and PBPK modeling,
`concomitant rifampin (strong CYP3A4 inducer) decreased the Cmax and AUC of ibrutinib by
`14-fold and 13-fold, respectively. PBPK modeling predicted that moderate CYP3A4 inhibitors
`can increase ibrutinib exposure 6 - 9 fold and mild inhibitors can increase ibrutinib exposure 2-
`fold. In addition, a moderate inducer is predicted to decrease ibrutinib exposure 3-fold. A
`dedicated hepatic impairment trial is currently ongoing. The applicant reported that preliminary
`data suggest a 6-fold increase in exposures in moderate hepatic impairment (Child-Pugh B;
`N=3).
`
`No exposure-response relationship was observed for effectiveness at the dose of 560 mg in MCL.
`
`Reference ID: 3400137
`
`4
`
`
`
`

`

`No exposure-response relationship was observed for Grade 3 or 4 infection and infestation and
`Grade 3 or 4 neutropenia in the dose range of 420 - 840 mg in the pivotal phase 2 trials. Dose-
`response relationship for BTK occupancy and clinical response in the phase 1 dose escalation
`trial showed that maximum BTK occupancy and maximum response were achieved at doses of ≥
`2.5 mg/kg (≥ 175 mg for average weight of 70 kg).
`
`Signatures:
`
`
`
`
`
`Elimika Pfuma, PharmD, PhD
`Clinical Pharmacology and Genomics Reviewer
`Division of Clinical Pharmacology 5 and Genomics
`and Targeted Therapy Group
`
`Bahru Habtemariam, PharmD
`Pharmacometrics Reviewer
`Division of Clinical Pharmacology 5
`
`Yuzhuo Pan, PhD
`PBPK Reviewer
`Division of Pharmacometrics
`
`Brian Booth, Ph.D.
`Deputy Division Director
`Division of Clinical Pharmacology 5
`
`
`Julie Bullock, PharmD
`Clinical Pharmacology Team Leader
`Division of Clinical Pharmacology 5
`
`Rosane Charlab Orbach, PhD
`Genomics Team Leader
`Genomics and Targeted Therapy Group
`
`Anshu Marathe, PhD
`Pharmacometrics Team Leader
`Division of Pharmacometrics
`
`Ping Zhao, PhD
`PBPK Team Leader
`Division of Pharmacometrics
`
`Nam Atiqur Rahman, Ph.D.
`Division Director
`Division of Clinical Pharmacology 5
`
`
`
`
`Reference ID: 3400137
`
`5
`
`
`
`

`

`
`
`QUESTION BASED REVIEW
`
`2
`
`2.1 GENERAL ATTRIBUTES
`
`2.1.1 What are the highlights of the chemistry and physical-chemical properties of the
`drug substance and the formulation of the drug product as they relate to the clinical
`pharmacology and biopharmaceutics review?
`
`Ibrutinib is planned to be available as 140 mg hard gelatin capsules for oral administration.
`
`Figure 1: Structural Formula of Ibrutinib and its Active Metabolite (PCI-45227)
`
`
`
`
`
`
`
`Established names: Ibrutinib
`Stereochemistry: The absolute configuration at the single stereocenter is (R).
`Molecular Weight: 440.5 g/mole
`Molecular Formula: C25H24N6O2
`Partition coefficient (log P): 3.97 (pH=7)
`Dissociation Constant (pKa): 3.74
`Chemical Name: 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4 d]pyrimidin-1-yl]-
`1-piperidinyl]-2-propen-1-one
`Melting Point Range: 149°C to 158°C
`Solubility: Ibrutinib is insoluble in water (0.003 mg/mL)
`
`2.1.2 What are the proposed mechanisms of action and therapeutic indications?
`
`Ibrutinib is an irreversible Bruton’s tyrosine kinase (BTK) inhibitor (IC50=0.46 nM) that binds to
`a cysteine residue (Cys-481) in the BTK active site. It is proposed for the treatment of patients
`with mantle cell lymphoma (MCL; Original NDA 1) and chronic lymphocytic leukemia (CLL;
`Original NDA 2) who have received at least one prior therapy. BTK is a signaling molecule of
`the B-cell antigen receptor (BCR) and cytokine receptor pathways. The BCR pathway is
`implicated in several B-cell malignancies, including MCL and B-cell CLL. Ibrutinib is also
`
`
`
`Reference ID: 3400137
`
`6
`
`

`

`
`
`expected to inhibit Blk, Bmx/Etk, FGR, CSK and Txk (IC50< 4 nM) to a lesser extent.
`
`2.1.3 What are the proposed dosage(s) and route(s) of administration?
`
`The applicant proposes oral dosing regimens of 560 mg once daily in MCL and 420 mg once
`daily in CLL.
`
`
`
`
`Primary Study Endpoint
`Treatment Groups
`
`Ibrutinib 560 mg/day ORR
`
`
`2.2 GENERAL CLINICAL PHARMACOLOGY
`
`2.2.1 What are the design features of the clinical pharmacology and clinical trials used to
`support dosing or claims?
`
`To support the approval of ibrutinib, the applicant submitted two pivotal clinical trials; a phase
`1b/2 trial (PCYC-1102-CA referred to as 1102-CA hereafter) in CLL and a phase 2 trial (PCYC-
`1104-CA referred to as 1104-CA hereafter) in MCL (Table 1).
`
`1104-CA was an open label, non-randomized trial in patients with relapsed or refractory MCL
`(N=111) that evaluated ibrutinib at 560 mg daily. The primary efficacy endpoint was investigator
`assessed ORR. The key secondary efficacy endpoints were duration of response, time to
`response, PFS and overall survival. Treatment with ibrutinib resulted in an ORR of 65.8% (95%
`CI: 56.2, 74.5) and a CR rate of 17.1% in the overall study population.
`
`1102-CA was an open-label trial in elderly treatment naïve (N=31) or relapsed/ refractory (N=82)
`patients with CLL that evaluated ibrutinib at daily doses of 420 mg or 840 mg. Of the
`relapsed/refractory patients, 48 received 420 mg daily and 34 received 840 mg daily. The primary
`efficacy endpoint was investigator assessed overall response rate (ORR) in the relapsed refractory
`patients at the 420 mg dose.
`
` Table 1: Summary of the Pivotal Efficacy Trials
`Study Number
`Study Description
`PCYC-1104-CA
`Phase 2, open label, nonrandomized
`(1104-CA)
`study in relapsed or refractory MCL
`(N=111)
`Phase 1b/2 open-label trial in treatment
`naïve (N=31) or relapsed/ refractory
`(R/R; N=85) CLL
`
`PCYC-1102-CA
`(1102-CA)
`
`Ibrutinib 420 mg/day or
`840 mg/day (N=34 of
`R/R)
`
`Overall Response Rate
`(ORR) in R/R at 420 mg dose
`
`
`Pharmacokinetic data are available for the two pivotal trials (intensive and sparse sampling) and
`three additional trials (intensive sampling). The three additional trials (Table 2) are a phase 1
`dose-escalation trial, a mass balance trial and a drug interaction trial.
`
`
`
`
`Reference ID: 3400137
`
`7
`
`(b) (4)
`
`

`

`Table 2: Overview of Clinical Pharmacology Related Trials Submitted in the NDA
`
`
`Study Number
`Treatment Regimen
`
`
`
`
`
`
`PCYC-04753
`(04753)
`
`Study Description
`
`
`Phase 1, dose-escalation trial
`to determine MTD, PK and PD
`in patients with recurrent B-cell
`lymphoma (N=66)
`
`
`
`Body Weight Based Cohorts: 1.25, 2.5, 5, 8.3
`and 12.5 mg/kg/day for 28 on/ 7 off (35 day
`cycle)
`Continuous Dosing Cohorts: 8.3 mg/kg/day and
`560 mg/day
`
`
`DDI Cohort (N=18):
`•
`Ibrutinib 120 mg on Day 1 and 40 mg on
`Day 7
`• Ketoconazole 400 mg on Days 4 to 9
`Exploratory Cohort (N=3): Ibrutinib 70 mg
`solution on Day 1 to determine dose for ADME
`trial
`
`
`140 mg of 14C-ibrutinib solution
`
`
`PCI-2765CLL1002
`(1002)
`
`
`Phase 1 DDI healthy volunteer
`trial evaluating the effect of
`ketoconazole on the PK of
`Ibrutinib (N=18+3)
`
`
`PCI-
`32765CLL1004
`(1004)
`
`
`
`Phase 1 mass-balance ADME
`healthy volunteer trial (N=6)
`
`
`2.2.2 What is the basis for selecting the response endpoints (i.e., clinical or surrogate
`endpoints) or biomarkers (collectively called pharmacodynamics (PD)) and how are they
`measured in clinical pharmacology and clinical trials?
`
`The primary endpoint for the pivotal trials was overall response rate as determined by
`investigators & confirmed by an independent review committee. This endpoint has been used for
`previous approvals in MCL. Single agent bortezomib was FDA approved in December 2006 for
`MCL using a single arm phase 2 trial evaluating response rates.
`
`BTK active-site occupancy was assessed in the three submitted trials with cancer patients. This
`PD marker was selected based on the mechanism of action of the drug (Refer to Section 2.2.4.1
`for further discussion).
`
`2.2.3 Are the active moieties in the plasma (or other biological fluid) appropriately
`identified and measured to assess pharmacokinetic parameters and exposure response
`relationships?
`
`Yes. Plasma samples from clinical trials were assessed for the parent drug (ibrutinib) and its
`metabolite, PCI-45227. Ibrutinib is an active moiety. PCI-45227 (M37) is an inhibitor of BTK,
`but is 15 times less potent compared to the parent. Ibrutinib is extensively metabolized to many
`metabolites. In the mass balance trial, ibrutinib and M37 combined were <10% of total
`radioactivity. Total radioactivity AUC0-last was 37-fold higher than that of ibrutinib in blood.
`However, other metabolites were not measured in other clinical trials.
`
`
`
`
`Reference ID: 3400137
`
`8
`
`

`

`
`
`Ibrutinib is an R-enantiomer
`
`
`
`
`
`
`
`
`2.2.4 Exposure-Response
`
`2.2.4.1 What are the characteristics of the exposure-response relationships (dose-response,
`concentration-response) for efficacy and PD marker?
`
`There is no evidence of an exposure-response relationship for overall response rate (ORR) in the
`range of exposures observed following an ibrutinib dose 560 mg in mantle cell lymphoma (MCL)
`in 1104-CA (Figure 2). Steady state trough plasma concentrations were available from a total
`of 48 patients with MCL. In 1104-CA, trough concentrations were obtained on Days 1, 8, 15 and
`22. Trough concentrations obtained on Day 8 or later were used to calculate the mean steady
`state trough concentrations used for exposure-response analyses.
`
`Figure 2: No Exposure Response Relationship for Objective Response Rate (ORR) at Exposures
`observed for MCL at a 560 mg dose
`
`30
`
`
`
`100
`
`Proportion of Patients With ORR (%)
`
`80
`
`60
`
`40
`
`20
`
`0
`
`9/12
`
`|
`
`|
`
`0
`
`8/12
`
`|
`
`8/12
`
`9/12
`
`|
`25
`20
`15
`10
`5
`Mean Steady State Ctrough (ug/mL)
`
`
`Dose-response relationships for BTK occupancy and clinical response in the phase 1 trial 04753
`showed that maximum BTK occupancy and maximum response were achieved at doses of ≥ 2.5
`mg/kg (≥ 175 mg for average weight of 70 kg; Figures 3 and 4).
`
`Trial 04753 evaluated ibrutinib daily doses of 1.25 to 12.5 mg/kg (actual doses of 80 - 1400 mg).
`Cohorts 1 - 5 received ibrutinib on 35-day treatment cycles (28 days on/ 7 days off). The doses of
`8.3 mg/kg and 560 mg were also evaluated on a continuous dose schedule. As shown in Figure
`3, maximum BTK occupancy was achieved at doses of 2.5 mg/kg (175 mg for the average 70 kg
`
`
`
`Reference ID: 3400137
`
`9
`
`(b) (4)
`
`

`

`
`
`body weight) and greater. Similarly, maximum clinical response (response rate) was also
`achieved at doses ≥ 2.5 mg/kg. BTK occupancy and clinical response rates were similar for
`continuous dosing (CD) and 35-day treatment cycle schedules. Patients with diffuse large B-cell
`lymphoma (DLBCL) had a lower response rate of 30%. For more details refer to the appendix in
`Section 3.1.
`
`Figure 3: BTK Occupancy of > 90% at Doses ≥ 2.5 mg/kg in Trial 04753
`
`
`Cohorts 1, II, III, IV and V received treatment in a 35-day treatment cycle and Cohorts CD-1,CD-2 and CD-3
`received treatment as continuous dosing
`Source: Applicant’s Figure 10 in study-report-pcyc-04753.pdf
`
`Figure 4: Maximal Clinical Response (ORR) was achieved at Doses > 2.5 mg/kg*.
`
`2.50 mg/kg
`
`5.00 mg/kg
`
`8.30 mg/kg
`
`12.5 mg/kg
`
`1.25 mg/kg
`
`n=8
`
`n=6
`
`n=5
`
`n=8
`
`n=7
`
`80
`
`60
`
`40
`
`20
`
`0
`
`Proportion of Patients With ORR (%)
`
`100
`
`0
`
`2
`
`4
`
`10
`8
`6
`Ibrutin b Dose (mg/kg)
`
`12
`
`14
`
`
`*ORR for the CD-1,CD-2, CD-3 cohorts were, 67%, 66.7, and 30%, respectively
`
`2.2.4.2 What are the characteristics of the exposure-response relationships (dose-response,
`concentration-response) for safety?
`
`There was no evidence of exposure-response relationships for Grade 3 or 4 infection and
`infestation and Grade 3 or 4 neutropenia observed in the range of exposures observed following
`
`
`
`Reference ID: 3400137
`
`10
`
`

`

`
`
`ibrutinib doses of 420 mg, 560 or 840 mg in the pivotal phase 2 trials.
`
`Steady state trough plasma concentrations were available from 48 patients with MCL and 110
`patients with CLL. In 1104-CA, trough concentrations were obtained on Days 1, 8, 15 and 22.
`In 1102-CA trough concentrations were obtained on Days 1, 8 and 15. Trough concentrations
`obtained on Day 8 or later were used to calculate the mean steady state trough concentrations
`used for exposure-response analyses. Exposure safety analyses for ibrutinib were conducted
`using data from the 179 patients who were enrolled in the two pivotal phase 2 trials. The most
`frequent and important Grade 3 or higher (Grade 3+) adverse events were infections and
`infestations and neutropenia. Pharmacokinetic data were available from 125 patients from the
`phase 2 trials. The proportion of patients with Grade 3+ infections and infestations does not
`increase with increasing ibrutinib concentrations (Figure 5). Similarly Grade 3+ neutropenia did
`not increase with increasing ibrutinib concentration.
`
`Figure 5: Proportion of Patients with Grade 3+ Infections and Infestations (A) and Grade 3+
`Neutropenia (B) Does Not Increase with Increasing Mean Steady State Trough Concentrations
` A
` B
`
`
`
`|
`
`0
`
`5/ 5
`
`4 46
`
`3/ 3
`
`8/45
`
`|
`
`|
`
`|
`
`25
`20
`15
`10
`5
`Mean Steady State Ctrough (ug/mL)
`
`30
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Proportion of Patients With Grade 3/4 Neutropenia(%)
`
`
`While an exposure response relationship for individual toxicities could not be identified (Grade
`3+ neutropenia and Grade 3+ infections and infestations), there was a slight increase in the
`proportion of patients with any Grade 3+ adverse events with increasing mean steady state trough
`concentrations (Figure 6).
`
`
`
`
`|
`
`0
`
`10/45
`
`8/46
`
`8/43
`
`10/45
`
`|
`
`|
`
`|
`
`25
`20
`15
`10
`5
`Mean Steady State Ctrough (ug/mL)
`
`30
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Proportion of Patients With Grade 3/4 Inf/Infes(%)
`
`
`
`Reference ID: 3400137
`
`11
`
`

`

`
`
`Figure 6: Proportion of Patients with any Grade 3+ Adverse Event Does Not Increase with Increasing
`Mean Steady State Trough Concentrations.
`
`Proportion of Patients With Any Grade 3/4 AEs(%)
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`|
`
`0
`
`26/45
`
`32/46
`
`|
`
`|
`
`30/43
`
`|
`
`37/45
`
`25
`20
`15
`10
`5
`Mean Steady State Ctrough (ug/mL)
`
`30
`
`
`
`
`2.2.4.3 Does this drug prolong the QT or QTc interval?
`
`The IC50 for inhibitory effect by ibrutinib on hERG channel current was 970 nM (427 ng/mL)
`and was 9600 nM (4229 ng/mL) for PCI-45227 (active metabolite). The non-clinical reviewer
`commented that ibrutinib can be considered a low-potency blocker of the hERG channel (Refer
`to non-clinical review).
`
` A
`
` formal thorough QT trial has not been performed for ibrutinib. Formal ECG monitoring was
`performed in 2 single-arm trials (PCYC-04753 [n = 45] and PCYC-1102-CA [n = 67]). The QT-
`IRT evaluated the relationships between ∆ QTcF and ibrutinib and PCI-45227 concentrations and
`did not observe an exposure-response relationship. QT-IRT has concluded that the submitted
`QTc data is inconclusive due to the following limita