CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`201023s000
`
`
`CROSS DISCIPLINE TEAM LEADER REVIEW
`
`

`

`Cross Discipline Team Leader Review
`
`Cabazitaxel NDA 201023
`
`Cross-Discipline Team Leader Review
`
`
`Date
`June 16, 2010
`
`John R. Johnson, MD.
`From
`m_ Cross-Disei ~ line Team Leader Review
`NDA/BLA #
`201023
`
`Su 0 vlement#
`
`
`
`
`Date of Submission
`3/31/10
`
`PDUFA Goal Date
`
`9/30/10
`
`——
`Proprietary Name /
`Jevtana
`Established
`S .
`Cabazitaxel In'ection Concentrate
`
`names
`
`Dosage forms / Strength
`
`Jetvana (cabazitaxel) Injection concentrate 60 mg/ 1.5 mL
`is supplied as a kit consisting of the following:
`
`— Jetvana 60mg/ 1.5 mL concentrate: contains 60 mg
`cabazitaxel in 1.5 mL polysorbate 80,
`M“) of
`Diluent for JEVTANA 60 mg/ 1.5 11le contains
`
`13% (w/w) ethanol in water for injection.
`Jetvana in combination with prednisone is indicated for
`the treatment of patients with honnone refractory
`metastatic prostate cancer previously treated with a
`docetaxel-containing regimen.
`
`Proposed Indication(s)
`
`Recommended:
`
`Approval
`
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`Cross Discipline Team Leader Review Cabazitaxel NDA 201023
`
`Table of Contents
`
`
`Introduction..........................................................................................................................3
`1.
`2. Background..........................................................................................................................3
`3. CMC/Device ........................................................................................................................5
`4. Nonclinical Pharmacology/Toxicology ...............................................................................9
`5. Clinical Pharmacology/Biopharmaceutics.........................................................................10
`6. Clinical Microbiology........................................................................................................13
`7. Clinical/Statistical- Efficacy..............................................................................................13
`8. Safety .................................................................................................................................21
`9. Pediatrics............................................................................................................................33
`10. Other Relevant Regulatory Issues......................................................................................33
`11. Labeling .............................................................................................................................34
`12. Recommendations/Risk Benefit Assessment.....................................................................35
`
`
`
`Table of Tables
`
`
`Table 1 Demography and Patient Characteristics....................................................................16
`Table 2 Prior Docetaxel-Containing Regimens ........................................................................18
`Table 3 Overall Survival by Treatment (ITT)...........................................................................19
`Table 4 Clinical Trials ..............................................................................................................22
`Table 5 Exposure ......................................................................................................................24
`Table 6 Deaths due to Treatment-Emergent Adverse Events Excluding Disease Progression
`and Occurring Within 30 Days of Last Dose on the Cabazitaxel Arm......................................25
`Table 8 Dose modifications ......................................................................................................26
`Table 9 Most Frequent TEAE (All Grades) Leading to Discontinuation (≥3 Patients) .........26
`Table 10 Summary of Safety ...................................................................................................27
`Table 11 Most Frequent Treatment-Emergent AEs Safety Population ...................................27
`Table 12 Neutropenia and Associated Events ..........................................................................28
`Table 13 Neutropenia and G-CSF Use..................................................................................29
`Table 14: Neutropenia in Cabazitaxel-Treated Patients Receiving <25 mg/m2 q3 Weekly
`Dosing vs. ≥25 mg/m2 q3 Weekly Dosing in ISS Database .......................................................29
`Table 15: Neutropenia in Cabazitaxel-Treated Patients Receiving 20 mg/m2 q3 Weekly Dosing
`in ISS Database..........................................................................................................................29
`Table 16: Hematuria Adverse Events1.......................................................................................31
`
`
`
`
`Table of Figures
`
`
`Figure 1 Cabazitaxel Structural Formula....................................................................................6
`Figure 2 TROPIC: Phase 3 Registration Trial Schema ............................................................15
`Figure 3 Kaplan-Meier Curves Overall Survival by Treatment (ITT) .....................................19
`Figure 4 Hazard Ratios Overall Survival by Treatment for Baseline Factors ..........................20
`
`
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`Cross Discipline Team Leader Review Cabazitaxel NDA 201023
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`1. Introduction
`
`
`Jevtana® (cabazitaxel injection) is a new molecular entity and is a novel taxane, similar to the
`taxanes docetaxel and paclitaxel. Like the taxanes docetaxel and paclitaxel, cabazitaxel acts
`by targeting tubulin, the protein component of microtubules, to stabilize microtubules and
`prevent progression of mitosis in the cell cycle.
`
`Cabazitaxel is not marketed anywhere in the world. The proposed indication is “Jetvana in
`combination with prednisone is indicated for the treatment of patients with hormone refractory
`metastatic prostate cancer previously treated with a docetaxel-containing regimen.” There is
`currently no effective therapy for patients with this condition.
`
`The application is supported primarily by one randomized controlled trial (RCT) conducted
`under an SPA agreement. The primary endpoint of the RCT showed a statistically significant
`improvement in median survival of 2.4 months for cabazitaxel in combination with prednisone
`compared to mitoxantrone in combination with prednisone. The mitoxantrone/prednisone
`combination has not been shown to improve survival. The cabazitaxel 25 mg/m2 dose every 3
`weeks causes considerable toxicity and may be unnecessarily high. However, we have no
`information from RCTs on any other cabazitaxel dose and do not know if a lower dose would
`be effective. Despite the increased toxicity and increase in deaths due to toxicity in the
`cabazitaxel arm relative to the control arm, there is still a survival advantage for the
`cabazitaxel treatment group. The cabazitaxel dose will be addressed with a PMR. The
`cabazitaxel toxicity will be addressed in the label and with several post marketing required
`trials and studies (PMRs).
`
`Chemistry has identified a concern with the supersaturated pre-mix and infusion solutions with
`the risk of introducing particulate matter intravenously. Clinical Pharmacology has concerns
`about use in patients with hepatic impairment, use with strong CPY3A4 inhibitors, use with
`strong CYP3A4 inducers and lack of adequate assessment of risk of QTc interval
`prolongation. These concerns will be addressed by PMRs
`
`
`2. Background
`
`
`Cabazitaxel is a new molecular entity and is a novel taxane, similar to the taxanes docetaxel
`and paclitaxel. Like the taxanes docetaxel and paclitaxel, cabazitaxel acts by targeting tubulin,
`the protein component of microtubules, to stabilize microtubules and prevent progression of
`mitosis in the cell cycle.
`
`Cabazitaxel is a semi-synthetic product derived from 10-deacetyl Baccatin III, which is
`extracted from European yew needles.
`
`First-line therapy for patients with metastatic prostate cancer is medical or surgical castration.
`Approximately 85% of patients will respond to this therapy, which includes gonadotropin-
`releasing hormone antagonists or surgery. However, approximately 15% of patients will not
`
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`Cross Discipline Team Leader Review
`
`Cabazitaxel NDA 201023
`
`respond to hormonal intervention and responders will eventually become refractory to
`hormonal intervention. For this metastatic hormone refractory (mHRPC) population,
`recommended first-line therapy is the combination of docetaxel and prednisone, which showed
`a survival advantage compared to the combination of mitoxantrone and prednisone in the
`randomized Phase 3 TAX327 trial.‘
`
`There is no available therapy for patients with mHRPC who have already progressed on or
`after a docetaxel regimen. This is the population studied in the submitted cabazitaxel RCT.
`
`This NDA is supported mainly by a single RCT conducted under an SPA. At end of Phase 2
`meeting and at the SPA FDA emphasized that a Phase 3 trial in mHRPC must win on its
`primary endpoint of overall survival before any analysis of secondary endpoints could be
`undertaken and that as the trial was unblinded,
`(hm)
`Furthermore, the FDA
`stressed that the composite secondary endpoint of PFS as defined by PSA progression, tumor
`progression by RECIST criteria or death would be considered an exploratory analysis (m4)
`
`The primary endpoint of the RCT showed a statistically significant improvement in median
`survival of 2.4 months for cabazitaxel in combination with prednisone compared to
`mitoxantrone in combination with prednisone. The mitoxantrone/prednisone combination has
`not been shown to improve survival. The cabazitaxel 25 mg/m2 dose every 3 weeks causes
`considerable toxicity and may be unnecessarily high. However, we have no information from
`RCTs on any other cabazitaxel dose and do not know if a lower dose would be effective.
`Despite the increased toxicity and increase in deaths due to toxicity in the cabazitaxel arm
`relative to the control arm, there is still a survival advantage for the cabazitaxel treatment
`group. The cabazitaxel dose will be addressed with a PMR. The cabazitaxel toxicity will be
`addressed in the label and with several PMRs.
`
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`Cross Discipline Team Leader Review Cabazitaxel NDA 201023
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`3. CMC/Device
`
`
`Recommendation abstracted from the Chemistry Review.
`
`
`This NDA is recommended for Approval from a Chemistry, Manufacturing, and Controls
`standpoint. There are no outstanding Chemistry, Manufacturing, and Controls issues.
`
`The following 2 PMRs are required.
`
`PMR 1649-1
`To evaluate the potential for a serious risk of intravenous infusion of particulate matter into the
`blood stream, it is necessary to better understand and characterize the supersaturated pre-mix.
`Conduct a study to provide data which address particulate nucleation and kinetic factors of
`precipitation in the pre-mix. Conduct this study using multiple samples drawn from multiple
`batches so as to more fully support an in-use life of the pre-mix.
`
`Study considerations include (but are not necessarily limited to); interior surface properties of
`the container closure (e.g., treatments, roughness, scratches, etc.), initial mixing agitation force
`(vigorous shaking), physical shock on standing (e.g., vigorous shaking during in-use storage),
`needle sticks, syringe use, temperature (and temperature changes during in-use storage), and
`additional time point sampling beyond the proposed duration of in-use storage of the pre-mix
`solution (e.g., 1 to 4 hours).
`
`Collect and provide photographs of the precipitate as it appears in the container and isolated
`photomicrographs of the particles, as feasible.
`
`Provide by mass balance, the mass of precipitated drug as precipitated mass and as mass
`percent of the total cabazitaxel content.
`
`PMR 1649-2
`To evaluate the potential for a serious risk of intravenous infusion of particulate matter into the
`blood stream, it is necessary to better understand and characterize the supersaturated infusion
`solution. Conduct a study which addresses particulate nucleation and kinetic factors of
`precipitation from the infusion solution. Conduct this study using multiple samples drawn for
`at least three additional batches in the containers (bags and sets) which you propose to label for
`this use so as to more fully support an in-use life of the infusion solution..
`
`Study factors include (but are not necessarily limited to); interior surface properties of the
`container (e.g.., treatments, roughness, plasticizers, etc.), initial mixing agitation force
`(vigorous shaking), physical shock on standing (e.g., vigorous shaking during in-use storage),
`needle sticks, temperature (and temperature changes during in-use storage), and additional
`time point sampling beyond the proposed duration of in-use storage of the infusion solution.
`
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`Cross Discipline Team Leader Review
`
`Cabazitaxel NDA 201023
`
`Collect and provide photographs of the precipitate as it appears in the container and isolated
`photomicrographs of the particles, as feasible, for each observed precipitation or evidence of
`precipitation (e.g., clogged filters, impeded infusion flow, etc.).
`
`Provide by mass balance, the mass of precipitated drug as precipitated mass and as mass
`percent of the total cabazitaxel content.
`
`Review
`
`The cabazitaxel structural formula is shown in Figure 1.
`
`Figure 1 Cabazitaxel Structural Formula
`
`
`
`0 General product quality considerations
`
`The following is abstracted from the Chemistry Review.
`
`Drug Substance
`
`Cabazitaxel (also referred as RPRI I 6258 /XRP6258) is an antineoplastic agent belonging to
`the taxane class. It is a diether derivative ofdocetaxel with the C-7 and C-10 hydroxy groups
`alkylated into methyl ethers. Cabazitaxel contains 11 asvmmetric centers. Cabazitaxel acetone
`solvate is a rod—like crystalline powder which is practically insoluble in water (8 ug/mL);
`freely soluble in acetone and dichloromethane; and soluble in ethanol. Due to its extreme low
`solubility in aqueous solution, the cabazitaxel drugproduct isformulated in the surfactant,
`polysorbate 80.
`
`Drug substance is manufactured
`
`A genotoxic impurity,
`
`, was identified in the Ames test. Test resultsfor
`
`(5) (4)
`
`(I'm
`
`(5) (4)
`
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`Cross Discipline Team Leader Review
`
`Cabazitaxel NDA 201023
`
`(km) in the 3 primary stability batches and the 3 production batches show less than
`Safety evaluation ofthe observed levels of
`(mo in the drug substance batches has
`been consulted to the pharm/tox reviewer. Up to
`M" of
`(I'm in the drug
`substance is acceptable considering the patientpopulation.
`
`(”(4)
`
`Drug Product
`
`The drugproduct, JEVTANA (cabazitaxel) Injection, 60 rug/1.5 mL, is supplied as a
`nonaqueous concentrated solutionfor infilsion co-packaged with a diluent vial containing 5. 7
`ml. ofa 13% w/w aqueous solution ofalcohol (USP). The diluent is to be usedforpreparation
`ofa premix solution of I 0 mg/mL ofcabazitaxel, followed by a second dilution ofthe
`appropriate dose in 0. 9% sodium chloride solution or 5% dextrose solution in an infusion bag.
`
`The entire content ofthe diluent vial is to be withdrawn and added to the concentrated drug
`vial to obtain a premix solution containing approximately 10 mg/mL ofcabazitaxel. Premix
`solution is prepared by repeated inversionsfor at least 45 seconds to assure complete mixing
`ofthe concentrated drug solution and the diluent. Immediatelyfollowingpreparation, a
`volume ofpremix solution (calculated based on a dose of25 tug/1112) is withdrawn and to be
`injected into a PVC-free container ofeither 0.9% sodium chloride solution or 5% dextrose
`solutionfor infilsion. Concentration ofthe infusion solution should be between 0.10 mg/mL
`and 0.26 mg/mL. Diluted infusion solution should be usedfor intravenous administration
`innnediately, or within 8 hours ifstored at room temperature or within 24 hours ifstored at
`refrigerated conditions (including the 1-hour infusion).
`
`Based on the 12 months primary stability data, 6 month ofaccelerated data, and
`36 months ofthe supportive stability datafor drug substance andper ICH QIE
`guidelines, an initial retest date of
`(ma) with storage at 50C can be granted.
`
`Based on the 12 months primary stability data, 6 month ofaccelerated datafor
`drugproduct and diluent, andper ICH QIE guidelines, an initial expiration
`datingperiod of 18-monthsfor the drugproduct stored under thefollowing
`conditions can be granted.
`
`- Store at 25°C (77°F); excursion permitted between 15°C — 30°C (59°F — 86°F)
`- Do not refrigerate
`
`Super saturation of Pre—mix and Infusion Solutions
`
`Both the pre—mix and infusion solution are supersaturated. To evaluate the potential for a
`serious risk of intravenous infusion of particulate matter into the blood stream two PMRs are
`required (See above under Recommendations).
`
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`Cross Discipline Team Leader Review
`
`Cabazitaxel NDA 201023
`
`Cabazitaxel Vial and Diluent Vial Overfill
`
`The reviewing chemist expressed concern about the cabazitaxel vial and Diluent vial overfill.
`The following is abstracted from the chemistry review.
`
`The cabazitaxel vial is manufactured with 0 00(4) overfill and the diluent vial is manufactured
`with a (no) oveflill. Data provided in tables 6, 7 and 8 (NDA section 3. 2.P. 2.3 Manufacturing
`Process Development) describes the variations in concentrations ofthe premix solutions Orom
`(mo mg/mL) obtained by three operators. Wefeel that the presence of
`the excess diluent and cabazitaxel could result in inaccurate dosing.
`
`The following Table abstracted from the Chemistry review compares the overfill for
`Taxotere and cabazitaxel concentrates and solvents.
`
`Table 2 — Comparison of fill volumes for Taxotere® and Cabazitaxel concentrates and solvents
`
`Concentrate for solution for
`infusion
`
`Solvent for dilution
`
`Taxotere®
`(80 mgl2 mL)
`
`Cabazitaxel
`(60mg/1.5 mL)
`
`Taxotere®
`(8 mL)
`
`Cabazitaxel
`(4.5 mL)
`
`Nominal volume
`
`2 mL
`
`1 5 mL
`
`8 mL
`
`4 5 mL
`
`Overfill
`
`(hm)
`
`
`
`Total fill volume (hm)
`
`The following abstract from the chemistry review shows the recommended resolution of
`this issue.
`
`Final Evaluation: Acceptable. Sanofi ’sjustificationfor overfill is that the overage will ensure
`an extractable volume of6 mL, and this practice has been usedfor Taxotere and other drugs
`that require dilutions. However, Sanofi did not address thefollowing concerns: Due to thefact
`that both vials are ovetfilled (the diluent vial has a slight more ovetfill than the drug vial), the
`entire content ofthe diluent vial is withdrawn and added into the drug vial. This practice may
`cause variations ofthe concentrationsfor the premix solution (from
`(I'm
`mg/mLfor the premix solution as demonstrated by the applicant), which could lead to
`inaccurate dosing (up to
`(5x4) overdosing). Note that the common
`pharmaceuticalproducts allow i10% assay variation. Ifconsidering the allowable assay
`variation ofi10%, the worst case scenario could be up to
`m"
`overdose. Ihese concerns have been conveyed to the applicant as well as to the review team in
`the internal labeling meeting. Due to the time constrain ofreviewing this NDA, it was decided
`at the May 25, 2010 meeting that the current approach is acceptable considering that both
`clinical trial and Taxotere used this approach, and no significant risk has been shown to be
`associated with it. Furthermore, changing to the new approach may also introduce other
`errors.
`
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`Cross Discipline Team Leader Review Cabazitaxel NDA 201023
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`• Facilities review/inspection
`
`The facilities inspection was judged satisfactory by the Offices of Compliance and New
`Drug Quality Assessment. Report received May 3, 2010.
`
` •
`
` Other notable issues (resolved or outstanding)
`
`
`None.
`
`
`
`4. Nonclinical Pharmacology/Toxicology
`
`
`Recommendation abstracted from the Supervisory Pharmacology Memorandum
`
` I
`
` concur with Drs. Helms’s and Khasar’s conclusion that pharmacology and toxicology data
`support the approval of NDA 201,023 for JEVTANA. There are no outstanding nonclinical
`issues related to the approval of JEVTANA for the proposed indication.
`
`Review abstracted from the Supervisory Pharmacology Memorandum
`
`The supporting information included studies of intravenously administered cabazitaxel
`that investigated the drug’s pharmacology, pharmacokinetics and ADME, safety
`pharmacology, general toxicology (rat and dog), genetic toxicity (in vivo and in vitro),
`and reproductive toxicity in both rats and rabbits. The studies cited in the review consist
`primarily of original research conducted by the applicant.
`
`The pharmacology studies submitted to the NDA demonstrate that cabazitaxel is a taxane
`which binds tubulin, promotes microtubule polymerization and prevents disassembly.
`Based on this, the pharmacological classification of cabazitaxel is a microtubule
`inhibitor, like other taxanes which have similar mechanisms of action.
`
` Drug induced toxicity, including gastrointestinal toxicity, bone marrow toxicity, and neuronal
`toxicity were observed non-clinically. These findings are not unexpected and were well
`characterized.
`
`Cabazitaxel increased micronuclei in rats, and increased numerical aberrations with or
`without metabolic activation in an in vitro test in human lymphocytes. No induction of
`structural aberrations was observed in human lymphocytes. Additionally cabazitaxel was
`negative in the Ames test. The positive in vivo genotoxicity findings are consistent with
`the pharmacological activity of the compound (inhibition of tubulin depolymerization).
`
`Like other taxanes, cabazitaxel is a highly toxic to the developing embryo or fetus
`causing embryolethality, pre and post implantation loss, fetal death and decreased fetal
`weight at a doses approximately 0.02-0.06 times the Cmax in cancer patients at the
`recommended human dose of 25 mg/m2. Teratogenesis was not detected however minor
`
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`Cross Discipline Team Leader Review Cabazitaxel NDA 201023
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`variations, (i.e. delays in skeletal ossifications) at doses 0.02x the maximum
`recommended human dose were observed. In the rabbit study abject maternal toxicity
`without fetal or embryonic toxicity was observed. Although these studies utilized doses
`that there far below the clinical dose maternal toxicity or development toxicity was
`observed in each study. Because the potential benefit from the use of the JEVTANA in
`pregnant women in this patient population may outweigh the potential risk to the
`developing fetus, Pregnancy Category D is recommended for this patient population.
`
`Numerous issues chemistry and manufacturing issues were identified during the review
`of JEVTANA which impacted the pharmacology and toxicology review of JEVTANA.
`These are discussed in detail in the primary review and include the potential propensity of
`the drug product to form a precipitate, and impurity and residual solvent qualification.
`The sponsor has adequately qualified impurities either through non-clinical studies or
`through provided information.
`
`With regard to precipitate formation, although the lung is the most sensitive organ for
`precipitate induced toxicity and wheezing was noted in the rat in chronic study, precipitate
`was not noted in the study and nor was there histopathological evidence of pulmonary toxicity
`associated with wheezing. Although this is a theoretical concern there is not data to indicate
`that precipitation occurred in the drug product in non-clinical studies.
`
`
`
`5. Clinical Pharmacology/Biopharmaceutics
`
`
`Recommendation abstracted from the Clinical Pharmacology review.
`
`The Office of Clinical Pharmacology has reviewed NDA 20-1023. This NDA is acceptable
`from a clinical pharmacology perspective provided that the applicant agrees to the labeling
`language and the post-marketing requirements listed below.
`
`
`1. Complete and submit the final report of trial TES10884, along with a thorough review of
`cardiac safety data, for the potential of cabazitaxel on QTc interval prolongation in
`patients.
`2. Conduct and submit the final report of trial POP6972 to determine the pharmacokinetics
`and safety of cabazitaxel in patients with hepatic impairment.
`3. Conduct a drug interaction trial to evaluate the effect of a strong CYP3A4 inducer (e.g.,
`rifampin) on the pharmacokinetics of cabazitaxel in humans.
`4. Conduct a drug interaction trial to evaluate the effect of a strong CYP3A4 inhibitor (e.g.,
`ketoconazole) on the pharmacokinetics of cabazitaxel in humans.
`
`Review abstracted from the Clinical Pharmacology review.
`
`Following a one-hour intravenous infusion, plasma concentrations of cabazitaxel can be
`described by a three-compartment pharmacokinetic (PK) model with α-, β-, and γ- half-lives of
`4 minutes, 2 hours, and 95 hours, respectively. Cabazitaxel demonstrates no major deviation
`
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`Cross Discipline Team Leader Review Cabazitaxel NDA 201023
`
`from dose proportionality between 10 mg/m² and 30 mg/m². No accumulation or changes in
`the pharmacokinetics were observed for up to three treatment cycles. Mean human plasma
`protein binding was 92%. Based on the population PK analysis, steady-state volume of
`distribution and plasma clearance of cabazitaxel were 4,864 L and 48.5 L/h (i.e., 2,643 L/m²
`and 26.4 L/h/m² for a patient with a median BSA of 1.84 m²), respectively.
`
`Cabazitaxel is the major circulating compound in plasma (70%) with no other relevant
`circulating metabolites. In addition, cabazitaxel was equally distributed between plasma and
`blood cells, with a blood to plasma ratio of 0.90 to 0.99 (Studies PKFAC 9901 and DMPK/FR
`2238). Therefore, plasma was an appropriate matrix for monitoring the PK of cabazitaxel.
`In plasma, the parent drug was the main circulating compound, representing an average
`70.2% (range: 49.8% to 89.9%) of radioactivity AUC. Seven metabolites were detected in
`plasma, each accounting for less than 10% of parent drug AUC. The main metabolite was
`RPR123142, the 10- O-demethylated derivative on the taxane ring, accounting for 3.6% of
`radioactivity AUC and 5.1% of parent drug AUC. All the other circulating metabolites
`(docetaxel, RPR111026, RPR111059, M09b, RPR130523, and RPR112698) represented on
`average less than 2.3% of the radioactivity AUC. Cabazitaxel and RPR123142 were the only
`compounds quantifiable 6 to 24 hours after the end of infusion.
`
`Cabazitaxel was extensively metabolized by hepatic cytochrome P450 (CYP) 3A4/5 (80% to
`90%) and to a lesser extent by CYP2C8. Cabazitaxel is primarily excreted into feces as
`metabolites (76% of the administered dose), with a low urinary excretion (3.7% of the
`administered dose, with 2.3% excreted as unchanged drug). At clinically relevant
`concentrations in vitro, cabazitaxel does not inhibit CYPs or transporters including P-
`glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug-resistance
`protein (MRP). Based on in vitro studies, the potential for cabazitaxel to inhibit or induce
`major CYPs is low. Furthermore, cabazitaxel is a substrate of P-gp, but not a substrate of
`MRP1, MRP2, or BCRP. Body surface area (BSA) and tumor type were identified as
`significant covariates on the plasma clearance of cabazitaxel. The BSA effect was accounted
`for by a BSA-based dosing regimen. Plasma clearance of cabazitaxel is 60% lower in patients
`with breast cancer compared to other tumor types. However, as 34 out of 37 breast cancer
`patients came from a single trial (ARD6191), it is difficult to distinguish if this is a trial effect
`or true tumor type effect.
`
`No formal studies have been conducted to assess the effect of age, gender, race, BSA, renal or
`hepatic function on cabazitaxel PK. No impact of intrinsic factors (age, race, renal function,
`or hepatic function) on the PK of cabazitaxel was identified by the population PK analysis. No
`dosage regimen adjustments were proposed for the special populations. The impact of BSA on
`the clearance has already been accounted for by the BSA-based dosing regimen. The dose
`adjustments were mainly based on the safety endpoints
`
`
`
`
`No formal hepatic impairment trials have been conducted. As cabazitaxel is extensively
`metabolized by CYP 3A in liver, liver dysfunction is expected to increase the plasma
`concentrations of cabazitaxel. Patients with impaired hepatic function (total bilirubin ≥ ULN,
`or AST and/or ALT ≥1.5 × ULN) were excluded from the randomized clinical trial.
`
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`Cross Discipline Team Leader Review Cabazitaxel NDA 201023
`
`Conducting a hepatic impairment trial will be a PMR to determine the dose regimen in
`patients with hepatic impairment. Population PK analysis did not determine transaminases as
`significant covariates influencing cabazitaxel PK, possibly due to the fact that only a small
`number of patients had elevated transaminases, bilirubin, or alkaline phosphatase levels (e.g.,
`one patient with a bilirubin ratio > ULN, four and 19 patients with ALT and AST ratios > 1.5
`x ULN, respectively, and 18 patients with ALP ratio >2.5 x ULN). Based on the limited
`number of patients with abnormal liver function at baseline, no dose adjustment can be
`recommended.
`
`No formal trial has been conducted in patients with renal impairment. Population PK analysis
`suggested renal function measured by creatinine clearance has no significant correlation with
`the cabazitaxel clearance. As only 2.3% of the administered dose of cabazitaxel is eliminated
`renally, cabazitaxel PK was not changed in patients with mild renal impairment (50mL/min
`≤CLCR≤80 mL/min) and moderate (30 mL/min≤CLCR≤50 mL/min). Patients with severe renal
`impairment (CLCR<30 mL/min) and end stage renal disease should be treated with caution
`and monitored carefully during treatment. Dose delay or reduction should be considered in
`the event of adverse drug reactions.
`
`The potential effects of race/ethnicity on cabazitaxel PK were not formally investigated.
`Population PK analysis did not identify race (non-Caucasian versus Caucasian) as a
`significant covariate influencing cabazitaxel pharmacokinetics. The model predicted a similar
`plasma CL value of cabazitaxel in Caucasian patients (24.2 L/h/m², N=144) and in non-
`Caucasian patients (24.3 L/h/m², N=26) (Table 8). Small changes in predicted CL in different
`races were observed: the predictive plasma CL values in non-Caucasian patients were 29.6 L/
`h/m² in oriental patients (N=9), 22.9 L/h/m² in black patients (N N=4), 22.0 L/h/m² in
`Hispanic patients (N=7), and 19.8 L/h/m² in “other” patients (N=6).
`
` conclusive exposure-response relationship could not be identified for overall survival
`possibly due to limited PK data (N=67) at one dose level (25 mg/m2) collected in the pivotal
`trial. The shallow slope of the exposure–response relationship for ≥ Grade 3 neutropenia
`suggested that dose reduction from 25 to 20 mg/m2 will reduce the risk of having ≥ grade 3
`neutropenia by 5% when no prophylactic G-CSF was used.
`
`The effect of cabazitaxel on cardiac repolarization has not been evaluated. A PMR will be
`issued to require the applicant to complete and submit the final report of ongoing trial
`TES10884, along with a thorough review of all available cardiac safety data, for the potential
`of cabazitaxel on QTc interval prolongation in patients.
`
` A
`
`Page 12 of 41
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`12
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`

`Cross Discipline Team Leader Review
`
`Cabazitaxel NDA 201023
`
`6. Clinical Microbiology
`
`Recommendations abstracted from the microbiologist review.
`
`A. Recommendation on Approvability — Recommendedfor
`approvalfrom a microbiology quality standpoint.
`
`B. Recommendations on Phase 4 Commitments and/or
`
`Agreements, ifApprovable — N/A
`
`Review abstracted from the microbiologist review.
`
`Summary ofMicrobiology Assessments
`
`A. BriefDescription ofthe Manufacturing Processes that relate to
`Product Quality Microbiology- CCSI is
`"’""
`andfilled into sterile,
`(mo 15 mL glass vials that are
`sealed wit