CENTER FOR DRUG EVALUATION AND
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`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
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`APPLICATION NUMBER:
`201023
`201023
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`APPLICA TION NUMBER:
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`CLINICAL PHARMACOLOGY AND
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`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`BIOPHARMACEUTICS REVIEW! S 2
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`Clinical Pharmacology Review
`NDA
`201023
`Submission Date:
`March 31, 2010
`JEVTANA®
`Brand Name:
`
`Generic Name:
`Cabazitaxel
`Formulation/Strength:
`Single Use Vial 60 mg/1.5 mL and Diluent
`OCP Reviewer:
`Pengfei Song, Ph.D.
`Pharmacometrics Reviewer:
`Nitin Mehrotra, Ph.D.
`OCP Team Leader:
`Qi Liu, Ph.D.
`Pharmacometrics Team Leader: Christine Garnett, Pharm.D.
`OCP Division:
`
`Division of Clinical Pharmacology 5
`ORM Division:
`Division of Drug Oncology Products
`Sponsor:
`Sanofi-aventis US LLC
`Submission Type; Code:
`Original NDA; 000
`Cabazitaxel 25 mg/m2 administered every three weeks as a
`Dosing Regimen:
`one-hour IV infusion in combination with oral prednisone
`10 mg administered daily throughout cabazitaxel treatment
`Metastatic hormone refractory prostate cancer previously
`treated with a docetaxel-containing regimen
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`Indication:
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`Table of contents
`1 Executive Summary .........................................................................................................................5
`1.1
`Recommendations ...............................................................................................................6
`1.2
`Post-Marketing Requirements.............................................................................................6
`1.3
`Clinical Pharmacology Summary........................................................................................7
`2 Question Based Review ...................................................................................................................9
`2.1
`General Attributes ...............................................................................................................9
`2.2
`General Clinical Pharmacology.........................................................................................10
`2.3
`Intrinsic Factors.................................................................................................................29
`2.4
`Extrinsic Factors................................................................................................................35
`2.5
`General Biopharmaceutics.................................................................................................40
`2.6
`Analytical Section .............................................................................................................41
`3 Detailed Labeling Recommendations ............................................................................................45
`4
`Pharmacometric Review.................................................................................................................51
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`List of Tables
`Table 1. Instantaneous solubility of cabazitaxel at 25°C in various solvent .................................. 9
`Table 2. Clinical trials supporting the dosing regimen................................................................. 11
`Table 3. Pharmacokinetic parameters of cabazitaxel after a 1-hour IV infusion at the first
`available cycle (mainly cycle 1) ................................................................................ 19
`Table 4. Cmax and AUC of cabazitaxel at the first available cycle following one-hour infusion at
`25 mg/m².................................................................................................................... 20
`Table 5. Pharmacokinetics of cabazitaxel in 4 patients treated with 25 mg/m² [14C]-cabazitaxel as
`a 1-hour IV infusion................................................................................................... 22
`Table 6. Predicted in vivo intrinsic and metabolic clearance values of cabazitaxel (XRP6258) in
`human ........................................................................................................................ 23
`Table 7. In vitro intrinsic clearance and fraction (mean ±SD) metabolized by CYP3A and overall
`CYP enzymes of XRP6258 in fresh human hepatocytes (n = 3)............................... 23
`Table 8. In vitro enzyme kinetics of cabazitaxel (RPR116258) metabolism in human liver
`microsomes................................................................................................................ 24
`Table 9. Pharmacokinetic parameters of cabazitaxel in patients treated at 10 to 30 mg/m²
`according to gender, age, race, tumor type, creatinine clearance, transaminase ratio,
`and alkaline phosphatase ratio................................................................................... 30
`Table 10. The proposed dose modifications for adverse reactions in patients treated with
`cabazitaxel ................................................................................................................. 31
`Table 11. Cmax and AUC of cabazitaxel at the first available cycle following 1-hour infusion at
`25 mg/m².................................................................................................................... 36
`Table 12. Ki and I/Ki of cabazitaxel on CYPs .............................................................................. 36
`Table 13. The potential of cabazitaxel (XRP6258) to induce CYP1A1/2, CYP2C9 and
`CYP3A4/5 enzyme activities (expressed as % of control) in fresh human hepatocytes
`following 72 hours treatment with cabazitaxel (0 to 10 μM) or reference inducers . 37
`Table 14. Bidirectional transport of cabazitaxel (XRP6258) using Caco-2 cells......................... 38
`Table 15. Composition of to-be-marketed cabazitaxel concentrate for solution for injection, 60
`mg/1.5 mL.................................................................................................................. 41
`Table 16. Summary of bioanalytical studies associated with clinical pharmacology studies and
`efficacy/safety clinical studies................................................................................... 42
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`List of Figures
`Figure 1: Exposure-response relationship of cabazitaxel (CBZ) for overall survival (left panel)
`in comparison with the same relationship excluding four patients with neutropenia
`related deaths on CBZ/PRED arm from the dataset (right panel). Small black, green
`and red vertical ticks on the plots are censored observations. MTX/PRED
`(Mitoxantrone/Prednisone) is the comparator arm.................................................... 13
`Figure 2: Exposure-response relationship of cabazitaxel (CBZ) for time to tumor progression.
`Small black, green and red vertical ticks on the plots are censored observation.
`MTX/PRED (Mitoxantrone/Prednisone) is the comparator arm............................... 14
`Figure 3: The probability of patients with ≥ grade 3 neutropenia-AUC relationship. Solid black
`symbols represent the observed proportion of patients experiencing ≥ grade 3
`neutropenia in each AUC quartile. The vertical black bars represent the 95%
`confidence interval. The solid red line represents the mean logistic regression
`prediction. The shaded area represents the 95% confidence interval of the prediction.
`The exposure range in each AUC quartile is denoted by the horizontal black line
`along with the number of subjects with adverse events/total number of subjects in
`each quartile. The horizontal dotted red and blue line represents the % of ≥ grade 3
`neutropenic events observed in the CBZ/PRED and MTX/PRED arm of the pivotal
`trial (EFC 6193), respectively. .................................................................................. 15
`Figure 4: The median time course of neutrophils among patients in cabazitaxel arm who never
`received G-CSF during the pivotal trial (EFC6193). The two black dashed lines
`represents cutoff for neutropenia (<1.5x109/L) and ≥ grade 3 neutropenia
`(<1.0x109/L). ............................................................................................................. 16
`Figure 5: The median time course of neutrophils among patients who received G-CSF at some
`point during the pivotal trial (EFC6193). The two black dashed lines represents
`cutoff for neutropenia (<1.5x109/L) and ≥ grade 3 neutropenia (<1.0x109/L).......... 17
`Figure 6: The time-concentration profiles of cabazitaxel in patients (n=13) with advanced
`tumors when a dose of 25 mg/m2 was administered via a one-hour intravenous
`infusion. ..................................................................................................................... 20
`Figure 7: Mass balance of total radioactivity after a single 1-hour IV infusion of [14C]-
`cabazitaxel in 4 patients with advanced solid tumors (mean ±SD)........................... 22
`Figure 8: The metabolites formed by heterologously expressed human cytochrome P450 and
`FMO isoenzymes that metabolize cabazitaxel (RPR 116258) at 1 μM (left bar) and
`10 μM (right bar) in vitro. ......................................................................................... 24
`Figure 9: Effect of chemical inhibitors of cytochrome P450 isoenzymes on the metabolism of
`cabazitaxel (RPR 116258) at 10 μM in human liver microsomes............................. 25
`Figure 10: Proposed metabolic pathways of [14C]-cabazitaxel in humans................................... 26
`Figure 11: Cabazitaxel AUC0-48hr in the first cycle increased with dose with a slope of 0.73 (0.31,
`1.15) from 10 to 30 mg/m2 of cabazitaxel every three weeks administered via 1-hour
`intravenous infusion. ................................................................................................. 28
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`Figure 12: Cycle-independent clearance of cabazitaxel in humans with pooled pharmacokinetic
`data from studies TED6188 and TED6190 ............................................................... 28
`Figure 13: Dose normalized AUC0-t versus cycle in breast cancer patients following weekly
`administration of cabazitaxel (1-hour IV infusions on Days 1, 8, 15, and 22 every 5
`weeks)........................................................................................................................ 29
`Figure 14: The effect of body surface area (BSA) on the plasma clearance (L/Hr) in the first
`treatment cycle estimated by population pharmacokinetic analysis.......................... 31
`Figure 15: The effect of tumor type (left) or trial (right) on the plasma clearance (CL) (L/h/m²)32
`Figure 16: The effect of sex on the BSA-normalized plasma CL (L/h/m²) estimated by
`population PK analysis. ............................................................................................. 32
`Figure 17: The effect of age on the BSA-normalized individual plasma clearnace (CL) (L/h/m²)
`predicted by population pharmacokinetic analysis. Each red dot represents a patient.
`................................................................................................................................... 33
`Figure 18: The effect of renal function on clearance of cabazitaxel as depicted creatinine
`clearance (CRCL) vs BSA normalized clearance (CL) relationship. Each red dot
`represents a patient. Three vertical lines represents cut off for mild, moderate and
`severe renal impairment............................................................................................. 34
`Figure 19: The effect of race/ethnicity on the BSA-normalized individual plasma CL (L/h/m²)
`predicted by population pharmacokinetic analysis. Each red dot represents a patient.
`................................................................................................................................... 34
`Figure 20: The effect of co-administration of prednisone/prednisolone on pharmacokinetics of
`cabazitaxel. Each red dot represents a patient. .......................................................... 38
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`1 EXECUTIVE SUMMARY
`
`Cabazitaxel is a new molecular entity in the taxane class. In the current original NDA
`submission, the applicant seeks approval of cabazitaxel in combination with prednisone for the
`treatment of metastatic hormone refractory prostate cancer (mHRPC) previously treated with a
`docetaxel-containing regimen.
`
`In a Phase 3 trial supporting the efficacy and safety of cabazitaxel, mHRPC patients were
`randomized to receive either cabazitaxel 25 mg/m2 (n=378) or mitoxantrone 12 mg/m2 (n=377),
`both of which were administered via intravenous infusion every three weeks (Q3W) in
`combination with 10 mg daily oral prednisone. Overall survival was significantly improved in
`cabazitaxel arm (median: 15.1 months) compared to mitoxantrone arm (median: 12.7 months),
`with a hazard ratio of 0.70 (95% CI: 0.59, 0.83). Neutropenia, febrile neutropenia, diarrhea,
`infection, and renal failure are the most prominent toxicities for cabazitaxel treatment.
`
`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 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.
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`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.
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`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.
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`A 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.
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`1.1 RECOMMENDATIONS
`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.
`1.2 POST-MARKETING REQUIREMENTS
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`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.
`Signatures:
`Pengfei Song, Ph.D.
`Qi Liu, Ph.D.
`Reviewer
`Team Leader
`Division of Clinical Pharmacology 5
`Division of Clinical Pharmacology 5
`Nitin Mehrotra, Ph.D.
`Christine Garnett, Pharm.D.
`Pharmacometrics Reviewer
`Pharmacometrics Team Leader
`Division of Pharmacometrics
`Division of Pharmacometrics
`Cc: DDOP: CSO - Christy Cottrell; MTL - John Johnson; MO - Amy Mckee; Ian Waxman
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`DCP-5: Reviewers - Pengfei Song, Nitin Mehrotra; TL - Qi Liu;
`PM TL - Christine Garnett; DDD - Brian Booth; DD – Atiqur Nam Rahman
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`1.3 CLINICAL PHARMACOLOGY SUMMARY
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`Cabazitaxel is a new molecular entity in taxane class. In the current original NDA submission,
`the applicant seeks approval of cabazitaxel for the treatment of metastatic hormone refractory
`prostate cancer (mHRPC) previously treated with a docetaxel-containing regimen.
`A Phase 3 trial (EFC6193) was conducted to support the efficacy and safety of cabazitaxel.
`mHRPC patients were randomized to receive either cabazitaxel 25 mg/m2 (n=378) or
`mitoxantrone 12 mg/m2 (n=377), both of which were administered via intravenous infusion every
`three weeks (Q3W) in combination with 10 mg daily oral prednisone. Overall survival was
`significantly improved in cabazitaxel arm (median: 15.1 months) compared to mitoxantrone arm
`(median: 12.7 months), with a hazard ratio of 0.70 (95% CI: 0.59, 0.83). Neutropenia, febrile
`neutropenia, diarrhea, and renal failure are the most prominent toxicities for cabazitaxel
`treatment.
`The dosage selection of 25 mg/m2 Q3W based on efficacy and safety during Phase 1, 2 and 3
`trials appears acceptable. In Phase 1 trials in patients with advanced solid tumors, the maximum
`tolerated dose (MTD) was independently determined as 30 mg/m² (TED6188) and 25 mg/m²
`(TED6190) via a one-hour IV infusion Q3W. The dose limiting toxicities (DLTs) were Grade 4
`neutropenia, febrile neutropnia, and Grade 3 diarrhea or infection. Therefore, the recommended
`dose for the Phase 2 trial (RP2D) were determined as 25 mg/m² and 20 mg/m², respectively.
`Subsequently, an initial dose level of 20 mg/m² Q3W was tested in a Phase 2 trial (ARD6191) in
`advanced breast cancer and intra-patient dose escalation to 25 mg/ m² was allowed if no Grade >
`2 toxicity was observed in Cycle 1. Of 71 patients, 21 patients could be escalated to 25 mg/m2
`Q3W in Cycle 2. The applicant then chose 25 mg/m² Q3W for the pivotal Phase 3 trial in
`mHRPC patients. However, conclusive exposure-response relationship could not be identified
`for overall survival with limited PK data (N=67) collected in pivotal trial at one dose level (25
`mg/m2). 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 ≥ Grade 3 neutropenia
`by 5% when no prophylactic G-CSF was used. The median neutrophil count data (Day 1, 8 and
`15 of the treatment cycle) for patients who did not use G-CSF in the trial showed that dose
`reduction alone provides modest increase in neutrophil counts. This is in accordance with a
`reduction of ≥ grade 3 neutropenia risk by 5% when reducing the dose from 25 to 20 mg/m2 as
`demonstrated by exposure-safety analysis. The neutrophil count data from patients who used G-
`CSF in the trial showed that use of G-CSF or G-CSF in combination with dose reduction is a
`reasonable option for management of neutropenia. Thus, the proposed dose modification scheme
`for treating ≥ grade 3 neutropenia appears reasonable from a clinical management perspective.
`Following a one-hour intravenous infusion, plasma concentrations of cabazitaxel can be
`described by a three-compartment PK model with α-, β-, and γ- half-lives of 4 minutes, 2 hours,
`and 95 hours, respectively. Cabazitaxel demonstrates no major deviation from the dose
`proportionality between 10 mg/m² and 30 mg/m². No accumulation or changes in the
`pharmacokinetics of cabazitaxel were observed for up to three treatment cycles at 25 mg/m²
`Q3W. Mean human plasma protein binding is 92%. Based on the population PK analysis, steady-
`state volume of distribution and plasma clearance of cabazitaxel are 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.
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`Cabazitaxel is extensively metabolized by cytochrome P450 (CYP) 3A4/5 (80% to 90%) and to
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`a lesser extent by CYP2C8. Cabazitaxel is excreted mainly into feces (76% of the administered
`dose) as approximately 20 metabolites, with a low urinary excretion (3.7% of the administered
`dose with 2.3% excreted as unchanged drug). In vitro, the potential for cabazitaxel is low to
`inhibit or induce major CYP isoenzymes or transporters including P-gp, BCRP, and MRP at
`clinically relevant concentration. In addition, cabazitaxel is a substrate of P-gp, but not a
`substrate of MRP1, MRP2, or BCRP.
`Population PK analysis identified body surface area (BSA) and tumor types as significant
`covariates on the clearance of cabazitaxel. BSA is positively correlated with clearance, which
`justifies the BSA-based dosing regimen. Plasma clearance is 60% lower in patients with breast
`cancer compared to other tumor types. However, since 34 out of 37 breast cancer patients came
`from a single trial (ARD6191), it is difficult to distinguish if this is a trial variation or a true
`tumor type effect. In addition, no significant effect of gender, age, race (Caucasians vs non-
`Caucasians), mild or moderate renal impairment on the PK of cabazitaxel was observed in
`patients. The concomitant use of weak CYP3A inducers prednisone or prednisolone did not
`affect the pharmacokinetics of cabazitaxel .
`The following issues should be addressed as post-marketing requirements: QTc risk evaluation;
`the effect of a strong CYP3A4 inhibitor, a strong CYP3A4 inducer; and hepatic impairment on
`the pharmacokinetics of cabazitaxel.
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`2 QUESTION BASED REVIEW
`2.1 GENERAL ATTRIBUTES
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`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 clinical
`pharmacology and biopharmaceutics review?
`Cabazitaxel is white to almost white power. JEVTANA (cabazitaxel) Injection is supplied as a
`kit consisting of the following:
`• Concentrate (60 mg/1.5 mL): contains 60 mg cabazitaxel in 1.5 mL polysorbate-80
`• Diluent: contains
` of 13% (w/w) ethanol in water for injection.
`Physico-chemical properties
`1. Structural formula:
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`
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`2. Established name: Cabazitaxel, RPR116258, XRP6258
`3. Molecular Weight: 894.01 (for the acetone solvate); 835.93 (for the solvent free)
`4. Molecular Formula: C45H57NO14 , C3H6O
`5. Partition coefficient (log P): 3.88±0.03, at 24°C, pH 7 in presence of 0.15 M potassium
`chloride (KCl)
`6. Chemical Name (CAS): (2α,5β,7β,10β,13α)-4-acetoxy-13-({(2R,3S)-3-
`[(tertbutoxycarbonyl) amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-7,10-
`dimethoxy-9-oxo-5,20-epoxytax-11-en-2-yl benzoate – propan-2-one(1:1).
`7. Solubility
`Table 1. Instantaneous solubility of cabazitaxel at 25°C in various solvent
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`2.1.2 What are the proposed mechanisms of action and therapeutic indications?
`Cabazitaxel is an antineoplastic agent in the taxane class. Cabazitaxel binds to tubulin and
`promotes the assembly of tubulin into microtubules while simultaneously inhibiting their
`disassembly. This leads to the stabilization of microtubules, which results in the inhibition of
`mitotic and interphase cellular functions. Cabazitaxel demonstrated a broad spectrum of
`antitumor activity, including activity in docetaxel-insensitive tumor models.
`The proposed indication of cabazitaxel in combination with prednisone is for treatment of
`patients with mHRPC previously treated with a docetaxel-containing regimen.
`2.1.3 What are the proposed dosage and route of administration?
`The proposed dose of cabazitaxel is 25 mg/m2 administered as a one-hour intravenous infusion
`every three weeks in combination with oral prednisone 10 mg administered daily throughout
`cabazitaxel treatment.
`The following premedications should be administered intravenously 30 minutes before each dose
`of JEVTANA:
`• Antihistamine (dexchloropheniramine 5.0 mg, diphenhydramine 25 mg or equivalent
`antihistamine)
`• Corticosteroid (dexamethasone 8 mg or equivalent steroid)
`• H2 antagonist (ranitidine or equivalent H2 antagonist)
`• Antiemetic prophylaxis (oral or IV) is recommended as needed
`Furthermore, patients treated with JEVTANA may receive prophylactic G-CSF to reduce the risk
`or manage neutropenia complications (febrile neutropenia, prolonged neutropenia or neutropenic
`infection).
`2.2 GENERAL CLINICAL PHARMACOLOGY
`
`2.2.1 What are the design features of the clinical pharmacology and clinical studies used
`to support dosing or claims?
`Seven clinical trials were submitted to support the clinical pharmacology of cabazitaxel. These
`studies included three Phase 1 dose finding trials (TED6188, TED6189, TED6190) in patients
`with solid tumors, one mass balance trial (BEX6702), two Phase 2 trials (ARD6191, ECD 6945)
`in patients with metastatic breast cancer, and one Phase 3 trial (EFC6193) in mHRPC patients
`previously treated with a docetaxel-containing regimen.
`Extensive blood sampling was performed in Q3W studies TED6188, TED6190, BEX6702 and
`weekly regimen TED6189 (one-hour IV infusion on Days 1, 8, 15, and 22 every five weeks).
`Sparse sampling was implemented in 34 patients in Trial ARD6191 (Cycle 1, Day 1) and in 67
`patients in Trial EFC6193 (Cycle 1).
`The applicant performed a population PK analysis with pooled data to assess the effects of
`intrinsic and extrinsic factors. PK/PD relations were also investigated using PK parameters of
`cabazitaxel as prognostic factors for efficacy and safety endpoints (e.g., overall survival and
`neutropenia) respectively.
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`Table 2. Clinical trials supporting the dosing regimen
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`2.2.2 What is the basis for selecting the response endpoints or biomarkers and how are
`they measured in clinical pharmacology and clinical studies?
`The primary efficacy endpoint was overall survival in the pivotal Phase 3 trial EFC6193. As
`overall survival is an unambiguous endpoint, improvement in overall survival is generally
`considered as the gold standard for drug approval in oncology. Overall survival was defined as
`the time interval from the date of randomization to the date of death due to any cause. In the
`absence of confirmation of death, the survival time was censored at the last date patient was
`known to be alive or at the cut-off date, whichever had come first.
`Being the main secondary efficacy endpoint, progression free survival was defined as the first
`occurrence of any of the following events: tumor progression per Response Evaluation Criteria
`In Solid Tumors [RECIST], prostate specific antigen [PSA] progression, pain progression, or
`death due to any cause.
`Because a large proportion of patients with mHRPC have nonmeasurable disease (45% of
`patients in Phase 3 trial EFC6193), secondary endpoints such as PFS, tumor response rate, and
`tumor progression have inherent limitations in assessment of disease in these patients due to
`inter-observer bias and variability. PSA response and PSA progression, although objective
`endpoints for assessment of treatment effect in this patient population, have not been fully
`validated as surrogates for overall survival.
`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. Cabazitaxel was the primary moiety in plasma appropriately identified and measured during
`clinical studies using validated LC-MS/MS methods.
`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.
`Also see Sections 2.2.5.2, 2.2.5.4, and 2.6.
`
`2.2.4 Exposure-response
`Conclusive exposure-response relationships could not be identified for overall survival or time to
`tumor progression possibly due to limited PK data (N=67) in pivotal trial at one dose level (25
`mg/m2). Shallow slope of the exposure-neutropenia (≥ Grade 3) relationship 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.
`2.2.4.1 Is there evidence of an exposure-response relationship for efficacy?
`There were insufficient exposure data collected in the pivotal trial to support evidence of
`exposure-response for efficacy endpoint of overall survival and time to tumor progression.
`• Only 67 patients (18% of the total enrolled in the cabazitaxel arm) were included in the
`exposure-efficacy analysis.
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`• Data from only one dose level (25 mg/m2) was available so the range of exposures might
`not be wide enough to explore exposure-efficacy relationship.
`Exploratory exposure-efficacy analysis was conducted using data from the pivotal trial
`(EFC6193) following 25 mg/m2 dose of cabazitaxel. Overall survival and time to tumor
`progression were the response variables utilized in the analysis. Due to few patients with PK data
`from only one dose level (N=67), exposure data were divided by median into two groups: AUC
`< 907 ng•hr/mL (N=35) and AUC > 907 ng•hr/mL (N=32). The left panel below (Figure 1)
`suggests that patients with higher exposures had lower overall survival. This relationship is,
`however, confounded by four deaths related to neutropenic complications within 30 days of
`dosing. The analysis was repeated without these four patients (three in higher and one in lower
`exposure groups). Results suggested that the separation between the two survival curves
`disappeared (right panel in Figure 1).
`The exposure-response analysis for time to tumor progression showed numerically higher (not
`statistically significant) median time to progression for the higher exposure group (Figure 2).
`
`
` MTX/PRED
` CBZ (Lower Exposure)
` CBZ (Higher Exposure)
`
`N=35
`
`N=32
`
`1.0
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`0.0
`
`
`
`0
`
`5
`
`20
`15
`10
`Time (Months)
`
`25
`
`30
`
`35
`
` MTX/PRED
` CBZ (Lower Exposure)
` CBZ (Higher Exposure)
`
`N=29
`
`N=34
`
`1.0
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`0.0
`
`0
`
`5
`
`30
`
`35
`
`25
`20
`15
`10
`Time (Months)
`Figure 1: Exposure-response relationship of cabazitaxel (CBZ) for overall survival (left panel) in
`comparison with the same relationship excluding four patients with neutropenia related deaths on
`CBZ/PRED arm from the dataset (right panel). Small black, green and red vertical ticks on the plots
`are censored observations. MTX/PRED (Mitoxantrone/Prednisone) is the comparator arm.
`
`
`
`
`
`NDA 201023 Review - cabazitaxel
`13
`
`
`
`

`

` MTX/PRED
` CBZ (Lower Exposure)
` CBZ (Higher Exposure)
`
`N=32
`
`N=35
`
`10
`5
`Time (Months)
`
`15
`
`20
`
`
`
`1.0
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`0.0
`
`0
`
`
`
`
`
`Figure 2: Exposure-response relationship of cabazitaxel (CBZ) for time to tumor
`progression. Small black, green and red vertical ticks on the plots are censored
`observation. MTX/PRED (Mitoxantrone/Prednisone) is the comparator arm.
`
`2.2.4.2 Is there an evidence of exposure-response for safety?
`Yes, there is evidence of exposure-response relationship for ≥ grade 3 neutropenia in patients
`with advanced solid tumors. Univariate logistic regression models were used to explore the
`relationship between exposure (AUC) and ≥ grade 3 neutropenia at the end of first cycle. Safety
`data from only Cycle 1 was taken to avoid the confounding effect of prophylactic G-CSF which
`was allowed later in the trial to treat ≥ grade 3 neutrop