CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`201023
`201023
`
`
`APPLICA TION NUMBER:
`
`SUMMARY REVIEW
`
`SUMMARY REVIEW
`
`
`
`
`
`

`

`6/17/2010
`Amna Ibrahim MD
`Division Director Summary Review
`201023
`Sanofi aventis
`5/31/2010
`9/30/2010
`Cabazitaxel (XRP6258)/
`JEVTANA®
`Intravenous formulation supplied as 60 mg/1.5 mL
` JEVTANA® is a microtubule inhibitor used in
`combination with prednisone indicated for the
`treatment of patients with hormone-refractory
`metastatic prostate cancer previously treated with a
`docetaxel-containing regimen
`Approval
`
`Names of discipline reviewers
`
`Amy McKee, MD (efficacy); Ian Waxman MD (safety)
`Chia-Wen Ko, PhD
`Sachia Khasar, PhD; Whitney Helms, PhD
`Xiao-Hong Chen, PhD
`Steven E Fong, PhD
`Pengfei Song, PhD
`Keith Olin
`Robert Young, MD
`John R. Johnson, MD
`Lubna Najam, MS, PharmD,
`Sharon Mills, BSN, RN, CCRP
`Ann Marie Trentacosti
`
`Action/Recommended Action for
`NME:
`
`
`Material Reviewed/Consulted
`OND Action Package, including:
`Medical Officer Review
`Statistical Review
`Pharmacology Toxicology Review
`CMC Review/OBP Review
`Microbiology Review
`Clinical Pharmacology Review
`DDMAC
`DSI
`CDTL Review
`OSE/DMEPA
`OSE/DRISK
`Other (SEALD)
`OND=Office of New Drugs
`DDMAC=Division of Drug Marketing, Advertising and Communication
`OSE= Office of Surveillance and Epidemiology
`DMEPA=Division of Medication Error Prevention and Analysis
`DSI=Division of Scientific Investigations
`DRISK=Division of Risk Management
`CDTL=Cross-Discipline Team Leader
`
`
`Summary Review for Regulatory Action
`
`Division Director Review
`
`
`Date
`From
`Subject
`NDA #
`Applicant Name
`Date of Submission
`PDUFA Goal Date
`Proprietary Name /
`Established (USAN) Name
`Dosage Forms / Strength
`Proposed Indication(s)
`
`
`
`
`
`
`Page 1 of 14
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`Division Director Review
`
`1. Introduction
`According to CDC, prostate cancer is the most common cancer in men. In 2005 (the most
`recent year for which statistics are available), 185,895 men were diagnosed with prostate
`cancer, and 28,905 men died from it. There is no drug approved for patients who require
`second-line treatment after Taxotere for metastatic, hormone-refractory prostate cancer.
`Cabazitaxel, a taxane, has been submitted for a New drug Application (NDA) for this patient
`population.
`
`As per CDTL review by John Johnson MD, “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 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.”
`
`
`2. Background
`One international study, EFC6193 (TROPIC) has been submitted as the major trial to support
`the proposed indication. It is titled “A randomized, open label multi-center study of XRP6258
`at 25 mg/m2 in combination with Prednisone every 3 weeks compared to Mitoxantrone in
`combination with Prednisone for the treatment of hormone refractory metastatic prostate
`cancer previously treated with a Taxotere®-containing regimen”. The protocol was granted a
`Special Protocol Assessment in September 2006. FDA granted a Fast Track designation on
`November 9, 2009 to cabazitaxel for metastatic prostate cancer which has progressed during or
`after a docetaxel-based therapy, and the NDA was submitted as a rolling review. The final
`section was submitted on 5/31/2010. A priority review was requested and granted.
`
`Despite active research, it has been difficult to develop effective drugs to treat metastatic,
`hormone-refractory prostate cancer. In 2004, Taxotere® (docetaxel) was approved in
`combination with prednisone as a treatment for patients with androgen independent (hormone
`refractory) metastatic prostate cancer. Since that time, two drugs have been presented to the
`Oncology Drug Advisory Committee for an indication similar to the one proposed. These
`drugs were not approved. Given the expected impact on public health, the review of the
`Jevtana NDA was expedited. There are few drugs available for the advanced form of this
`common cancer and none for this indication. An improvement in overall survival, the
`prespecified primary endpoint, was demonstrated with the use of cabazitaxel. The expedited
`review was also made possible by the rapid responses by the applicant to FDA questions and
`concerns. The review of this NDA was completed in less than 3 months.
`
` total of 755 patients were randomized to receive either JEVTANA 25 mg/m2 intravenously
`every 3 weeks for a maximum of 10 cycles with prednisone 10 mg orally daily (n=378), or to
`receive mitoxantrone 12 mg/m2 intravenously every 3 weeks for 10 cycles with prednisone 10
`mg orally daily (n=377) for a maximum of 10 cycles. A major issue observed during review
`
` A
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`Randomization
`
`Division Director Review
`
`was the high rate of toxicity including toxic deaths on the investigational arm. Because an
`improvement in overall survival (OS) was demonstrated despite deaths due to adverse
`reactions, these toxicity issues will be addressed with post-marketing requirements (PMRs) as
`well as labeling. Other issues such as those including potential for precipitation of the drug,
`hepatic impairment trials, potential for QTc prolongation, drug-drug interaction studies will
`also be addressed by PMRs. Please see action letter for the description of the PMRs.
`
`
`Figure 1: Study Schema
`
`
`
`Patients with
`metastatic hormone-refractory
`prostate cancer previously treated
`with docetaxel
`
`Stratification factors
`ECOG PS (0, 1 vs. 2)
`Measurable versus non-measurable disease
`
`
`
`
`Jevtana has not been marketed anywhere in the world at this time.
`3. CMC/Device
`
`Cabazitaxel 25 mg/m² q 3 wk
` + prednisone q day
`(n=378)
`
`
`
`Mitoxantrone 12 mg/m² q 3 wk
`+ prednisone q day
`(n=378)
`
`
`CMC review states that the NDA is approvable and was signed by Xiao-Hong Chen, PhD and
`cosigned by William Adams, PhD on 6/2/10.
`
`There have been concerns regarding overfill in the cabazitaxel vial and the diluent. According
`to Dr. Chen, both the drug and diluent vials have overfill. If the entire content of the diluent
`vial is withdrawn and added into the drug vial, there may be greater than 10% variation in the
`concentration of the premix solution. Per Dr. Chen, the worst case scenario could be up to
` overdose. She also states in her review that “Sanofi’s
` under dose and
` and this
`justification for overfill is that the overage will ensure an extractable volume of
`practice has been used for Taxotere and other drugs that require dilutions. However, Sanofi
`did not address the following concerns: Due to the fact that both vials are overfilled (the
`diluent vial has a slight more overfill than the drug vial), the entire content of the diluent vial
`is withdrawn and added into the drug vial. This practice may cause variations of the
`concentrations for the premix solution (from
` for the premix
`
`solution as demonstrated by the applicant), which could lead to inaccurate dosing (up to
`under dosing or up to
` overdosing). Note that the common pharmaceutical products allow
`±10% assay variation.” Dr. Chen also states that “Although it is not the preferred approach, it
`was found to be acceptable as it is the same approach used by Taxotere® Injection.”
`Particular attention was paid to labeling to make instructions for preparation of infusion
`solution clear.
`
`Page 3 of 14
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`(b) (4)
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`(b) (4)
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`(b) (4)
`
`(b) (4)
`
`(b) (4)
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`(b) (4)
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`Division Director Review
`
`
`Richard Lostritto, PhD (Division Director, ONDQA) expressed concern that the applicant has
`not adequately characterized a precipitation problem both in the first premix dilution and in the
`final infusion solution and it is not known whether a standard in-line filter has the capacity to
`not clog from precipitate. This was also discussed in an internal meeting. Because a survival
`advantage was observed, the team decided to implement PMRs to resolve the issue of possible
`precipitation. Please see the action letter for the description of PMRs. Dr. Lostritto states in his
`memo dated 6/8/2010 that the approved drug substance retest interval to be conveyed to the
`sponsor is eighteen
`. He recommended approval in this memo.
`
`The chemistry review finds the manufacturing of the drug product and drug substance
`acceptable. Manufacturing site inspections were acceptable.
`
`Based on the 12 months primary stability data, 6 month of accelerated data, and 36 months of
`the supportive stability data for drug substance and per ICH Q1E guidelines, an initial retest
` with storage at 5oC can be granted.
`date of
`
`Based on the 12 months primary stability data, 6 month of accelerated data for drug product
`and diluent, and per ICH Q1E guidelines, an initial expiration dating period of 18-months for
`the drug product stored under the following conditions can be granted:
`
`
`- Store at 25°C (77°F); excursion permitted between 15°C – 30°C (59°F – 86°F)
`- Do not refrigerate.
`
` concur with the conclusion that there are no other outstanding issues.
`
` I
`
`
`
`4. Nonclinical Pharmacology/Toxicology
`
`
`Gabriel S. Khasar, PhD and Whitney Helms, PhD state that the non-clinical studies with
`cabazitaxel support the safety of its use in hormone-refractory metastatic prostate cancer. They
`recommend approval.
`
`S. Leigh Verbois, PhD, provided concurrence to the conclusions of Drs. Helms and Khasar
`and stated, “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”
`
` I
`
` concur with the conclusions reached by the pharmacology/toxicology reviewers that there are
`no outstanding pharm/tox issues that preclude approval.
`
`
`Page 4 of 14
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`(b) (4)
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`(b) (4)
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`Division Director Review
`
`5. Clinical Pharmacology/Biopharmaceutics
`
`
`According to the review by Pengfei Song, PhD, co-signed by several people including Nam
`Atiqur Rahman PhD, the NDA is acceptable from clinical pharmacology perspective. Dr. Song
`states the following in his review:
`
`“Following a one-hour intravenous infusion, plasma concentrations of cabazitaxel can be
`described by a three-compartment pharmacokinetic (PK) model with a-, ß-, and .- 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.”
`
`“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.”
`
`“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.”
`
`Four PMRs will be implemented. These will be to assess the potential for QTc prolongation, to
`determine the PK and safety of this drug in patients with hepatic impairment, and to assess
`drug interactions with strong CYP3A4 inducers and inhibitors. Please see the action letter for
`the description of the PMRs.
`
` concur with the conclusions reached by the clinical pharmacology/biopharmaceutics reviewer
`that there are no outstanding clinical pharmacology issues that preclude approval.
`
`
` I
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`Division Director Review
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`6. Clinical Microbiology
`
`
`Steven Fong, PhD recommends approval from a microbiology quality standpoint in his review.
`I concur with the conclusions reached by the clinical microbiology reviewer that there are no
`outstanding clinical microbiology or sterility issues that preclude approval.
`
`
`7. Clinical/Statistical-Efficacy
`
`
`As in the label “The efficacy and safety of JEVTANA in combination with prednisone were
`evaluated in a randomized, open-label, international, multi-center study in patients with
`hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing
`treatment regimen.”
`
`“A total of 755 patients were randomized to receive either JEVTANA 25 mg/m2 intravenously
`every 3 weeks for a maximum of 10 cycles with prednisone 10 mg orally daily (n=378), or to
`receive mitoxantrone 12 mg/m2 intravenously every 3 weeks for 10 cycles with prednisone 10
`mg orally daily (n=377) for a maximum of 10 cycles.”
`
`“This study included patients over 18 years of age with hormone-refractory metastatic
`prostate cancer either measurable by RECIST criteria or non-measurable disease with rising
`PSA levels or appearance of new lesions, and ECOG (Eastern Cooperative Oncology Group)
`performance status 0-2. Patients had to have neutrophils >1,500 cells/mm3, platelets >
`100,000 cells/mm3, hemoglobin > 10 g/dL, creatinine < 1.5 x upper limit of normal (ULN),
`total bilirubin < 1xULN, AST < 1.5 x ULN, and ALT < 1.5 x ULN. Patients with a history of
`congestive heart failure, or myocardial infarction within the last 6 months, or patients with
`uncontrolled cardiac arrhythmias, angina pectoris, and/or hypertension were not included in
`the study.”
`
`“Demographics, including age, race, and ECOG performance status (0-2) were balanced
`between the treatment arms. The median age was 68 years (range 46-92) and the racial
`distribution for all groups was 83.9% Caucasian, 6.9% Asian, 5.3% Black, and 4% Others in
`the JEVTANA group”
`
`The median number of cycles was 4 in the Mitoxantrone/Prednisone arm and 6 in the
`Cabazitaxel/Prednisone arm.
`Table 1: Efficacy of Cabazitaxel in the Treatment of Patients with Hormone Refractory
`Metastatic Prostate Cancer (Intent-to-Treat Analysis)
`
`Cabazitaxel + Prednisone
`n=378
`
`234 (61.9 %)
`15.1 (14.1-16.3)
`
`Overall Survival
`Number of deaths (%)
`Median survival (month) (95% CI)
`Hazard Ratio1 (95% CI)
`0.70 (0.59-0.83)
`<0.0001
`p-value
`1Hazard ratio estimated using Cox model; a hazard ratio of less than 1 favors Cabazitaxel
`
`
`Mitoxantrone + Prednisone
`n=377
`
`279 (74%)
`12.7 (11.6-13.7)
`
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`Division Director Review
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`
`Figure 2: Kaplan-Meier Overall Survival Curves
`Applicant figure
`
`
`
`
`
`The primary clinical review by Drs. McKee and Waxman recommends approval for this NDA.
`They state that “The single clinical trial enrolled 755 men with mHRPC who had progressed
`on or after a docetaxel-containing regimen. The cabazitaxel arm had a median overall
`survival of 15.1 months compared to 12.7 months on the mitoxantrone arm. Although there
`were deaths due to toxicity on the cabazitaxel arm, an overall survival advantage was still
`demonstrated for cabazitaxel-treated patients. Furthermore, as some of the deaths were due to
`infectious complications during a period of neutropenia, infection-related deaths may be
`better prevented in the post-marketing setting with the use of prophylactic G-CSF in patients
`at high risk of neutropenic complications. The proposed patient population currently has no
`treatment options which offer a survival benefit, and the robust results in overall survival
`demonstrated by cabazitaxel would provide a new treatment option for these patients.”
`
`In the statistical review, Chia-Wen Ko PhD., states that “the pivotal trial met its study
`objective by showing a hazard ratio of 0.70 (95% confidence interval: 0.59-0.83, p<0.0001)
`for the experimental arm versus the control arm in overall survival. The median survival time
`was 15.1 months in the experimental arm compared to 12.7 months for patients in the control
`arm. Subgroup analyses showed consistent results in favor of cabazitaxel. There were no
`identified major statistical issues in efficacy analyses to prevent approval.”
`
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`Division Director Review
`
`The CDTL, Dr. John Johnson, also recommended approval of cabazitaxel for the following
`indication. “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”.
`
`
`8. Safety
`According to the clinical review “The safety of cabazitaxel was evaluated in 371 patients with
`hormone-refractory prostate cancer in the phase 3 trial EFC6193, in which patients were
`randomized to receive either cabazitaxel 25 mg/m2 with prednisone every three weeks or
`mitoxantrone 12 mg/m2 with prednisone every three weeks for up to ten cycles. A summary of
`important safety results is included below.”
`
`
`• “Deaths not directly attributed to disease progression and occurring within 30 days of
`the last dose of study drug were reported in 18 (5%) cabazitaxel-treated patients and
`three (<1%) mitoxantrone-treated patients. The most common fatal adverse reactions
`in cabazitaxel-treated patients were infections (n=5) and renal failure (n=4). The
`majority (80%) of fatal infection-related adverse reactions occurred after a single dose
`of cabazitaxel. Other fatal adverse reactions in cabazitaxel-treated patients included
`electrolyte imbalance in a patient with diarrhea, ventricular fibrillation, cerebral
`hemorrhage, and dyspnea.”
`• “The most common (> 10%) grade 1-4 adverse reactions in cabazitaxel-treated
`patients were neutropenia, anemia, leukopenia, thrombocytopenia, diarrhea, fatigue,
`nausea, vomiting, constipation, asthenia, abdominal pain, hematuria, back pain,
`anorexia, peripheral neuropathy, pyrexia, dyspnea, dysgeusia, cough, arthralgia, and
`alopecia.”
`• “The most common (> 5%) grade 3-4 adverse reactions in cabazitaxel-treated patients
`were neutropenia, leukopenia, anemia, febrile neutropenia, diarrhea, fatigue, and
`asthenia.”
`• “Adverse reactions of interest in cabazitaxel-treated patients included neutropenic
`complications (febrile neutropenia and infection), renal failure, hematuria, and
`cardiac toxicity.”
`• “Treatment discontinuations due to adverse drug reactions occurred in 18% of
`patients who received cabazitaxel and 8% of patients who received mitoxantrone. The
`most common adverse reactions leading to treatment discontinuation on the
`cabazitaxel arm were neutropenia and renal failure.”
`• “Dose reductions were reported in 12% of cabazitaxel-treated patients and 4% of
`mitoxantrone-treated patients. Dose delays were reported in 28% of cabazitaxel-
`treated patients and 15% of mitoxantrone-treated patients.”
`
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`Division Director Review
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`
`Table 2: Dose modifications
`
`Cabazitaxel + Prednisone
`N = 371
`138 (37.2%)
`95 (25.6%)
`35 (9.4%)
`11 (3.0%)
`18 (4.9%)
`
`Mitoxantrone + Prednisone
`N=371
`68 (18.3%)
`52 (14.0%)
`9 (2.4%)
`4 (1.1%)
`4 (1.1%)
`
`Any Modification
` Delay
` Reduction
` Delay and Reduction
` Interruption
`From CDTL Review by Dr Johnson
`
`Table 3: Most Frequent TEAE (All Grades) Leading to Discontinuation (≥3 Patients)
`
`Cabazitaxel +
`Mitoxantrone +
`Prednisone
`Prednisone
`N
`%
`18.3
`8.4
`2.4
`0
`1.3
`0.3
`1.1
`0.3
`1.1
`0.3
`1.1
`0
`0.8
`0
`0.8
`0
`0.8
`0
`0.8
`0
`
`Any TEAE
`
`
`Neutropenia
`
`Hematuria
`
`Diarrhea
`
`
`Fatigue
`
`Acute renal failure
`
`Abdominal pain
`
`Febrile neutropenia
`
`Renal failure
`
`Sepsis
` Applicant Table
`
` A
`
` high degree of toxicity including toxic deaths was observed on trial, particularly in patients
`65 years of age or older. More than a third of the patients required some dose modification (see
`table 2 above) and approximately 18% patients required treatment discontinuation because of
`treatment emergent adverse reactions (see table 3 above). According to Dr. Waxman, the most
`common fatal adverse reactions in cabazitaxel-treated patients were infections (n=5) and renal
`failure (n=4). Four of the five were infection-related deaths, 3 of 4 deaths were related to renal
`failure, and all 4 cardiac deaths occurred in patients ≥65 years of age. Among 18 cabazitaxel-
`treated patients with treatment-emergent deaths, only 3 were <65 years of age. The following
`wording was including in the Warning and Precaution section of the label: “In the randomized
`clinical trial, 3 of 131 (2%) patients < 65 years of age and 15 of 240 (6%) ≥ 65 years of age
`died of causes other than disease progression within 30 days of the last cabazitaxel dose.
`Patients ≥ 65 years of age are more likely to experience certain adverse reactions, including
`neutropenia and febrile neutropenia.”
`
`
`
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`Division Director Review
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`
`Table 4: Neutropenia and Associated Events
`
`Mitoxantrone +
`Cabazitaxel +
`Prednisone
`Prednisone
`N=371
`N = 371
`All grades Grade >3 All grades Grade >3
`347 (93.5)
`303 (81.7)
`325 (87.5)
`215 (58)
`126 (34)
`38(10.2)
`84 (22.6)
`19 (5.1)
`9 (2.4)
`9(2.4)
`6 (1.6)
`5 (1.3)
`4 (1.1)
`4(1.1)
`0
`0
`2(0.5)
`2(0.5)
`0
`0
`28(7.5)
`28(7.5)
`5 (1.3)
`5 (1.3)
`
`
`Neutropenia
`Infections and infestations
`Sepsis
`Septic shock
`Neutropenic infections
`Febrile neutropenia
`Adapted from applicant’s table
`
`
`Neutropenia: According to the Clinical Review, 82% patients experienced grade 3 or
`greater neutropenia with five deaths related to neutropenia on the cabazitaxel arm
`compared to one death on the mitoxantrone arm. Approximately half of the patients
`received secondary prophylaxis with GCSF. However, most of the deaths related to
`neutropenia occurred in the first cycle and in patients older than 65 years in age.
`Consequently, consideration for primary prophylaxis for patients with high risk clinical
`features (age > 65 years, poor performance status, previous episodes of febrile
`neutropenia, extensive prior radiation ports, poor nutritional status, or other serious
`comorbidities) adapted from ASCO guidelines has been included in the Warning and
`Precautions section of the label.
`
`Renal Failure: According to the Clinical Review, 15 cabazitaxel-treated patients and no
`mitoxantrone-treated patients treated in the phase 3 trial EFC6193 experienced renal
`failure of any grade and among 12 patients with grade ≥3 renal failure, 7 (58.3%) did
`not recover. While the majority of these events were possibly attributed by the FDA
`clinical reviewer to other conditions such as infection, dehydration, and structural
`abnormalities, 3 of the 12 grade ≥3 renal failure events could not be readily attributed
`to other conditions. Four patients with treatment-emergent renal failure died within 30
`days of last dose on the cabazitaxel-treated arm compared to none on the mitoxantrone-
`treated arm (see table 18 of clinical review). Some deaths due to renal failure did not
`have a clear etiology. There were patients who had hematuria. The clinical reviewer
`commented that “As all cabazitaxel-treated patients with grade >2 hematuria who
`delayed or discontinued therapy eventually recovered and only one case of irreversible
`renal failure occurred among all cabazitaxel-treated patients with hematuria, the
`occurrence of hematuria appears to be manageable and not closely correlated with
`irreversible renal failure.”
`
`PMRs will be instituted to understand the etiology of renal failure with cabazitaxel and
`to come up with mechanisms to mitigate this toxicity.
`
`Gastrointestinal symptoms: A patient on the cabazitaxel-treated arm died from
`electrolyte imbalance after experiencing diarrhea.
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`Cardiac events: Per clinical review “Although there were more grade 5 cardiac
`adverse events on the cabazitaxel arm, three of the four patients had confounding
`factors including diabetes, hypertension, atrial fibrillation, prior warfarin use, and
`history of pulmonary embolism. The only patient without a past cardiac history was an
`83 year-old male whose death appears to have been secondary to myocardial
`infarction. Hence, there is no clear relationship between cabazitaxel exposure and
`fatal cardiotoxicity.”
`
`
`Other subsections included in the Warning and Precautions section include hypersensitivity,
`risk for toxicity from use in patients with hepatic impairment (the drug is excreted mostly from
`the hepatic route), and use in pregnancy. Boxed warning includes neutropenic complications
`including death and hypersensitivity. Although no grade 3-5 adverse reactions were noted for
`hypersensitivity on trial, this reaction was included in the boxed warning because of the
`potential for severe reactions including death particularly if premedication is not used.
`
` I
`
` agree with the CDTL’s conclusions and recommendation on safety. He says “The 25 mg/m2
`cabazitaxel dose in this trial may be too high. In one Phase 1 trial the MTD was 20 mg/m2 and
`in the other Phase 1 trial the MTD was 25 mg/m2. In the Phase 2 breast cancer trial the dose
`was 20 mg/m2 with the plan to escalate in the 2nd cycle to 25 mg/m2 in patients who did not
`have serious toxicity on the first cycle. They were able to increase the dose to 25 mg/m2 in
`only 21 of 71 patients.”
`
`“The risk/ benefit ratio in the Phase 3 trial is favorable, but suboptimal. The severity of
`toxicity would be more acceptable in a setting where cure is the objective. But the severity of
`toxicity is suboptimal where the objective is palliation in a group of elderly men. The
`necessity for almost 50% of patients to be supported with G-CSF is not what we would desire
`for this setting.’
`
`“Prophylactic G-CSF was not permitted in the first cycle of the RCT. The FDA review team
`has revised the package insert to indicate that “Primary prophylaxis with G-CSF should be
`considered in patients with high-risk clinical features (age > 65 years, poor performance
`status, previous episodes of febrile neutropenia, extensive prior radiation ports, poor
`nutritional status, or other serious comorbidities) that predispose them to increased
`complications from prolonged neutropenia. Therapeutic use of G-CSF and secondary
`prophylaxis should be considered in all patients considered to be at increased risk for
`neutropenia complications”.
`
`“Because the risk/benefit ratio is favorable and 25 mg/m2 is the only dose we have data on,
`we are stuck with this dose. Unfortunately so are elderly men with HRPC. There should be a
`PMR to study a lower dose in prostate cancer, probably in a different population such as
`initial chemotherapy of mHRPC. Two additional PMRs are required to assess renal toxicity.”
`
`DRISK agreed that no REMS were required.
`
`Page 11 of 14
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`

`

`Division Director Review
`
`9. Advisory Committee Meeting
`Cabazitaxel is being recommended for approval based on a survival advantage, which is
`considered a gold standard in the field of oncology. The review was expedited with action
`being taken within 3 months in the interest of public health. These timelines also do not allow
`for an advisory committee meeting.
`10.
`Pediatrics
`
`
`Prostate cancer does not occur in pediatric patients and a waiver was granted.
`
`
`11.
`
`Other Relevant Regulatory Issues
`
`
`DSI Audits:
`According to Dr. Robert Young’s memo, co-signed by Dr. Tejashri Purohit- Sheth, “Four
`clinical investigators were inspected in support of this application, two domestic and two
`foreign. Although regulatory violations were noted for three of the four clinical investigators,
`the findings are considered isolated in nature and unlikely to significantly impact data
`integrity. The data from these investigators are considered reliable and may be used to
`support approval of the application.”
`
`Financial Disclosure:
`According to the clinical review, “Eight investigators in the key study supporting this NDA
`were found to have financial conflict of interest, either a proprietary interest or significant
`payments from or equity interest in the applicant. These investigators received payments as
`honoraria for speaking events, professional fees and consulting fees ranging from totals of
`$29,550 to $94,000. Amount of honoraria was not provided for three investigators.”
`
`“There were 142 sites where patients were enrolled on the pivotal, Phase 3 trial. The number
`of patients enrolled at each of the sites for the investigators with a financial disclosure was not
`found to drive the efficacy or safety data.”
`
`DDMAC:
`Suggestions made in the DDMAC consult by Keith Olin were used to amend the label if
`applicable and if in accordance with the PLR format.
`
`There are no other unresolved relevant regulatory issues
`
`
`12.
`
`Labeling
`
`
`Proprietary name:
`A letter dated 5/26/2010 from Carol Holquist RPh was sent to the applicant. Ms. Holquist
`stated that “We have completed our review of the proposed proprietary name, Jevtana and
`have concluded that it is acceptable.”
`
`Page 12 of 14
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`

`Division Director Review
`
`
`Physician labeling
`As per Dr Johnson’s review, “Much labeling discussion focused on proper format and editing
`to improve clarity. Special attention was directed to clarity and content of the Boxed Warning,
`Contraindications, Warnings and Precautions sections. Emphasis was on neutropenia, febrile
`neutropenia, infection, diarrhea, hypersensitivity reactions and renal failure.”
`
`Neutropenia and hypersensitivity have been included in the boxed warning. Hypersensitivity
`has also been included in the boxed warning even though only grade 1 and 2 adverse reactions
`were observed in the trial.
`
`Because of the higher mortality in the first cycle from complications of neutropenia in patients
`65 years of age and older, physicians are being asked to consider primary prophylaxis with
`GCSF in patients with high risk features. In the trial, only secondary prophylaxis with GCSF
`was proposed.
`
`Premedication is required.
`
`Attention was given the preparation of the dilution solution to avoid confusion and issue with
`over- or underdosing.
`
`Carton and immediate container labels
`No major revisions required
`
`Patient labeling/Medication guide
`No REMS or medication guide were recommended. The issues for cabazitaxel are similar to
`the Taxotere label, another drug in the same class. There are no REMS or medication guide in
`Taxotere.
`13.
`
`Decision/Action/Risk Benefit Assessment
`
`
`
`• Regulatory Action
`
` recommend approval for the following indication:
`
` I
`
`
`
`
`
`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
`
`• Risk Benefit Assessment
`
`
`As indicated by the