CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
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`
`
`
`
`APPLICATION NUMBER:
`20-1023
`20-1023
`
`
`APPLICA TION NUMBER:
`
`OFFICE DIRECTOR MEMO
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`OFFICE DIRECTOR MEMO
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`

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`Office Director Review
`NDA 201023_Jevtana (cabazitaxel)
`
`Office Director Summary Review for Regulatory Action
`
`
`
`Date
`From
`Subject
`NDA/BLA #
`Supplement #
`Applicant
`Date of Submission
`PDUFA Goal Date
`Proprietary Name / Established
`(USAN) names
`Dosage forms / Strength
`
`June 17, 2010
`Richard Pazdur, MD
`Office Director Summary
`NDA 201023
`
`Sanofi-Aventis
`March 31, 2010
`September 30, 2010
`Jevtana® (cabazitaxel) Injection Concentrate
`
`Jevtana (cabazitaxel) Injection Concentrate 60 mg/1.5 mL is
`supplied as a kit consisting of the following:
`− Jevtana 60mg/1.5 mL concentrate: contains 60 mg
`cabazitaxel in 1.5 mL polysorbate 80
`− Diluent for Jevtana 60 mg/1.5 mL: contains
`13% (w/w) ethanol in water for injection
`Jevtana in combination with prednisone is indicated for the
`treatment of patients with hormone refractory metastatic
`prostate cancer previously treated with a docetaxel-containing
`regimen
`Approval
`
` of
`
`Names of discipline reviewers
`
`Amna Ibrahim, MD
`John Johnson, MD
`Amy McKee, MD (efficacy); Ian Waxman, MD (safety)
`Chia-Wen Ko, PhD; Shenghui Tang, PhD; Rajeshwari
`Sridhara, PhD
`Sachia Khasar, PhD; Whitney Helms, PhD; S. Leigh Verbois,
`PhD; John Leighton, PhD
`Xiao-Hong Chen, PhD; Sue Ching Lin, PhD; Brian D. Rogers,
`PhD; William M. Adams, PhD; Richard Lostritto, PhD
`Steven E Fong, PhD; Bryan S. Riley, PhD
`Pengfei Song, PhD; Nitin Mehrotra, PhD; Qi Liu, PhD;
`Christine Garnett, PharmD; Nam Atiqur Rahman, PhD
`Keith Olin, PharmD
`Robert Young, MD; Tejashri Purohit-Sheth, MD
`Lubna Najam, MS, PharmD
`N/A
`Sharon Mills BSN, RN, CCRP
`
`Proposed Indication
`
`Recommended:
`
`Material Reviewed/Consulted
`OND Action Package, including:
`Division Director Review
`CDTL Review
`Medical Reviews
`Statistical Review
`
`Pharmacology Toxicology
`Review
`CMC Review/OBP Review
`
`Microbiology Review
`Clinical Pharmacology Review
`
`DDMAC
`DSI
`OSE/DMEPA
`OSE/DDRE
`OSE/DRISK
`OND = Office of New Drugs
`
`Page 1 of 5
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`(b) (4)
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`Office Director Review
`NDA 201023_Jevtana (cabazitaxel)
`
`DDMAC = Division of Drug Marketing, Advertising and Communications
`OSE = Office of Surveillance and Epidemiology
`DMEPA = Division of Medication Error Prevention and Analysis
`DSI = Division of Scientific Investigations
`DDRE = Division of Drug Risk Evaluation
`DRISK = Division of Risk Management
`CDTL = Cross-Discipline Team Leader
`
`
`I. Introduction/Background
`
`First-line therapy for patients with metastatic prostate cancer is medical or surgical
`castration (which includes gonadotropin-releasing hormone antagonists or surgery)
`where approximately 85% will respond and approximately 15% will not respond but
`will become refractory to hormonal intervention (i.e., resulting in metastatic hormone
`refractory prostate cancer (mHRPC)). For this refractory population, recommended
`first-line therapy is combination docetaxel and prednisone. For patients who have
`progressed on docetaxel/prednisone combination therapy, there is no approved
`therapy.
`
`Jevtana (cabazitaxel) is a new molecular entity, similar to docetaxel and paclitaxel,
`and is currently not marketed anywhere in the world. The proposed indication is
`“Jevtana in combination with prednisone is indicated for the treatment of patients with
`hormone refractory metastatic prostate cancer previously treated with a docetaxel-
`containing regimen”—an indication for which there is no currently approved therapy.
`Review of this application was expedited due to anticipated impact on public health.
`
`
`II. Efficacy and Safety
`
`This application is primarily supported by a single randomized, open label, multi-
`center, international study (EFC6193 (TROPIC)) entitled, “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”.
`
`As in Dr. Ibrahim’s Division Director Review, “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. A major issue observed during 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.”
`
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`Page 2 of 5
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`Office Director Review
`NDA 201023_Jevtana (cabazitaxel)
`
`The primary clinical review by Drs. McKee and Waxman states “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.”
`
`Statistical reviewer, Dr. Ko, recommends approval based on the following: “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.”
`
`For safety as indicated in 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.”
`
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`•
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`“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.”
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`Page 3 of 5
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`Office Director Review
`NDA 201023_Jevtana (cabazitaxel)
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`•
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`•
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`“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.”
`
`
`The risk-benefit assessment by Dr. Johnson’s (CDTL), in which I agree, states “(t)he
`single 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 most common (≥ 5%) grade 3-4
`adverse reactions in cabazitaxel-treated patients were neutropenia, leukopenia,
`anemia, febrile neutropenia, diarrhea, fatigue, and asthenia. The cabazitaxel dose
`will be addressed in a PMR. The cabazitaxel toxicity will be addressed in the label and
`with several PMRs (See below for a complete list of PMRs).”
`
`“There were no disagreements among review team members regarding Risk Benefit
`Assessment.”
`
`For the above safety findings, DRISK agreed that no REMS were required. However,
`to further characterize the safety of cabazitaxel, 10 PMRs will be conducted by the
`sponsor. As indicated in Dr. Ibrahim’s review, “Two PMRs will evaluate the potential
`for a serious risk of intravenous infusion of particulate matter into the blood stream to
`understand and characterize the supersaturated pre-mix and in the infusion solution.
`PMRs will be implemented to assess the unusually high incidence and severity of
`toxicity observed in the randomized trial in metastatic hormone refractory prostate
`cancer and the increased incidence of drug-related death. A lower Jevtana®
`(cabazitaxel) Injection dose may be equally effective with less toxicity. PMRs will also
`be implemented to assess the signals of the serious risks of hepatic impairment, Q-T
`prolongation and drug-drug interaction with Jevtana® (cabazitaxel) Injection.”
`
`Please refer to the action letter for a description of these PMRs.
`
`
`III. CMC
`For CMC, there were concerns regarding overfill of both the cabazitaxel vial and
`diluent. If the entire content of the diluent were added into the drug vial, there may be
`a greater than 10% concentration variation of the resulting premix solution. Dr. Chen,
`CMC reviewer, notes that “Although it is not the preferred approach, it was found to
`be acceptable as it is the same approach used by Taxotere® Injection.” As indicated
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`Page 4 of 5
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`Office Director Review
`NDA 201023_Jevtana (cabazitaxel)
`
`by Dr. Ibrahim’s review, particular attention was given to instructions for preparation of
`the infusion solution in labeling.
`
`Dr. Lostritto, Division Director, ONDQA, was concerned that precipitation problems
`were not fully characterized in both the premix solution and in the final infusion
`solution, and it was unknown whether a standard in-line filter would not clog due to
`the precipitation. However due to the observed survival advantage, this issue will be
`further characterized in a PMR. ONDQA recommends approval of this application. In
`addition, manufacturing site inspections were acceptable.
`
`
`IV. Nonclinical
`Drs. Khasar, Helms, Verbois and Leighton recommend approval of this application
`and state that nonclinical studies with cabazitaxel support the safety of its use in the
`proposed population. They concluded, “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”.
`
`
`V. Clinical Pharmacology
`Clinical Pharmacology recommends approval of this application; however, 4 PMRs
`will be implemented to assess the following: Potential for QTc prolongation, PK and
`safety in patients with hepatic impairment, drug interactions with strong CYP3A4
`inducers and inhibitors. Please see the action letter for description of PMRs.
`
`
`VI. Clinical Microbiology
`Dr. Fong recommends approval from a microbiology quality standpoint.
`
`
`VII. Other Disciplinary Reviews
`This application was also reviewed by the Division of Scientific Investigations (DSI),
`DDMAC, DMEPA and DRISK. DSI supports approval of this application. Issues
`brought forth by the other disciplines have been addressed in labeling. There are no
`outstanding issues from these disciplines.
`
`
`VIII. Regulatory Action
`Approval based on a single, randomized clinical trial (N=755) in men with mHRPC
`who had progressed on or after a docetaxel-containing regimen, a population with no
`approved therapy, where a statistically significant improvement in median survival of
`2.4 months was observed for combination cabazitaxel/prednisone compared to
`mitoxantrone/prednisone. Approval is contingent upon the conduct of 10 PMRs as
`described above and in the action letter.
`
`Page 5 of 5
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`Application
`Type/Number
`--------------------
`NDA-201023
`
`Submission
`Type/Number
`--------------------
`ORIG-1
`
`Submitter Name
`
`Product Name
`
`--------------------
`SANOFI AVENTIS
`SPA
`
`------------------------------------------
`CABAZITAXEL (XRP6258)
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`TAMY E KIM
`06/17/2010
`T. Kim entered into DARRTS for Dr. Pazdur signature.
`
`RICHARD PAZDUR
`06/17/2010
`
`