CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
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`APPLICA TION NUMBER:
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`'
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`NDA 22-249
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`OFFICE DIRECTOR MEMO
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`

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`March 18, 2008
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`NDA#: 22-249
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`Applicant Name: Cephalon, Inc.
`PDUFA Goal Date: March 20, 2008
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`Proprietary Name/USAN Name: TREANDA/BENDAMUSTINE HCl
`Action/Recommended Action for NME: Approval
`
`Indication:
`
`TREANDA (bendamustine hydrochloride) for Injection is indicated for the treatment of
`patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first line therapies
`other than chlorambucil has not been established.
`
`Clinical:
`
`The safety and efficacy of bendamustine were evaluated in a randomized, controlled,
`European multi-center trial comparing bendamustine to chlorambucil as first-line
`treatment for CLL patients. The trial was conducted in 301 patients (153 on
`bendamustine and 148 on chlorambucil) with Binet Stage B or C (Rai Stages I - IV) CLL
`requiring treatment. Need-to-treat criteria included hematopoietic insufficiency, B-
`symptoms, rapidly progressive disease, or risk of complications from bulky
`lymphadenopathy. Patients with autoimmune hemolytic anemia or autoimmune
`thrombocytopenia, Richter’s syndrome,’or transformation to prolymphocytic leukemia
`were excluded. Patients were randomized to receive either bendamustine, 100 mg/m2
`intravenously on days 1 and 2 every 28 days, or to receive chlorambucil, 0.8mg/kg/day
`orally on days 1 and 15 every 28 days. Up to 6 cycles were administered to each patient.
`
`The efficacy analyses were based on National Cancer Institute-Sponsored Working
`Group criteria. The overall response rate was 59% for bendamustine versus 26% for
`chlorambucil (p <0.0001) with 8% versus <1% complete responses on the bendamustine
`and chlorambucil arms, respectively. The median progression-free survival was 18
`months for bendamustine versus 6 months for chlorambucil (hazard ratio 0.27, 95% CI
`0.17, 0.43; p < 0.0001). Survival data are not mature.
`
`Patients treated with bendamustine had a higher incidence of adverse reactions (89%)
`than those treated with chlorambucil (79%). The most common adverse reactions
`(frequency 215%) were neutropenia, pyrexia, thrombocytopenia, nausea, anemia,
`leucopenia, and vomiting. Neutropenic fever was more common in the bendamustine
`group compared the chlorambucil group. Red blood cell transfusions were administered
`to 20% of the bendamustine-treated patients compared to 6% of those receiving
`chlorambucil.The most frequent adverse reactions leading to study withdrawal for
`patients receiving bendamustine were hypersensitivity and pyrexia. The number of deaths
`during the treatment period was similar in both the treatment arms.
`
`

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`The Division Director (see Dr. Robert Justice’s review) and clinical review team agreed
`that the application with the above indication be approved. The clinical review
`recommended that “the applicant should continue to follow subjects of the study
`02CLLIII for survival outcomes.” The Cross-Discipline Team Leader Review
`recommended that “pending reviews of DMETS and DDMAC, all disciplines
`recommend approval of TREANDA for CLL. A statistically significant improvement in
`response rate and progression-free survival was observed. The adverse event profile is
`acceptable.”
`
`The Pharmacology/Toxicology review stated that the non-clinical studies submitted to
`this NDA provide sufficient information to support the use of Treanda for patients with
`CLL and that no additional non-clinical studies are required. The Clinical
`Pharmacology/Biopharmaceutics review considered the NDA to be deficient from a
`clinical pharmacology perspective due to the lack of data available regarding the
`pharrnacokinetics at the proposed dose, dose proportionality, human excretion and
`metabolism, effect on QT prolongation, in viva drug-drug interactions and in vitro p-
`glycoprotein screens. To address these problems, the following phase 4 commitments
`were requested. The sponsor is requested to submit the completed report and data sets for
`the mass-balance evaluation. Results from this report may indicate a need for a dedicated
`renal and/or hepatic organ impairment study. The sponsor is also requested to investigate
`the potential for bendamustine to affect QT intervals, the influence of CYP1A2 inducers
`and inhibitors on bendamustine in vivo pharmacokinetics’, and if bendamustine is an
`inhibitor or substrate of p-glycoprotein. There were no outstanding issues in the clinical
`microbiology review.
`
`This application was not presented at the Oncologic Drugs Advisory Committee. The
`endpoints (response rate and PFS) had been used previously in drug approvals. The
`observed improvements in these endpoints provide internal consistency of a therapeutic
`effect and are statistically robust. The safety profile is consistent with other drugs used
`for the treatment of CLL.
`
`

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`This'Is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Richard Pazdur
`
`- 3/20/2008 09:52:15 AM
`MEDICAL OFFICER
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`