EXHIBIT 2007
`
`EXHIBIT 2007
`
`Cephalon Exhibit 2007
`Fresenius v. Cephalon
`
`IPR2016-00098
`
`

`
`Downloaded from
`
`http://theoncologist.alphamedpress.org/
`
` by guest on July 19, 2015
`
`TheOncologist®
`
`Regulatory Issues: FDA
`
`FDA Drug Approval Summary: Alemtuzumab as Single-Agent
`Treatment for B-Cell Chronic Lymphocytic Leukemia
`
`SUZANNE DEMKO, JEFFREY SUMMERS, PATRICIA KEEGAN, RICHARD PAZDUR
`
`Division of Biologic Oncology Products, Office of Oncology Drug Products, Center for Drug Evaluation and
`Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA
`
`Key Words. Chronic lymphocytic leukemia (cid:127) Progressive disease (cid:127) First-line therapy (cid:127) Alemtuzumab (cid:127) Chlorambucil
`
`Disclosure: No potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.
`
`LEARNING OBJECTIVES
`
`After completing this course, the reader will be able to:
`1. Discuss the results of the CAM 307 randomized trial of alemtuzumab in patients with B-cell chronic lymphocytic
`leukemia.
`2. Describe the pretreatment and prophylactic medications recommended for patients treated with alemtuzumab.
`3. Identify the most common toxicities seen with alemtuzumab treatment.
`
`CMECME
`
`clo
`ABSTRACT
`On September 19, 2007, the U.S. Food and Drug Ad-
`ministration granted regular approval and expanded
`labeling for alemtuzumab (Campath®; Genzyme Cor-
`poration, Cambridge, MA) as single-agent treatment
`for B-cell chronic lymphocytic leukemia (B-CLL). Al-
`emtuzumab was initially approved in 2001 under accel-
`erated approval regulations. Conversion to regular
`approval was based on a single study submitted to verify
`clinical benefit. Efficacy and safety were demonstrated
`in an open-label, international, multicenter, random-
`ized trial of 297 patients with previously untreated, Rai
`stage I–IV B-CLL experiencing progression of their dis-
`ease. Patients were randomized to either alemtuzumab,
`
`Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™ at CME.TheOncologist.com
`
`30 mg i.v. over 2 hours three times per week on alternate
`days for a maximum of 12 weeks, or chlorambucil,
`40 mg/m2 orally every 28 days for a maximum of 12
`months. The progression-free survival time, the pri-
`mary study endpoint, was significantly longer in the al-
`emtuzumab arm than in the chlorambucil arm. Both the
`overall and complete response rates were also signifi-
`cantly higher in the alemtuzumab arm. No differences
`in survival were observed. There were no new safety sig-
`nals identified in patients receiving alemtuzumab. The
`most serious, and sometimes fatal, toxicities of alemtu-
`zumab are cytopenias, infusion reactions, and infec-
`tions. The Oncologist 2008;13:167–174
`
`Correspondence: Suzanne Demko, P.A.-C., U.S. Food and Drug Administration, 10903 New Hampshire Avenue, WO#22 Room 2307,
`Mail Stop 2343, Silver Spring, Maryland 20993, USA. Telephone: 301-796-2108; Fax: 301-796-9849; e-mail: suzanne.demko@fda.hhs.
`gov Received November 2, 2007; accepted for publication January 8, 2008. ©AlphaMed Press 1083-7159/2008/$30.00/0 doi: 10.1634/
`theoncologist.2007-0218
`
`The Oncologist 2008;13:167–174 www.TheOncologist.com
`
`CEPHALON, INC. -- EXHIBIT 2007 0001
`
`

`
`Downloaded from
`
`http://theoncologist.alphamedpress.org/
`
` by guest on July 19, 2015
`
`168
`
`FDA Drug Approval Summary: Alemtuzumab
`
`INTRODUCTION
`Alemtuzumab (Campath®; Genzyme Corporation, Cam-
`bridge, MA) is a recombinant DNA-derived humanized
`IgG1 kappa monoclonal antibody specific for the cell sur-
`face glycoprotein CD52 expressed on normal and malig-
`nant human peripheral blood B and T lymphocytes as well
`as natural killer cells, monocytes, macrophages, and other
`tissues. The mechanism of action is not completely under-
`stood, but involves a number of effects, including comple-
`ment-mediated cell lysis, antibody-dependent cellular
`toxicity, and the induction of apoptosis. Because of its im-
`munosuppressive properties, alemtuzumab was investi-
`gated initially for the treatment of autoimmune diseases
`and in transplant [1, 2]. Clinical activity was then dem-
`onstrated in a number of malignancies, including chronic
`lymphocytic leukemia (CLL) and T-cell prolymphocytic
`leukemia [3–5], which led to further investigation in
`these settings.
`The U.S. Food and Drug Administration (FDA) granted
`accelerated approval for alemtuzumab on May 7, 2001, for
`the treatment of patients with B-cell chronic lymphocytic
`leukemia (B-CLL) who had been treated with alkylating
`agents and failed fludarabine therapy based on evidence of
`durable objective response rates in the range of 21%–33%
`across three single-arm studies. U.S. regulatory approval
`was contingent upon completion of a postmarketing com-
`mitment to confirm clinical benefit in the CAM 307 trial.
`CAM 307 was an open-label, international, multicenter,
`randomized trial designed to demonstrate a longer progres-
`sion-free survival (PFS) duration with single-agent alemtu-
`zumab than with single-agent chlorambucil in patients with
`previously untreated, Rai stage I–IV B-CLL experiencing
`progression of their disease requiring initiation of antileu-
`kemia treatment. The analyses of the primary (PFS) and key
`secondary endpoints were performed on an intent-to-treat
`(ITT) population of 297 patients. Conversion from acceler-
`ated to regular approval for alemtuzumab and a new label-
`ing claim for the initial treatment of B-CLL on September
`19, 2007, were supported by evidence of a significant and
`clinically meaningful longer PFS time, supported by higher
`overall and complete response rates.
`
`PATIENTS AND METHODS
`The CAM 307 trial was an open-label, randomized (1:1),
`multicenter trial conducted in Europe and the U.S., compar-
`ing the safety and efficacy of single-agent alemtuzumab
`with those of single-agent chlorambucil in previously un-
`treated patients with B-CLL who required systemic therapy
`for progressive disease [6]. The intended sample size of 284
`patients was chosen to detect a 50% difference in the me-
`dian PFS time (14 versus 21 months), with 80% power and
`
`␣⫽ 0.05 (two-sided). Randomization was stratified with an
`adaptive randomization method used to achieve balance be-
`tween the treatment arms for study center, Rai stage group
`(Rai I–II versus Rai III–IV), age (⬍65 years versus ⱖ65
`years), World Health Organization (WHO) performance
`status score (0 or 1 versus 2), gender, and maximum lymph
`node size (nonpalpable or ⬍5 cm versus ⱖ5 cm).
`The primary efficacy endpoint for the trial was the PFS
`duration, calculated from the date of randomization to the
`date of disease progression or relapse as documented by an
`independent response review panel (IRRP) or the date of
`death from any cause, whichever occurred earlier. Patients
`without IRRP-documented disease progression who were
`alive on the date of last evaluation were censored at the date
`of last contact. Patients with missing tumor response as-
`sessments were considered to have progressed on the date
`of the inevaluable response determination plus 1 day. The
`statistical analysis plan specified a single interim analysis
`of PFS after 95 events and a final analysis of PFS after 70%
`of the population had progressed or died (190 events). Pro-
`tocol-specified exploratory analyses of PFS were planned
`to assess for consistency of treatment effect within the fol-
`lowing subgroups: age (⬍65 years versus ⱖ65 years), max-
`imum lymph node diameter (nonpalpable or ⬍5 cm versus
`ⱖ5 cm), gender, performance status (0 or 1 versus 2), per-
`cent marrow involvement, ␤
`2-microglobulin, and cytoge-
`netic abnormalities. Additional study endpoints included
`overall survival, investigator-determined PFS, IRRP-deter-
`mined overall and complete response rates, duration of re-
`sponse, time to treatment failure, and time to alternative
`treatment. Complete response (CR) and partial response
`(PR) were defined using the 1996 National Cancer Institute
`Working Group (NCIWG) criteria summarized in Table 1.
`The protocol defined duration of response as the interval
`between the date of first documented objective response
`and the date of documented progressive disease or death
`from any cause as determined by the IRRP. The design of
`the case report forms, which were reviewed by the IRRP,
`did not clearly indicate that the intended date of response
`was the date of initial response. As a result, the IRRP pro-
`vided the date of best response, and the duration of response
`analysis was performed using this time point and the cen-
`soring rules from the primary PFS analysis. Patients were
`evaluated for disease status response and survival monthly
`during treatment and at the completion of treatment or early
`discontinuation. Response assessments included physical
`examination, lymph node, liver, and spleen measurements,
`assessment of disease-related symptoms, and CBC with
`differential. In addition, at 1, 2, and 3 months after treat-
`ment had begun, flow cytometry was performed on periph-
`eral blood and bone marrow aspirate samples, and bone
`
`Oncologist
`Oncologist
`
`CEPHALON, INC. -- EXHIBIT 2007 0002
`
`

`
`Downloaded from
`
`http://theoncologist.alphamedpress.org/
`
` by guest on July 19, 2015
`
`Demko, Summers, Keegan et al.
`
`169
`
`Table 1. 1996 NCIWG response criteria
`Type of response
`CR (duration ⬎2 months)
`Normal physical examination (including nodes, liver, spleen) and x-ray
`No constitutional symptoms
`Lymphocytes ⱖ4.0 ⫻ 109/l
`Neutrophils ⱖ1.5 ⫻ 109/l
`Platelets ⬎100 ⫻ 109/l
`Hemoglobin ⬎11.0 g/dl (untransfused)
`Marrow normocellular for age, lymphs ⬍30%, no nodules; if hypocellular marrow, repeat in 4 weeks
`PR (duration ⬎2 months)
`Lymphocyte ⱖ50% decrease from baseline, and
`Lymphadenopathy ⱖ50% decrease from baseline, and/or
`Liver and/or spleen ⱖ50% decrease from baseline
`Plus at least one of: neutrophils ⱖ1.5 ⫻ 109/l or 50% increase over baseline, platelets ⬎100 ⫻ 109/l or 50% increase over
`baseline, hemoglobin ⬎11.0 g/dl or 50% increase over baseline (untransfused)
`Otherwise CR with persistent nodules classified as nodular PR
`Otherwise CR with persistent anemia or thrombocytopenia because of drug toxicity classified as PR and monitored
`prospectively
`Abbreviations: CR, complete response; NCIWG, National Cancer Institute Working Group; PR, partial response.
`
`marrow biopsy samples were obtained for histology if indi-
`cated (i.e., to confirm a CR at least 2 months after a patient
`met the NCIWG laboratory and clinical criteria for CR, and
`to confirm achievement of a CRm (complete response with-
`out evidence of residual disease at the molecular level) sta-
`tus only if peripheral blood was negative for B-CLL by flow
`cytometry). Patients who did not progress by 18 months af-
`ter their initial dose were evaluated for disease status every
`3 months until the time of progression or requirement for
`alternative therapy. Patients with disease progression were
`followed every 3 months for survival. Investigators and the
`IRRP used the NCIWG criteria to assess tumor response to
`study treatment.
`Patients with previously untreated B-CLL exhibiting
`evidence of progressive disease were eligible to participate
`in the trial. Other relevant eligibility criteria are summa-
`rized in Table 2.
`The dosing scheme for alemtuzumab included a dose-
`escalation phase to achieve the recommended dose. The
`dose-escalation phase consisted of an initial dose of 3 mg
`as a daily i.v. infusion administered over 2 hours until
`infusion-related side effects were tolerated followed by
`10 mg as a daily 2-hour i.v. infusion until infusion-
`related side effects were tolerated, with final escalation
`to the recommended dose. The recommended dose was
`30 mg as a 2-hour i.v. infusion administered three times
`per week on alternate days. The total course of alemtu-
`zumab was administered over a maximum of 12 weeks,
`
`www.TheOncologist.com
`
`which included the dose-escalation period. Patients ran-
`domized to the alemtuzumab arm were permitted to re-
`ceive a second treatment course if a CR or PR, durable
`for at least 6 months, was achieved with the initial treat-
`ment course. Premedication for alemtuzumab treatment,
`consisting of diphenhydramine and acetaminophen or
`paracetamol, was given. Meperidine, hydrocortisone (or
`equivalent), and other supportive measures were permit-
`ted as clinically indicated for alemtuzumab infusion re-
`actions. Allopurinol was given prior to the first treatment
`with alemtuzumab and for 14 days thereafter. Tri-
`methoprim/sulfamethoxazole for Pneumocystis carinii
`pneumonia prophylaxis (or therapeutic equivalent) and
`famciclovir (or therapeutic equivalent) for herpes pro-
`phylaxis were required for all patients receiving alemtu-
`zumab. Prophylactic antibiotics to prevent recurrence of
`an infection were allowed at
`the investigator’s
`discretion.
`Dose modifications (delay or discontinuation of alemtu-
`zumab) were required for serious infection, disease pro-
`gression, Common Toxicity Criteria (CTC) grade ⱖ3
`pulmonary, renal, or hepatic toxicity, a positive qualitative
`polymerase chain reaction assay for cytomegalovirus
`(CMV), autoimmune anemia, or autoimmune thrombocy-
`topenia, an absolute neutrophil count ⱕ0.25 ⫻ 109/l, a
`platelet count ⱕ50% of the baseline value in patients with a
`baseline value ⱕ0.25 ⫻ 109/l; if alemtuzumab dosing was
`held for ⬎4 weeks, treatment was terminated.
`
`CEPHALON, INC. -- EXHIBIT 2007 0003
`
`

`
`Downloaded from
`
`http://theoncologist.alphamedpress.org/
`
` by guest on July 19, 2015
`
`170
`
`FDA Drug Approval Summary: Alemtuzumab
`
`Table 2. CAM 307 eligibility criteria
`Inclusion criteria
`B-CLL (histopathologically confirmed)
`Rai stage I–IV
`CD5⫹, CD19⫹, or CD23⫹
`No prior systemic chemotherapy
`Adequate renal function (serum creatinine ⱕ2.0⫻ ULN)
`Adequate hepatic function (total bilirubin, AST, ALT
`ⱕ2.0⫻ ULN)
`WHO performance status score of 0, 1, or 2
`Progressive disease (one or more of):
`
`Disease-related B symptoms
`Marrow failure (manifested by decreased hemoglobin
`to ⬍11 g/dl, or platelet count ⬍100 ⫻ 109/l within
`prior 6 months, or ANC ⬍1.0 ⫻ 109/l within prior 6
`months)
`Progressive splenomegaly (⬎2 cm below left costal
`margin or other organomegaly with progressive
`increase over two clinic visits ⱖ2 wks apart)
`Progressive lymphadenopathy (at least 5 sites of
`involvement with either two nodes at least 2 cm in
`longest diameter or one node ⱖ5 cm in longest
`diameter with progressive increase over two
`consecutive clinic visits ⱖ2 wks apart)
`Progressive lymphocytosis (increase of ⬎50% over a
`2-month period or anticipated doubling time ⬍6
`months)
`
`Exclusion criteria
`ANC ⬍0.5 ⫻ 109/l
`Platelet count ⬍10 ⫻ 109/l
`Chronic use of oral corticosteroids
`Autoimmune thrombocytopenia
`Prior bone marrow transplant
`Investigational agent in past 30 days
`
`HIV positive
`History of anaphylaxis to rat- or mouse-derived humanized
`monoclonal antibodies
`Active infection
`Serious cardiac or pulmonary disease
`
`Active TB in past 2 yrs or current antibiotics for TB
`
`Active secondary malignancy
`
`Central nervous system CLL
`
`Other severe, concurrent diseases or mental disorders
`Pregnant or lactating
`Quantitative PCR positive for CMV
`diagnosis of mantle cell lymphoma
`Abbreviations: ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate aminotransferase; B-CLL,
`B-cell chronic lymphocytic leukemia; CLL, chronic lymphocytic leukemia; CMV, cytomegalovirus; PCR, polymerase chain
`reaction; TB, tuberculosis; ULN, upper limit of normal; WHO, World Health Organization.
`
`Chlorambucil was administered at a dose of 40 mg/m2
`orally once every 28 days for a maximum of 12 months.
`Chlorambucil was interrupted or discontinued for disease
`progression, CTC grade ⱖ3 pulmonary, renal, hepatic, or
`nonhematologic toxicity, serious infection, autoimmune
`anemia or autoimmune thrombocytopenia, complete remis-
`sion, and a response plateau. Allopurinol was given prior to
`the first day of chlorambucil treatment and for 8 days there-
`after for the first three treatment cycles.
`
`RESULTS
`Two hundred ninety-seven patients were enrolled and ran-
`domized from December 2001 to July 2004, which consti-
`tuted the ITT population for analyses of efficacy endpoints.
`The last patient received drug in May 2005; the data cutoff
`for efficacy analyses was June 1, 2006. Of these 297 pa-
`
`tients, 149 were randomized to alemtuzumab and 148 to
`chlorambucil. The majority (273/297) were enrolled at sites
`outside the U.S. There were 294 patients who received the
`assigned treatment with alemtuzumab (n ⫽ 147) or
`chlorambucil (n ⫽ 147) for which adverse drug reaction
`data were analyzed.
`The baseline characteristics for the ITT population, by
`treatment arm, are shown in Table 3. The treatment arms
`were balanced for major demographic and prognostic fac-
`tors. Gender stratification was similar to that seen in B-
`CLL, where there is a 2:1 male-to-female ratio. Ninety-nine
`percent of patients were white, and 65% were ⬍65 years of
`age. The majority of patients enrolled in the study were
`IRRP-confirmed RAI stage I–II (63%), had a WHO perfor-
`mance status score of 0 or 1 (96%), and had a maximal
`lymph node diameter of ⬍5 cm (77%).
`
`Oncologist"
`Ofiecologist
`
`CEPHALON, INC. -- EXHIBIT 2007 0004
`
`

`
`Demko, Summers, Keegan et al.
`
`171
`
`Downloaded from
`
`http://theoncologist.alphamedpress.org/
`
` by guest on July 19, 2015
`
`with a hazard ratio of 0.68 (95% CI, 0.418 –1.107). Because
`of the limited number of patients, exploratory analyses
`comparing effects on PFS conducted in the following sub-
`groups were not meaningful: WHO performance status
`score of 2 (n ⫽ 10), lymph node size ⱖ5 cm (n ⫽ 67), and
`enrollment at U.S. sites (n ⫽ 24).
`The study demonstrated a significantly higher overall
`response rate (83% versus 55%; p ⬍ .0001, ␹2 test) for al-
`emtuzumab-treated patients than for those treated with
`chlorambucil, with an estimated odds ratio for response of
`3.99 (95% CI, 2.33– 6.84). The study also demonstrated a
`significantly higher complete response rate for alemtu-
`zumab of 24% versus 2% when compared with chloram-
`bucil (p ⬍ .0001, ␹2 test). The median duration of response
`for patients treated with alemtuzumab was 492 days (16.4
`months), and it was 386 days (12.9 months) for patients
`treated with chlorambucil. The impact on the resolution of
`B-symptoms was also evaluated. At study entry, night
`sweats were common, reported in 43% of patients who re-
`ceived alemtuzumab and 47% who received chlorambucil.
`After 3 months of treatment, night sweats were reported in
`3% of patients treated with alemtuzumab and 13% treated
`with chlorambucil.
`In the analysis of time to alternative treatment, defined
`as the time from randomization to the date of alternative
`treatment or death, patients in the alemtuzumab arm expe-
`rienced a longer time to alternative treatment than patients
`in the chlorambucil arm; the median time to alternative
`treatment was 708 days (23.3 months) among patients in the
`alemtuzumab arm and 447 days (14.7 months) among pa-
`tients in the chlorambucil arm (p-value ⬍ .0001, log-rank
`test, unadjusted for multiplicity).
`An additional secondary endpoint was time to treatment
`failure, defined as the time from randomization to the date
`of progression, death from any cause, study discontinuation
`because of an adverse event, or treatment interruption be-
`cause of an adverse event resulting in treatment delay over
`4 weeks, whichever was earliest. The time to treatment fail-
`ure was not significantly different between the two treat-
`ment arms, with a median time to treatment failure of 299
`days (10 months) for alemtuzumab and of 344 days (11.5
`months) for chlorambucil.
`There was no difference detected in overall survival be-
`tween treatment arms; there were 24 deaths in each study
`arm at the time of analysis. However, the study was not
`powered to detect a difference in overall survival. There
`were not enough events or long enough follow-up to detect
`a difference in survival, and there was no plan for continued
`follow-up of patients in this study.
`
`Table 3. Baseline demographics
`Alemtuzumab
`(n ⴝ 149)
`
`Chlorambucil
`(n ⴝ 148)
`
`43 (29%)
`106 (71%)
`
`41 (28%)
`107 (72%)
`
`Characteristic
`Gender
`Female
`Male
`Age
`⬍65 yrs
`ⱖ65 yrs
`Lymph nodes
`⬍5 cm
`ⱖ5 cm
`WHO grade
`0 or 1
`2
`Rai group per IRRP
`I–II
`III–IV
`Rai group per INV
`I–II
`III–IV
`Months from
`randomization to
`diagnosis, mean (SD)
`Abbreviations: INV, investigator; IRRP, independent
`response review panel; SD, standard deviation; WHO,
`World Health Organization.
`
`96 (64%)
`53 (36%)
`
`115 (77%)
`33 (22%)
`
`143 (96%)
`5 (3%)
`
`93 (62%)
`50 (34%)
`
`96 (65%)
`52 (35%)
`
`114 (77%)
`34 (23%)
`
`142 (97%)
`5 (3%)
`
`96 (65%)
`49 (33%)
`
`98 (66%)
`51 (34%)
`20.54 (27.78)
`
`95 (64%)
`51 (35%)
`19.72 (27.76)
`
`The final analysis of PFS was conducted after 191 PFS
`events occurred among 297 patients in the ITT population
`(149 randomized to alemtuzumab and 148 randomized to
`chlorambucil). There were 11 patients with IRRP-uncon-
`firmed B-CLL Rai stage I–IV who were censored at day 1
`(seven in the alemtuzumab arm and four in the chloram-
`bucil arm).
`The difference in PFS duration between the alemtu-
`zumab and chlorambucil treatment arms using the log-rank
`test, stratified by Rai stage (I–II versus III–IV) was highly
`statistically significant, with a p-value of .0001 and an es-
`timated hazard ratio of 0.58 (95% confidence interval [CI],
`0.43– 0.77). The median PFS time was 445 days (14.6
`months) in the alemtuzumab arm compared with 357 days
`(11.7 months) in the chlorambucil arm (Table 4). Figure 1
`represents the Kaplan-Meier curves for PFS.
`Across all subgroups, there was a consistently longer
`PFS time favoring the alemtuzumab arm. The effect was
`not significant in the following subgroups: patients with Rai
`stage III–IV (n ⫽ 98), with a hazard ratio of 0.651 (95% CI,
`0.411–1.033), and patients ⱖ65 years of age (n ⫽ 104),
`
`www.TheOncologist.com
`
`CEPHALON, INC. -- EXHIBIT 2007 0005
`
`

`
`172
`
`FDA Drug Approval Summary: Alemtuzumab
`
`Table 4. Major efficacy results for the CAM 307 trial
`
`Downloaded from
`
`http://theoncologist.alphamedpress.org/
`
` by guest on July 19, 2015
`
`0.576 (0.43–0.77)
`.0001
`
`⬍.0001
`3.99 (2.33–6.84)
`
`⬍.0001
`
`⬍.0001
`
`Chlorambucil
`357 (300–401)
`
`55%
`
`2%
`
`386
`447
`
`344
`24
`
`47%
`13%
`
`nia (44% versus 26%), and leukopenia (63% versus 1%).
`Treatment with alemtuzumab also resulted in decreased
`CD3⫹CD4⫹ and CD3⫹CD8⫹ counts of ⬍200 cells/␮l, and
`recovery after discontinuation of alemtuzumab was longer,
`with a median time to CD4 cell partial recovery (⬎200
`CD4⫹ cells/␮l) of 6 months.
`The most common adverse reactions of alemtuzumab
`(NCI-CTC version 2.0 grades 1– 4) were infusion reactions,
`which were experienced by 86% of patients receiving al-
`emtuzumab. The most common signs and symptoms of an
`infusion reaction were pyrexia (69%), chills (53%), nausea
`(18%), hypotension (16%), urticaria (16%), headache
`(14%), dyspnea (14%), and vomiting (11%). Seen less fre-
`quently, with incidence rates of ⱕ10%, were tachycardia,
`anxiety, pruritis, tremor, and bronchospasm. The occur-
`rence of infusion reactions was greatest during the initial
`week of treatment and decreased with subsequent doses.
`All patients were pretreated with antipyretics and antihista-
`mines, and 43% received glucocorticoids as pretreatment.
`Infections occurred in 90% of patients treated with al-
`emtuzumab and 65% of patients treated with chlorambucil.
`CMV infection was reported in 16% of patients treated with
`alemtuzumab, of these, 5% were serious adverse events. No
`patients treated with chlorambucil developed CMV infec-
`tion. CMV viremia was reported in 56% of patients treated
`with alemtuzumab and 8% treated with chlorambucil. An-
`tiviral treatment was administered in 44% of patients who
`developed CMV viremia. Serious adverse events were ex-
`
`acologist"
`Ofiecologist
`
`1.00-
`100-
`
`0.75-
`0.75-
`
`050-
`050-
`
`025-
`025-
`
`000_
`0.00-
`
`Survival Disirthution Function
`Survival Distribution Function
`
`0 (cid:9)
`0
`
`
`
`280 200 (cid:9)
`
`
`
`400 400 (cid:9)
`
`
`
`600 600 (cid:9)
`
`800
`800
`
`
`
`1000 1000
`
`
`
`1200 1200
`
`PFS (IRRP) Ral 1-18 patient
`PFS (IRRP) Rai I—IV patient
`
`
`STRATA: — ARMDC=AlerntUnntab (cid:9)STRATA: — ARMDC=Alemtuzumab (cid:9)
`Censored ARMDC= Alemtuzumab
`° ° ' Censored ARMDC=Alemtuzumab
`ARMDC=Chbrambucil (cid:9)
`'- Censored ARMDC=Chlorambucil
` ARMDC=Chlorambueil (cid:9)
`° (cid:9)
`Censored ARMDC= Chlorambuoil
`Figure 1. CAM 307 Kaplan-Meier curves for progression-
`free survival (PFS).
`Abbreviation: IRRP, independent response review panel.
`
`SAFETY
`The CAM 307 study did not reveal new safety signals for
`alemtuzumab. The most common as well as the most seri-
`ous alemtuzumab toxicities were cytopenias, infusion reac-
`tions, and infections, especially CMV infection. Safety
`findings are summarized in Table 5.
`National Cancer Institute Common Terminology Crite-
`ria for Adverse Events version 3.0 (NCI-CTCAE) grade 3
`or 4 cytopenias occurred more frequently in patients receiv-
`ing alemtuzumab than in those receiving chlorambucil.
`These included lymphopenia (99% versus 1%), neutrope-
`
`Median PFS in days (95% CI)
`Hazard ratio (95% CI)
`Adjusted log-rank p-value
`Overall response
`p-value (␹2 test)
`Estimated odds ratio (95% CI)
`Complete response
`p-value (␹2 test)
`Median duration of response in days
`Median time to alternative treatment in days
`Unadjusted log-rank p-value
`Time to treatment failure in days
`n of deaths
`B-symptoms
`At study entry
`After 3 months’ treatment
`Abbreviations: CI, confidence interval; PFS, progression-free survival.
`
`Alemtuzumab
`445 (374–661)
`
`83%
`
`24%
`
`492
`708
`
`299
`24
`
`43%
`3%
`
`CEPHALON, INC. -- EXHIBIT 2007 0006
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`
`Demko, Summers, Keegan et al.
`
`173
`
`Table 5. CAM 307 per patient incidence of common toxicities
`
`Alemtuzumab
`(n ⴝ 147)
`
`Chlorambucil
`(n ⴝ 147)
`
`Downloaded from
`
`http://theoncologist.alphamedpress.org/
`
` by guest on July 19, 2015
`
`Grades
`3–4 (%)
`99
`44
`13
`13
`10
`3
`4
`5
`26
`2
`1
`0
`1
`5
`1
`0
`4
`1
`0
`0
`0
`
`All grades
`(%)
`9
`51
`54
`70
`11
`1
`8
`0
`65
`1
`4
`1
`0
`2
`8
`1
`7
`4
`3
`1
`1
`
`Grades
`3–4 (%)
`1
`26
`18
`14
`1
`0
`0
`0
`10
`0
`0
`0
`0
`1
`0
`0
`3
`0
`0
`0
`0
`
`All grades
`(%)a
`99
`Lymphopenia
`77
`Neutropenia
`76
`Anemia
`71
`Thrombocytopenia
`69
`Pyrexia
`53
`Chills
`CMV viremiab
`56
`16
`CMV infection
`90
`Infections
`16
`Urticaria
`13
`Rash
`4
`Erythema
`16
`Hypotension
`14
`Hypertension
`14
`Headache
`3
`Tremor
`14
`Dyspnea
`10
`Diarrhea
`10
`Insomnia
`8
`Anxiety
`10
`Tachycardia
`Cardiac disorders
`Listed are those toxicities occurring at a higher relative frequency with alemtuzumab.
`aNCI-CTC version 2.0 for adverse reactions; NCI CTCAE version 3.0 for laboratory values.
`bCMV viremia (without evidence of symptoms) included both cases of single PCR-positive test results and of confirmed
`CMV viremia (at least two occasions in consecutive samples 1 wk apart); for the latter, ganciclovir (or equivalent) was
`initiated per protocol.
`Abbreviations: CMV, cytomegalovirus; NCI-CTC, National Cancer Institute Common Toxicity Criteria; NCI-CTCAE,
`National Cancer Institute Common Terminology Criteria; PCR, polymerase chain reaction.
`
`Blood and lymphatic system disorders
`
`General disorders and administration site
`conditions
`
`Infections and infestations
`
`Skin and s.c. tissue disorders
`
`Vascular disorders
`
`Nervous system disorders
`
`Respiratory, thoracic, and mediastinal disorders
`Gastrointestinal disorders
`Psychiatric disorders
`
`perienced by 11% of patients, all of whom were treated with
`alemtuzumab.
`Anti-human antibodies to alemtuzumab were detected
`in 8% of patients tested using an enzyme-linked immu-
`nosorbent assay. Patients with detectable antibody titers
`were also weakly positive when analyzed for neutralizing
`antibodies in 25% of cases.
`
`DISCUSSION
`The design of study CAM 307 was predicated on alemtu-
`zumab’s initial accelerated approval. The U.S. FDA’s ac-
`celerated approval
`regulations for serious or
`life-
`threatening illnesses (21 CFR 601 Subpart E) include a
`requirement for a postmarketing study to verify clinical
`benefit. CAM 307 was designed to fulfill this commitment.
`At the time the study was designed, chlorambucil was ap-
`
`proved for the first-line treatment of B-CLL. The currently
`available therapies for this patient population in the first-
`line setting have expanded. Clinical practice has evolved to
`include a more limited first-line use of chlorambucil as
`treatment for B-CLL in favor of fludarabine as a single
`agent or in combination with other therapies. As a result, the
`relevance of the results from the CAM 307 trial are being
`questioned [7]. It is inevitable that approaches to therapy in
`the field of oncology will change while clinical trials de-
`signed in another era are being completed. While it is
`agreed that a trial designed in the current practice setting
`with fludarabine as the comparator would likely be more in-
`formative, the choice of chlorambucil as the comparator in
`this trial was appropriate and fulfilled the regulatory re-
`quirement for confirmation of clinical benefit.
`Single-agent alemtuzumab provided a statistically sig-
`
`www.TheOncologist.com
`
`CEPHALON, INC. -- EXHIBIT 2007 0007
`
`

`
`Downloaded from
`
`http://theoncologist.alphamedpress.org/
`
` by guest on July 19, 2015
`
`174
`
`FDA Drug Approval Summary: Alemtuzumab
`
`nificant and clinically meaningful longer PFS time than
`with chlorambucil in patients with B-CLL who had been
`previously untreated, had evidence of disease progression,
`and were in need of treatment. The data from this random-
`ized, open-label, international, multicenter trial demon-
`strate that alemtuzumab led to an 88 days (2.9 months)
`longer median PFS time when compared with chlorambucil
`and a 42% longer time to disease progression or death. The
`secondary endpoints of overall response rate and complete
`response rate were supportive of the primary results, with a
`significantly higher overall response rate (83% vs. 55%)
`and complete response rate (24% versus 2%) for alemtu-
`zumab-treated patients. Survival data are immature; there
`was no evidence of any effect on survival.
`No new safety signals were identified in this study. The
`most common and most serious adverse reactions of al-
`emtuzumab identified during this study were severe and
`life-threatening cytopenias, infusion reactions, and infec-
`tions, especially CMV; some of these events were fatal. The
`
`toxicity profile of alemtuzumab as demonstrated in this
`study was consistent with the information already con-
`tained in the prescribing information. While the risks asso-
`ciated with alemtuzumab treatment can be significant, in a
`risk– benefit analysis of this agent for B-CLL treatment, the
`potential benefits mitigate the frequency and severity of the
`risks.
`
`ACKNOWLEDGMENTS
`The views expressed are the result of independent work and
`do not necessarily represent the views and findings of the
`U.S. FDA.
`
`AUTHOR CONTRIBUTIONS
`Conception/design: Suzanne Demko
`Collection/assembly of data: Suzanne Demko
`Data analysis and interpretation: Suzanne Demko, Jeffrey Summers
`Manuscript writing: Suzanne Demko
`Final approval of manuscript: Richard Pazdur
`Preliminary editing: Jeffrey Summers
`Final editing, Division approval: Patricia Keegan
`
`REFERENCES
`
`1
`
`Isaacs JD, Watts RA, Hazelman BL et. al. Humanised monoclonal antibody
`therapy for rheumatoid arthritis. Lancet 1992;340:748 –752.
`
`2 Hale G, Waldmann H. Recent results using CAMPATH-1H antibodies to
`control GVHD and graft rejection. Bone Marrow Transplant 1996;17:305–
`308.
`
`3 Osterborg A, Fassas AS, Anagnostopoulos A et al. Humanized CD52
`monoclonal antibody Campath-1H as first-line treatment in chronic lym-
`phocytic leukaemia. Br J Haematol 1996;93:151–153.
`
`4 Osterborg A, Dyer MJ, Bunjes D et. al. Phase II multicenter study of human
`
`CD52 antibody in previously treated chronic lymphocytic leukemia. Euro-
`pean Study Group of CAMPATH-1H Treatment in Chronic Lymphocytic
`Leukemia. J Clin Oncol 1997;15:1567–1574.
`
`5 Pawson R, Dyer MJ, Barge R et al. Treatment of T-cell prolymphocytic
`leukemia with human CD52 antibody. J Clin Oncol 1997;15:2667–2672.
`
`6 Hillmen P, Skotnicki AB, Robak T et. al. Alemtuzumab compared with
`chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin
`Oncol 2007;25:5616 –5623.
`
`7 Flynn JM, Byrd JC. Have we forgotten the purpose of phase III studies?
`J Clin Oncol 2007;25:5553–5555.
`
`Oncologist
`Oncologist
`
`CEPHALON, INC. -- EXHIBIT 2007 0008