EXHIBIT 2006
`EXHIBIT 2006
`
`Fresenius v. Cephalon IPR201 6-D0098
`
`Cephalon Exhibit 2006
`Cephalon Exhibit 2006
`Fresenius v. Cephalon
`IPR2016-00098
`
`
`
`

`
`Comparison of Fludarabine, Cyclophosphamide/Doxorubicin/
`Prednisone, and Cyclophosphamide/Doxorubicin/Vincristine/
`Prednisone in Advanced Forms of Chronic Lymphocytic
`Leukemia: Preliminary Results of a Controlled Clinical Trial
`
`The French Cooperative Group on Chronic Lymphocytic Leukemia
`
`In a multicenter clinical trial conducted by the French
`Cooperative Group on Chronic Lymphocytic Leukemia
`(CLL) between June 1, 1990, and October 1, 1992, 183
`patients with stage B CLL and 79 patients with stage C
`CLL were randomized to receive either cyclophospha-
`mide/doxorubicin/prednisone (CAP) (71 stage B patients
`and 25 stage C patients), or cyclophosphamide/doxo-
`rubicin/vincristine/prednisone (CHOP) (56 stage B pa-
`tients and 27 stage C patients), or fludarabine (FDB) (56
`stage B patients and 27 stage C patients). The mean
`follow-up was 14 months (standard deviation, 7
`months). At the 6-month follow-up examination, the re-
`sults suggested that FDB was more effective than CAP
`and CHOP in patients with stage B disease (n = 183),
`with 19% of FDB-treated patients achieving "clinical and
`hematological remission" (CR) compared with 11% of
`the CHOP-treated patients and 7% of the CAP-treated
`patients (P = .08; 6 degrees of freedom; chi-squared
`test). The rates of partial remission (PR) and overall re-
`sponse (CR + PR) were, respectively, 75% and 94% for
`the FDB-treated patients, 64% and 75% for the CHOP-
`treated patients, and 65% and 72% for the CAP-treated
`patients. However, in patients with stage C CLL (n
`= 77) at entry to the study, the remission status at 6
`months showed slightly greater improvement in the
`CAP-treated group (n = 25), in which 84% of patients
`achieved remission (CR + PR) compared with 64% of
`patients in the FOB-treated group (n = 27) and 63% of
`patients in the CHOP-treated group (n = 27). Further
`analysis of the study data may help to clarify the signif-
`icance of these findings and to determine whether FDB
`improves survival in patients with advanced CLL.
`Copyright © 1993 by W.B. Saunders Company
`
`IN JUNE 1990, the French Cooperative Group
`
`on Chronic Lymphocytic Leukemia (CLL)
`activated a multicenter randomized clinical trial
`in which Binet stage B and stage C CLL patients
`were allocated to receive either fludarabine (FDB)
`or one of two polychemotherapeutic regimens
`that included doxorubicin. We report the pre-
`liminary results of this trial, based on October 1,
`1992, as the reference date.
`
`MATERIALS AND METHODS
`Diagnosis of CLL was based on the International Workshop
`on Chronic Lymphocytic Leukemia criteria.' Patients younger
`than 75 years who had not been previously treated and who
`were classified as stage B or C2 were eligible for this trial.
`There were 51 participating centers, and randomization was
`performed through a centralized telephone assignment pro-
`
`cedure according to stage. Follow-up examinations were
`scheduled for the third and sixth month after randomization,
`and every 6 months thereafter.
`Patients were randomly allocated to receive either FDB 25
`mg/m2 intravenously (IV) daily for 5 days; cyclophosphamide
`750 mg/m2 IV day 1, doxorubicin 50 mg/m2 IV day 1, and
`prednisone 40 mg/m2 orally on days 1 to 5 (CAP); or vin-
`cristine 1 mg/m2 IV and doxorubicin 25 mg/m2 IV on day I
`plus cyclophosphamide 300 mg/m2 and prednisone 40 mg/
`m2 orally on days 1 to 5 (CHOP). The first six courses of
`treatment were given at monthly intervals and the last six
`courses at 3-month intervals. In case of disease progression
`within the first 3 months after randomization, initial treatment
`was continued, but thereafter choice of treatment could be
`made according to the following rule. At 3 months, patients
`allocated to receive CAP or FDB who were considered to be
`treatment failures (see below) were switched to FDB or CAP,
`respectively. At 6 months, patients exhibiting disease pro-
`gression were given FDB, with the exception of previous FDB
`treatment failures; reduction by 50% (doxorubicin dose) was
`made whenever remission was observed. Finally, all re-
`sponders (see below) who received FDB at 6 months were
`randomized either to continuation for six courses or dis-
`continuation of FDB.
`The main endpoint was overall survival from the date of
`randomization. Remission status ("clinical and hematological
`remission" [CR], partial remission [PR], stable disease [SD],
`progressive disease [PD]) and stage at 6 months were also
`analyzed. Complete remission was defined by the absence of
`clinical signs, lymphocytosis less than 4 X 109/L, hemoglobin
`greater than 120 g/L, and platelets greater than 150 x 109/L;
`PR was defined by a decrease of at least 50% in the diameter
`of the involved lymph nodes and a decrease of at least 75%
`in the lymphocyte count, both compared with the initial ex-
`amination; PD was defined as either progression to stage C,
`increase in lymphocyte count, or increase in tumoral mass;
`and SD was defined as the absence of both remission and
`progression.
`Statistical analysis (using SAS software; SAS Institute, Cary,
`NC) was made on an intention-to-treat basis based on the
`log-rank and the chi-squared tests.
`
`RESULTS
`
`From June 1, 1990, to October 1, 1992, 183
`stage B patients and 79 stage C patients were re-
`
`Address reprint requests to M. Leporrier, MD, Service
`d'Hematologie, CHU, Avenue Georges Clernenceau, 14033
`Caen Cedex, France.
`Copyright © 1993 by W.B. Saunders Company
`0093-7754/93/2005-0703.05.00/0
`
`Seminars in Oncology, Vol 20, No 5, Suppl 7 (October), 1993: pp 21-23
`
`21
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`CEPHALON, INC. -- EXHIBIT 2006 0001
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`22 (cid:9)
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`THE FRENCH COOPERATIVE GROUP ON CHRONIC LYMPHOCYTIC LEUKEMIA
`
`cruited and randomized to receive either CAP
`(71 stage B patients and 25 stage C patients),
`CHOP (56 stage B patients and 27 stage C pa-
`tients), or FDB (56 stage B patients and 27 stage
`C patients). The mean follow-up was 14 months
`(standard deviation, 7 months). At the reference
`date, 19 patients had died (five stage B patients
`and 14 stage C patients) and information was
`incomplete for 30 patients (22 stage B patients
`and eight stage C patients).
`Although there were slight imbalances, no ma-
`jor difference in the distribution of clinical and
`biologic parameters was observed between treat-
`ment groups in each stage. In stage B and stage
`C patients, the mean age was 60 and 62 years,
`the mean lymphocyte count was 58 X 109/L and
`112 X 109/L, the mean hemoglobin level was 133
`g/L and 96 g/L, the mean platelet count was 192
`X 109/L and 114 X 109/L, and the mean lym-
`phocyte bone marrow infiltration was 73% and
`84%, respectively.
`Stage B Chronic Lymphocytic Leukemia
`In the follow-up examination at 6 months, re-
`mission status (CR, PR, SD, and PD), assessed
`in 151 patients, differed between the three treat-
`ment groups, but not significantly (P = .08; 6
`degrees of freedom; chi-squared test). Complete
`remission was observed in nine (19%) patients in
`the FDB-treated group compared with four (7%)
`in the CAP-treated group and five (11%) in the
`CHOP-treated group (Table 1). Moreover, stage
`at 6 months differed between the treatment
`groups (P = .02; 6 degrees of freedom; chi-
`squared test), with 39 (83%) of the 47 FDB-treated
`patients in stage A or in remission compared with
`31 patients (54%) in the CAP-treated group and
`27 patients (56%) in the CHOP-treated group.
`Among the five deaths, three occurred in the
`CAP-treated group and two occurred in the
`CHOP-treated group (P = .30; 2 degrees of free-
`dom; log-rank test).
`
`Stage C Chronic Lymphocytic Leukemia
`Remission status at 6 months was not different
`between the three groups (P = .17; 6 degrees of
`freedom; chi-squared test), although slight im-
`provement could be observed in the CAP-treated
`group, with 84% patients exhibiting remission
`(CR or PR) compared with 64% in the FDB-
`treated group and 63% in the CHOP-treated
`group (Table 1). In terms of staging at the 6-
`month follow-up examination, differences were
`no longer observed between the three groups (P
`= .94; 6 degrees of freedom; chi-squared test),
`with 55% of the CAP-treated patients in stage A
`or in remission compared with 50% of patients
`in the FDB-treated group and 43% of patients in
`the CHOP-treated group.
`Among the 14 deaths, five occurred in the
`CAP-treated group, four occurred in the CHOP-
`treated group, and five occurred in the FDB-
`treated group (P = .73; 2 degrees of freedom; log-
`rank test).
`
`DISCUSSION
`In advanced forms of CLL, the efficacy of FDB,
`a fluorinated analog of adenine, recently has been
`claimed,3'4 with reported complete response rates
`ranging from 29% in previously treated CLL cases
`to 75% in previously untreated CLL cases; mild
`toxicity also has been reported. Unfortunately,
`these results were based on uncontrolled studies
`and, thus, no conclusion in terms of superiority
`of FDB could be demonstrated.
`We report the short-term results of a multi-
`center, randomized clinical trial based on 262
`stage B and C CLL patients comparing FDB with
`classically used CAP and CHOP regimens. Our
`results appear surprisingly controversial accord-
`ing to stage, and suggest that FDB is more effec-
`tive than the polychemotherapy regimens con-
`taining anthracycline in stage B while CAP may
`be slightly superior in stage C. This may be ex-
`
`Table 1. Response Status 6-Months Follow-up Examination According to Stage and Randomization
`
`CR
`PR
`SD
`PD
`
`CAP
`
`4 (7)
`37 (65)
`12 (21)
`4 (7)
`
`Stage B (96)
`
`CHOP (cid:9)
`
`5 (11)
`30 (64)
`9 (19)
`3 (6)
`
`P= .08
`
`FOB
`
`9 (19)
`35 (75)
`1 (2)
`2 (4)
`
`CAP
`
`1 (5)
`15 (79)
`2 (11)
`1 (5)
`
`Stage C (%)
`
`CHOP (cid:9)
`
`2 (8)
`13 (54)
`9 (38)
`
`P .17
`
`FOB
`
`3(14)
`11 (50)
`5 (23)
`3 (13)
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`CEPHALON, INC. -- EXHIBIT 2006 0002
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`(cid:9)
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`CAP, CHOP, AND FDB FOR CLL (cid:9)
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`23
`
`plained by the distinct pathophysiology of this
`latter form of the disease.
`However, even if FDB induces a higher re-
`sponse rate in stage B CLL, in agreement with
`previous results from Keating et a1,3A its effect
`on survival is still undetermined. Although cor-
`relation between treatment response and survival
`in CLL has been described, it was not analyzed
`in statistical terms, so that further analysis is war-
`ranted. Moreover, we are now segregating the
`"clinical and hematologic remissions" and the
`"biologic remissions" (defined by bone marrow
`biopsy, blood lymphocyte phenotypes, and im-
`munoglobulin rearrangement). Finally, studies by
`our group and by other investigators have shown
`that, at least in stage B patients, the CHOP reg-
`imen improved response without improving sur-
`vival. Whether this is explained through a selec-
`tion process leading to the appearance of a
`resistant clone remains unclear. Vie hope this
`study is able, in the near future, to answer the
`question of whether FDB could improve survival
`in CLL cases.
`
`APPENDIX
`
`The members of the French Cooperative Group on Chronic
`Lymphocytic Leukemia (protocol CLL 90) include the De-
`partments of Hematology and Physicians from the following
`institutions: CHU de Lilies (P. Fenaux); CHU Pitie-Salpetriere,
`Paris (J-L. Binet and K. Maloum); CHU de Caen (M. Le-
`porrier); CHU de Nantes (M-J. Rapp); Centre Henri Becquerel,
`Rouen (H. Piguet); CHU de Besancon (A. Brion); HOpital
`Mustapha, Alger (N. Boudjerra); Poitiers (B. Dreyfus); HOpital
`Sud, Rennes (R. Leblay); Institut Paoli Calmettes, Marseille
`(A-M. Stoppa); Hospital du Morvan, Brest (J-P. Autrand);
`Hopital Edouard Herriot, Lyon (C. Sebban); CHU Brabois,
`Nancy (J-F. Paitel); Hopital de La Roche-sur-Yon (P. Mai-
`sonneuve); H8pital Lapeyronic, Montpellier (T. Rousset);
`
`Hopital Bretonneau, Tours (M. Linassier); Hopital Saint-
`Louis, Paris (P. Brice); Hotel-Dieu, Clermont-Ferrand (Ph.
`Travade); Hopital Henri-Mondor, Creteil (M. Divine); CHU
`d'Amiens (B. Desablens); HOpital Nord, Saint-Etienne (J.
`Jaubert); HOpital de Meaux (C. Allard); Hopital Saint-Antoine,
`Paris (D. Cheron); Fondation Bergonie, Bordeaux (J-P. Egh-
`bali); Centre Jean Bernard, Le Mans (Ph. Solal Celigny); CHU
`de Limoges (D. Bordessoule); Hopital Robert Debit, Reims
`(B. Pignon); HOpital d'Orleans (G. Vaugier); Hopital Jean
`Verdier, Bondy (F. Lejeune); Hopital de Chalon-sur-Saone
`(B. Salles); Centre Henri Dunan, Corbel! (M. Devidas); Hopital
`de Chambery (M. Blanc); HOpital Jeanne Delanoue, Saumur
`(M. Maigre); Hopital de Vichy (A. Reigner); Hotel-Dieu, Val-
`enciennes (Ph. Simon); Hopital de Bon Secours, Metz (B.
`Christian); CHU de Nimes (J-F. Schved); Hopital Antoine
`&dere, Clamart (P. d'Oiron); Hopital de Blois (M. Rodon);
`Institut Gustave Roussy, Villejuif (P. Carde); Hospital Labo-
`chee, Saint-Brieue (I. Yakoub); Hopital de la Durance, Avig-
`non (P. Souteyrand); Centre Hospitalier de la Cote Basque,
`Bayonnes (M. Renoux); Hopital de Pontoise (J. Facquet-
`Danis); Hotel-Dieu, Nantes (M. Hamidou); Hopital Rene
`Huguenin, Saint-Cloud (F. Turpin); HOpital d'Antibes (J-F.
`Dor); Hopital Saint-Louis, Paris (J-P. Fermand); HOpital Av-
`icenne, Bobigny (N. 'Vigneron); Hopital 8e Cimiez, Nice (A.
`Gamier); HOpital de Saint-Germain en Laye (J.P. Le Loster).
`Statisticians: S. Chevret and C. Chasting, Departement de
`Statistiques et d'Informatique Medicate, Hopital Saint Louis,
`Paris.
`
`REFERENCES
`1. International Workshop on Chronic Lymphocytic Leu-
`kemia: Chronic lymphocytic leukemia: Recommendations for
`diagnosis, staging and response criteria. Ann Intern Med 110:
`236-238, 1989
`2. Binet JL, Auquier A, Dighiero G, et al: A new prognostic
`classification of chronic lymphocytic leukemia derived from
`a multivariate survival analysis. Cancer 48:198-206, 1981
`3. Keating MJ, Kantarjian M, Redman J, et al: Fludarabine:
`A new agent with major activity against chronic lymphocytic
`leukemia. Blood 74:19-25, 1989
`4. Keating MJ: Fludarabine phosphate in the treatment of
`chronic lymphocytic leukemia. Semin Oncol 17:49-62, 1990
`(suppl 8)
`
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