Cationic liposomal paclitaxel in combination with gemcitabine in

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					                                                         Cationic liposomal paclitaxel in combination with gemcitabine in patients with unresectable
                                                                         pancreatic cancer: a randomized controlled Phase II trial
                                                                         Matthias Löhr1,2, Ullrich Graeven3, György Bodoky4, Angela Märten5, Carmen Lilla6, Ines Meyer6, Dmitry Osinsky7, Karel Cwiertka8, Ulrich Fölsch9, Manfred P. Lutz10
      Dept. of Internal Medicine, University Hospital Mannheim / Molecular Gastroenterology DKFZ Heidelberg, Germany; 2Gastrocentrum, Karolinska Institutet, Stockholm, Sweden; 3Hospital Maria-Hilf/St. Franziskus, Mönchengladbach, Germany; 4Szent Laszlo Hospital,
   1II.

                                                                                                                            Budapest, Hungary;
     5National Cancer for Tumor Diseases, University Hospital Heidelberg, Germany; 6Clinical Research & Development, MediGene AG, Martinsried, Germany; 7Institute of Oncology AMS of Ukraine, Kiev, Ukraine; 8University Hospital Olomouc, Olomouc, Czech Republic
                                                                                      9University Hospital Schleswig-Holstein, Kiel, Germany; 10Caritas Hospital Saarbrücken, Germany




Background:                                                                                                          Results - Efficacy:                                                                                                                                                                               Summary:
• Treatment options for advanced pancreatic cancer are still unsatisfactory
                                                                                                                                                                                                                                                                                                                       Study population:
• EndoTAGTM-1 is a novel formulation of cationic liposomes carrying paclitaxel embedded in the
  liposome membrane (Fig. 1)
                                                                                                                                                                                                                            %
                                                                                                                                                                                                                                100                                                                                    • Demographics were comparable across treatment groups (Table 1)

• Cationic liposomes bind and internalize at tumor endothelial cells after intravenous administration                                                                                                                                                                                                                  • 80% of patients had metastatic disease at enrollment (Table 1)
                                                                                                                                                                                                                                 90
• EndoTAGTM-1 specifically displays antivascular and antiangiogenic activity
                                                                                                                                                                                                                                                                                                       80%             • 28 patients received repeated cycles of EndoTAGTM-1 combination
                                                                                                                                                                                                                                 80                                                72%                                 treatment (up
                                                                                                       Figure 1.                                                                                                                                                67%
                                                                                                                                                                       Adjusted hazard ratios (95% CI)
                                                                                                                                                                                                                                 70                                                                                      to 8 cycles)
                                                                                                       EndoTAGTM-1                                                     GEM                                                                  63%
                                                                                                                                                                       GEM + Endo 11         1.02 [0.65,
                                                                                                                                                                                                                                 60                                                                                    Efficacy:
 Methods:                                                                                                                                                              1.59]
                                                                                                                                                                       GEM + Endo 22         0.72 [0.46,

 • Patient Population:unresectable, locally advanced or metastatic pancreatic cancer (PC); N=200
                                                                                                                                                                       1.13]                                                     50                                                                                    • Prolongation of overall survival in EndoTAGTM-1 treatment groups
                                                                                                                                                                       GEM + Endo 44         0.67 [0.43,
                                                                                                                                                                                                                                                                                                                       compared to
                                                                                                                                                                       1.07]
                                                                                                                                                                                                                                 40                                                       36%
                                                                                                                                                                                                                                                                                                             32%
 • Open-label phase II study of first line combination treatment with weekly gemcitabine (G) (arm 1: G                                                                                                                                                                                                                   GEM mono group (Fig. 3)
 mono 1000 mg/m²) and twice weekly EndoTAGTM-1 at 3 different dose levels (arms 2/3/4: 11/22/44                                                                                                                                  30                                   22%                                              • Higher 6 and 12 month survival rates in EndoTAGTM-1 treatment groups
 mg/m²).                                                                                                                                                                                                                                          17%
                                                                                                                                                                                                                                 20                                                                                    (Fig. 4)
 • Treatment duration: 7 weeks                                                                                                                                                                                                                                                                                         • Higher rate of tumor stabilization (Table 2) and prolongation of PFS (data
                                                                                                                                                                                                                                 10
                                                                                                                                                                                                                                                                                                                       not
                                                  R
                                                                   Gemcitabine (1000 mg/m2) weekly     N = 50                                                                                                                      0                                                                                     shown) in EndoTAGTM-1 treatment groups
                                                  A                                                                                                                                                                                              GEM           GEM+Endo 11        GEM+Endo 22         GEM+Endo 44
                                                  N                                                                                                                                                                                                                                                                    Safety:
                                                  D                11 mg/m2 EndoTAGTM-1 twice                                                                                                                                                      6-Month survival rate 12-Month survival rate
                                                  O
                                                                   weekly                              N = 50                                                                                                                                                                                                          • Marginal additive adverse reactions compared to GEM monotherapy




                                                                                                                                                                                                                                                                                                                                                                                                                             DOI: 10.3252/pso.eu.11wgic.2009
                                                  M
              Locally advanced                    IZ               + GEM (1000 mg/m2) weekly                                                                                                                                      Figure 4. 6 and 12 month survival rates                                              • Dose-dependent, manageable infusion-related reactions (grade 1/2 chills
                                                                                                                      Figure 3. Kaplan-Meier plots for overall survival (OS)
              or metastatic                       A                                                                                                                                                                                                                                                                    and
              pancreatic cancer                   TI                                                                                                                                                                                                                                                                     pyrexia) and transient thrombocytopenia (Table 3)
                                                  O                22 mg/m2 EndoTAGTM-1 twice weekly
                                                                                                     N = 50                                                                                                            Results - Safety:
                                                  N                + GEM (1000 mg/m 2) weekly                                                                                                                                                                                                                          • No evidence for clinically relevant organ toxicity or neurotoxicity

                                                                                                                                          GEM       GEM+EndoTAGTM-1    GEM+EndoTAGTM-1        GEM+EndoTAGTM-1
                                                                                                                                                                                                                                                                                                                       • No deaths possibly or probably related to study medication
                                                                                                                                          mono         11 mg/m²           22 mg/m²               44 mg/m²                                            GEM         GEM+EndoTAGTM-1 GEM+EndoTAGTM-1 GEM+EndoTAGTM-1
                                                                                                                                                                                                                                                    mono             11 mg/m²       22 mg/m²        44 mg/m²
                                                                                                                                                                                                                                                                                                                       • No indication for cumulative toxicity of EndoTAGTM-1 in combination with
                                                                   44 mg/m2 EndoTAGTM-1 twice weekly                                     (n=50)         (n=50)             (n=50)                 (n=50)
                                                                                                     N = 50                                                                                                                                         (n=50)            (n=50)          (n=50)          (n=50)           GEM
                                                                   + GEM (1000 mg/m 2) weekly
                                                                                                                     Evaluable for      37 (100%)      37 (100%)            37 (100%)              31 (100%)                                                                                                             after repeated treatment cycles
                                                                                                                     tumor response*                                                                                   Any AE, N (%)               46 (92.0)          49 (98.0)           48 (96.0)       50 (100.0)

                 Treatment for 7 weeks (=1 cycle)                                                                   Complete              0               0                    0                      0               Number (%) of patients with AEs:
                 Repeated treatment cycles in case of clinical benefit possible after                               response
                  amendment (Jan. 2007) for patients in EndoTAGTM-1 groups                                                                                                                                                              Chills      4 (8.0)           11 (22.0)           18 (36.0)       26 (52.0)    Conclusion:
                                                                                                                     Partial response   5 (13.5%)      5 (13.5%)            5 (13.5%)               5 (16%)
                                                                                                                                                                                                                                       Pyrexia     8 (16.0)           12 (24.0)           17 (34.0)       23 (46.0)    • EndoTAGTM-1 combination therapy demonstrated a clinically relevant
          Figure 2. Study design                                                                                     Stable disease     11 (30%)        17 (46%)             19 (51%)             11 (35.5%)
                                                                                                                                                                                                                                  Neutropenia      17 (34.0)          12 (24.0)           12 (24.0)       23 (46.0)    survival
                                                                                                                     Non-progressive    16 (43%)       22 (59.5%)            24 (65%)              16 (52%)                  Thrombocytopenia      7 (14.0)           9 (18.0)            14 (28.0)       22 (44.0)      benefit in patients with advanced pancreatic cancer
                                                                                                                     disease
 Study population:                                                                                                   Progressive        21 (57%)       15 (40.5%)            13 (35%)              15 (48%)
                                                                                                                                                                                                                                   Leukopenia      9 (18.0)           8 (16.0)            9 (18.0)        12 (24.0)
                                                                                                                                                                                                                                                                                                                       • Favorable safety profile and positive benefit-risk ratio of EndoTAGTM-1 in
                                                                                                                     disease                                                                                                           Anemia      11 (22.0)          6 (12.0)            8 (16.0)        20 (40.0)
 • 200 patients were randomized. Demographics and baseline characteristics are shown in Table 1.                                                                                                                                                                                                                         combination with gemcitabine




                                                                                                                                                                                                                                                                                                                                                                                                      Pancreatic Cancer
                                                                                                                     Table 2. Tumor response according to RECIST after 1st treatment                                       Table 3. Relevant Adverse Events                                                            • Positive data from phase II clinical trial strongly supports further
                                      GEM          GEM+EndoTAGTM-1 GEM+EndoTAGTM-1 GEM+EndoTAGTM-1                   cycle
                                                                                                                                                                                                                                                                                                                       development of




                                                                                                                                                                                                                                                                                                                                                                                                                          Matthias Lhr
                                      mono            11 mg/m²        22 mg/m²        44 mg/m²
                                                                                                                     Acknowledgements:                                                        CT4001 study group                                                                                                         EndoTAGTM-1 in advanced pancreatic cancer
                                     (n=50)            (n=50)          (n=50)          (n=50)
                                                                                                                                                           •Charles University, Prague, Czech Rep.
                                                                                                                                                                                                                           •Schwarzwald- Baar Hospital, Villingen-Schwenningen, Germany
             Median age (range)                                                                                                                            •Hospital Ceske Budejovice, Ceske Budejovice, Czech Rep.
                                                                                                                                                                                                                           •Reinhard-Nieter Clinic, Wilhelmshaven, Germany
                                   59.5 (34-80)        63.0 (32-75)      61.0 (44-72)   62.5 (33-81)                                                       •Fakultni nemocnice v Motole, Prague, Czech Rep.
                                                                                                                                                                                                                           •St. Josef Hospital, Bochum, Germany
                                                                                                                                                           •Hospital Pardubice, Pardubice, Czech Rep.
                                                                                                                                                                                                                           •Martin Luther University Hospital, Halle, Germany
                                                                                                                                                           •University Hospital Kralovske Vinohrady, Prague, Czech Rep.
             Male patients          32 (64%)            34 (68%)          32 (64%)       33 (66%)                                                          •Krajska nemocnice Liberec, Liberec, Czech Rep.
                                                                                                                                                                                                                           •University Hospital Essen, Essen, Germany
                                                                                                                                                                                                                           •University Hospital Saarland, Homburg/Saar, Germany
                                                                                                                                                           •Fakultni nemocnice Olomouc, Olomouc, Czech Rep.
              ECOG at baseline                                                                                                                                                                                             •Institute of Oncology AMS of Ukraine, Kiev, Ukraine
                                                                                                                                                           •Oddeleni klinicke a radiacni onkologie, Brno, Czech Rep.
                                                                                                                                                                                                                           •Kiev City Oncology Hospital, Kiev, Ukraine
               Grade 0               20 (40%)           22 (44%)          20 (40%)       18 (36%)                                                          •University Hospital Mannheim, Mannheim, Germany
                                                                                                                                                                                                                           •Donetsk Oncology Center, Donetsk, Ukraine
                                                                                                                                                           •Klinikum rechts der Isar, Munich, Germany
               Grade 1               26 (52%)           22 (44%)          20 (40%)       23 (46%)                                                          •Klinikum Aschaffenburg, Aschaffenburg, Germany
                                                                                                                                                                                                                           •Lugansk Oncology Center, Lugansk, Ukraine
               Grade 2                4 ( 8%)            6 (12%)1         10 (20%)1       9 (18%)1                                                                                                                         •University Hospital Frankfurt/Main, Germany
                                                                                                                                                           •Helios Kliniken Wuppertal, Wuppertal, Germany
                                                                                                                                                                                                                           •Medical University of Debrecen, Debrecen, Hungary
                                                                                                                                                           •University Hospital Schleswig-Holstein, Kiel, Germany
                                                                                                                                                                                                                           •MAV Hospital, Budapest, Hungary
             Current TNM staging                                                                                                                           •Hospital Maria-Hilf/St. Franziskus, Mönchengladbach, Germany
                                                                                                                                                                                                                           •Medical University of Szeged, Szeged, Hungary




                                                                                                                                                                                                                                                                                                                                                                                                              7-O
                                                                                                                                                           •Caritas Clinic St. Theresia, Saarbrücken, Germany
               Locally advanced     12 (24%)            8 (16%)           11 (22%)       12 (24%)                                                          •National Center for Tumor Diseases, Heidelberg, Germany
                                                                                                                                                                                                                           •Szent Laszlo Hospital, Budapest, Hungary
               Metastatic           38 (76%)            42 (84%)          39 (78%)       38 (76%)
             Table 1. Demographics and baseline characteristics of the study population (N=200)                                                                                                                                                                                                                                                         Abstract O-0007                                    11wgic
                                                                                                                                                                                                                                                                                                                                               Date: June 24, 2009 Time: 4:45 PM

				
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