The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. Study No.: SKF-104864-A/201 Title: A Phase III, Open-Label, Multicenter, Randomized, Comparative Study of Topotecan, Ara-C and G-CSF () versus Idarubicin, Ara-C and G-CSF () in MDS Patients with RAEB (High-Risk), RAEB-t or in Patients with AML from a Preceding Phase of MDS Rationale: Recent data from another Phase II study suggests a combination regimen of topotecan plus Ara-C is active in inducing remissions in myelodysplastic syndrome (MDS). Demographics and response rates of subjects from this study were compared with retrospective data collected from MD Anderson trials conducted in the 1980's. The comparison is valid with the assumption that high-risk MDS subjects with refractory anemia with excess blasts (RAEB) and RAEB in transformation (RAEB-t) respond to chemotherapy comparably with acute myelogenous leukemia (AML). It appears that subjects with poor risk chromosomal abnormalities (-5/-7) have a better response rate with topotecan plus Ara-C (80%) than with Ara-C alone (26%). Based on that data, this trial was initiated to compare the efficacy of topotecan plus Ara-C versus idarubicin plus Ara-C in subjects with advanced MDS, and in subjects with AML which evolved from MDS. Phase: III Study Period: 02 December 1998 to 02 July 2001 Study Design: An open-label, multicenter, randomized, comparative study. Subjects were stratified according to initial disease diagnosis. Centres: This study was conducted in 55 sites in 10 countries; Austria, Belgium, Canada (2 sites), France (20 sites), Germany, Italy (4 sites), Norway, Spain, United Kingdom (4 sites), Unites States (20 sites). Indication: Myelodysplastic syndrome (MDS)/ acute myelogenous leukemia (AML) Treatment: (topotecan, Ara-C and granulocyte-colony stimulating factor [G-CSF]): Topotecan at starting dose 1.25 mg/m 2 by continuous 24-hour infusion on Days 1 5. Intravenous Ara-C at 1.0 g/m 2 (within 12-hours of topotecan start ) over 2 hours daily on Days 1 5. G-CSF at 5 mcg/kg/day to all subjects in Course 1 (Day 14 until recovery of counts/ counts stable for three days). In subsequent courses, G-CSF was administered at 5 mcg/kg/day on Day 6. Consolidation therapy was to continue at least two courses beyond a complete remission (CR) at a reduced dose of topotecan (0.625 mg/m 2 ) and Ara-C (500 mg/m 2 ). (idarubicin, Ara-C and G-CSF): Idarubicin at 12 mg/m 2 /day by slow intravenous injection (10 15 minutes) on Days 1 3. Intravenous Ara-C at 1.0 g/m 2 /day over 2 hours on Days 1 5. G-CSF was administered at 5 mcg/kg/day to all subjects in Course 1 (Day 14 until recovery of counts/ counts stable for three days). In subsequent courses, G-CSF was administered at 5 mcg/kg/day on Day 6. Consolidation therapy was to continue at least two courses beyond a CR at a reduced dose of idarubicin (6 mg/m 2 /day) and Ara-C (500 mg/m 2 /day). Objectives: To evaluate the efficacy of when compared to in subjects with MDS, high-risk RAEB, RAEB-t and those with poor risk AML from a preceding phase of MDS. To characterize the toxicity and compare the risk/benefit between the two regimens, versus. Primary Outcome/Efficacy Variable: Complete remission rate (CR) (to be confirmed by an independent pathologist after treatment completed) required all of the following: blood: neutrophil count 1000/ul, platelet count 75 x 10 3 /ul; bone marrow: 5% blasts, normo or hypocellular (>20%). Secondary Outcome/Efficacy Variable(s): The secondary efficacy endpoints were partial remission rate (PR), hematologic improvement rate (HI), durations of CR, PR and HI, survival, transfusion status changes and assessment of symptoms of disease (Functional Assessment of Cancer Therapy- Anemia [FACT-An]). Durations of CR, PR and HI were not assessed as date of response and/or date of progression was not always collected. Statistical Methods: The intent-to-treat population was analyzed for efficacy and safety and included all subjects who were randomized and received at least one dose of study medication. A total of 116 subjects per treatment group would provide 90% power to detect a difference in complete response rates of 76% (the expected rate) and 56% (the expected rate) using a two-sided chi-square test with a 0.050 significance level. CR rates for and were summarized using binomial methodology and compared using Pearson Chi-square statistic. Survival was summarized using Kaplan-Meier method and Cox regression method. In the analysis of transfusions, the proportion of subjects successfully converted to transfusion independence was to be compared between groups. Summary statistics were presented for total FACT-An scores for each course and changes in scores between courses. In addition, the mean subscores for each dimension (fatigue and non-fatigue) were calculated in each course as well as the change in each subscore between courses. Qualitative and quantitative results were summarized for hematologic toxicities relating to white blood cells, neutrophils, platelets and hemoglobin. Qualitative data were summarized by 1
course and by subject and included time to onset and duration of grade 4 toxicities (grade 3 and 4 for anemia). Qualitative assessments of hematologic toxicities included calculation of nadirs, percentage change from baseline and day of occurrence of nadirs. Non-hematologic toxicities were summarized within subject and within course. Study Population: Subjects aged 18 years with a diagnosis of MDS, subcategories of RAEB, INT-2, high risk, or RAEB-t or a diagnosis of AML that had evolved from a preceding phase of MDS defined as the presence of antecedent hematologic disorder existing for at least the prior three months and/or poor prognosis cytogenetics (specifically abnormalities of chromosomes 5 or 7), performance status 2, life expectancy 6 weeks, no prior chemotherapy for this diagnosis of MDS or AML except low dose Ara-C, hydroxyurea, or intrathecal methotrexate or Ara-C,recovery from all toxicities since last chemotherapy and/or biologic therapy unless specific conditions discussed with medical monitor, previous malignancies in CR for one year or greater and screening laboratory parameters within defined criteria,subjects were not to be candidates for curative allogenic bone marrow transplantation without additional treatment and must have a left ventricular ejection fraction (LVEF) of at least 50%. Number of Subjects: Planned, N 120 120 Randomised, N 120 120 Treated, N 119 119 Completed, n (%) 85 (71.4) 68 (57.1) Total Number Subjects Withdrawn, N (%) 34 (28.6) 51 (42.9) Withdrawn due to Adverse Events n (%) 22 (18.5) 34 (28.6) Withdrawn due to Lack of Efficacy n (%) 0 0 Withdrawn for other reasons n (%) 12 (10.1) 17 (14.3) Demographics N (ITT) 119 119 Females (%): Males (%) 48 (40.3):71 (59.7) 47 (39.5):72 (60.5) Mean Age, years (range) 61.9 (20-84) 59.7 (20 81) Caucasian, n (%) 112 (94.1) 116 (97.5) Primary Efficacy Results (ITT population): Complete remission Number of subjects (%) with CR 48 (40.3) 55 (46.2) 95% Confidence Interval (31.25, 49.15) (37.26, 55.18) p-value 0.3598 Secondary Outcome Variable(s): Partial remission (PR) and hematologic improvement (HI) Number of subjects (%) with PR 8 (6.7) 10 (8.4) Number of subjects (%) with HI 10 (8.4) 7 (5.9) Number of subjects (%) with CR, PR or HI 66 (55.5) 72 (60.5) 95% CI for overall response (CR,PR or HI) 51.72, 69.29 46.53, 64.39 Survival Median (weeks) 44.3 43.7 95% CI (34.3, 49.4) (36.1, 57.7) Hazard Ratio (95%C.I.) 1.20 (0.89, 1.63) Transfusion status change (all transfusions) Post Month Improved No Change Worsened Improved No Change Worsened n* n (%) n (%) n (%) n n (%) n (%) n (%) 1 49 40 (88.89) 5 (11.11) 0 47 41 (87.23) 5 (10.64) 1 (2.13) 2 38 31 (81.58) 4 (10.53) 3 (7.89) 39 30 (76.92) 3 (7.69) 6 (15.38) 3 31 18 (58.06) 4 (12.90) 9 (29.03) 30 26 (86.67) 2 (6.67) 2 (6.67) 4 26 11 (42.31) 6 (23.08) 9 (34.62) 25 19 (76.00) 2 (8.00) 4 (16.00) 5 20 12 (60.00) 3 (15.00) 5 (25.00) 22 18 (81.82) 1 (4.55) 3 (13.64) 6 17 12 (70.59) 3 (17.65) 2 (11.76) 20 15 (75.00) 3 (15.00) 2 (10.00) 2
7 15 8 (53.33) 2 (13.33) 5 (33.33) 18 13 (72.22) 2 (11.11) 3 (16.67) 8 10 8 (80.00) 2 (20.00) 0 14 10 (71.43) 2 (14.29) 2 (14.29) 9 10 8 (80.00) 2 (20.00) 0 13 11 (84.62) 1 (7.69) 1 (7.69) * number of subjects with any pre-therapy transfusions that were still in the study at the end of that month and is denominator for percentages at that course Change in FACT-An scores Total scores, mean change (SE) n n Course 1 57 1.63 (1.95) 55 1.36 (2.16) Course 2 33 5.22 (1.86) 36 3.23 (2.05) Course 3 27 4.37 (2.44) 18-0.63 (2.59) Course 4 9 4.16 (4.66) 7 2.06 (5.71) Fatigue sub-scores, mean change (SE) Course 1 57 1.27 (1.62) 55 0.58 (1.70) Course 2 34 4.36 (1.53) 36 1.95 (1.63) Course 3 27 3.68 (1.87) 18-1.15 (2.10) Course 4 9 2.49 (3.30) 7 0.91 (4.75) Non-fatigue sub-scores, mean change (SE) Course 1 57 0.37 (0.46) 55 0.78 (0.63) Course 2 33 0.66 (0.65) 36 1.28 (0.59) Course 3 28 0.56 (0.74) 18 0.52 (0.79) Course 4 9 1.67 (1.72) 7 1.14 (1.18) Safety Results: All AEs/SAEs from randomization until the last clinic visit associated with the study up until 52 days after last administration of drug were included in the summary tables regardless of treatment attribution. Most Frequent Adverse Events On-Therapy n (%) n (%) Subjects with haematological AE(s), n (% of subjects with available laboratory data) Grade 3 leukopenia 8 (6.7) 1 (0.8) Grade 4 leukopenia 109 (91.6) 118 (99.2) Grade 3 neutropenia 8 (6.9) 12 (10.6) Grade 4 neutropenia 103 (88.8) 90 (79.6) Grade 3 thrombocytopenia 3 (2.5) 6 (5.0) Grade 4 thrombocytopenia 116 (97.5) 113 (95.0) Grade 3 anemia 74 (62.2) 66 (55.5) Grade 4 anemia 20 (16.8) 13 (10.9) Number (%) of Subjects and Courses with Febrile Neutropenia and Associated Adverse Events Fever Grade 2 including Febrile Neutropenia* 29 (24.4) 23 (19.3) Fever Grade 2 with Grade 4 Neutropenia* 21 (17.6) 15 (12.6) Infection Grade 2** 39 (32.8) 48 (40.3) Infection Grade 2 With Grade 4 Neutropenia** 28 (23.5) 37 (31.1) Sepsis 39 (32.8) 41 (34.5) * Excludes infection or sepsis, ** Excludes sepsis Subjects with non-haematological AE(s), n (%) 119 (100.0) 119 (100.0) Fever 81 (68.1) 83 (69.7) Diarrhea 69 (58.0) 60 (50.4) Nausea 63 (52.9) 63 (52.9) Constipation 45 (37.8) 40 (33.6) Hypokalemia 45 (37.8) 42 (35.3) Sepsis 39 (32.8) 41 (34.5) Vomiting 35 (29.4) 45 (37.8) Abdominal pain 30 (25.2) 46 (38.7) Insomnia 30 (25.2) 27 (22.7) Purpura 30 (25.2) 27 (22.7) Respiratory disorder 22 (18.5) 36 (30.3) 3
Headache 25 (21.0) 31 (26.1) Serious Adverse Events - On-Therapy n (%) [n considered by the investigator to be related to study medication] n (%) [related] n (%) [related] Subjects with any SAEs, n (%) 67 (56.3)[35] 72 (60.5)[44] includes both fatal and non-fatal SAEs Sepsis 19 (16.0) [11] 19 (16.0) [11] Fever 17 (14.3) [11] 13 (10.9) [8] Granulocytopenia 10 (8.4) [8] 8 (6.7) [5] Febrile neutropenia 9 (7.6) [6] 7 (5.9) [7] Dyspnea 5 (4.2) [0] 2 (1.7) [1] Marrow depression 5 (4.2) [5] 4 (3.4) [3] Infection 4 (3.4) [1] 2 (1.7) [0] Pancytopenia 4 (3.4) [2] 4 (3.4) [4] Pleural effusion 4 (3.4) [0] 0 Pneumonia 4 (3.4) [2] 7 (5.9) [1] Respiratory disorder 4 (3.4) [1] 12 (10.1) [9] Thrombocytopenia 4 (3.4) [3] 5 (4.2) [5] Coagulation disorder 3 (2.5) [1] 0 Aplasia bone marrow 2 (1.7) [2] 1 (0.8) [1] Cardiac arrest 2 (1.7) [0] 1 (0.8) [0] Cerebrovascular disorder 2 (1.7) [0] 0 Diarrhea 2 (1.7) [1] 2 (1.7) [1] Epistaxis 2 (1.7) [0] 1 (0.8) [1] Gastrointestinal hemorrhage 2 (1.7) [2] 2 (1.7) [1] Hepatic function abnormal 2 (1.7) [2] 1 (0.8) [0] Melena 2 (1.7) [1] 1 (0.8) [1] Respiratory insufficiency 2 (1.7) [0] 7 (5.9) [1] Thrombophlebitis 2 (1.7) [0] 1 (0.8) [0] Abdominal pain 1 (0.8) [1] 0 Arthrosis 1 (0.8) [0] 0 Asthma 1 (0.8) [0] 0 Carcinoma 1 (0.8) [1] 0 Cardiac failure 1 (0.8) [0] 1 (0.8) [1] Cellulitis 1 (0.8) [1] 1 (0.8) [0] Cerebral hemorrhage 1 (0.8) [0] 1 (0.8) [0] Chest pain 1 (0.8) [0] 0 Confusion 1 (0.8) [1] 0 Fibrillation atrial 1 (0.8) [0] 3 (2.5) [1] Folliculitis 1 (0.8) [0] 0 Hematemesis 1 (0.8) [0] 0 Hemoptysis 1 (0.8) [0] 2 (1.7) [2] Hemorrhage, not otherwise specified 1 (0.8) [1] 1 (0.8) [0] Hypertension 1 (0.8) [0] 0 Hypokinesia 1 (0.8) [0] 0 Hypotension 1 (0.8) [0] 1 (0.8) [0] Hypovolemia 1 (0.8) [0] 0 Infection fungal 1 (0.8) [0] 4 (3.4) [0] Injection site inflammation 1 (0.8) [1] 0 Intestinal obstruction 1 (0.8) [0] 1 (0.8) [0] Leukocytosis 1 (0.8) [0] 0 Lymphadenopathy 1 (0.8) [0] 0 Moniliasis 1 (0.8) [0] 1 (0.8) [0] 4
Mucositis, not otherwise specified 1 (0.8) [1] 0 Paresthesia 1 (0.8) [0] 0 Pulmonary carcinoma 1 (0.8) [0] 0 Pulmonary hemorrhage 1 (0.8) [0] 2 (1.7) [0] Rigors 1 (0.8) [0] 0 Sarcoma 1 (0.8) [0] 0 Skeletal pain 1 (0.8) [0] 1 (0.8) [0] Therapeutic response increased 1 (0.8) [0] 1 (0.8) [0] Thrombosis pulmonary 1 (0.8) [0] 0 Nausea 0 2 (1.7) [1] Renal failure acute 0 2 (1.7) [1] Vomiting 0 2 (1.7) [1] Anaphylactic shock 0 1 (0.8) [0] Anemia 0 1 (0.8) [1] Angina pectoris 0 1 (0.8) [0] Angina pectoris aggravated 0 1 (0.8) [1] Arrhythmia 0 1 (0.8) [0] Bladder carcinoma 0 1 (0.8) [0] Circulatory failure 0 1 (0.8) [0] Colitis 0 1 (0.8) [0] Death, not otherwise specified 0 1 (0.8) [1] Dermatitis fungal 0 1 (0.8) [0] Enteritis 0 1 (0.8) [0] Fluid overload 0 1 (0.8) [0] Hematuria 0 1 (0.8) [0] Hypocalcemia 0 1 (0.8) [0] Infection bacterial 0 1 (0.8) [1] Myocardial ischemia 0 1 (0.8) [1] Pharyngitis 0 1 (0.8) [1] Pneumothorax 0 1 (0.8) [0] Pulmonary edema 0 1 (0.8) [1] Rash erythematous 0 1 (0.8) [1] Rash maculo-papular 0 1 (0.8) [0] Renal function abnormal 0 1 (0.8) [0] Renal pain 0 1 (0.8) [0] Respiratory depression 0 1 (0.8) [0] Syncope 0 1 (0.8) [0] Tachycardia ventricular 0 1 (0.8) [0] Thinking abnormal 0 1 (0.8) [0] Thrombosis 0 1 (0.8) [0] Urinary tract infection 0 1 (0.8) [0] n (%) [related] n (%) [related] Subjects with fatal SAEs, n (%) 8 (6.7) [4] 8 (6.7) [2] Hematological toxicity 5 (4.2) [3] 2 (1.7) [0] Non-hematological toxicity 3 (2.5) [1] 6 (5.0) [2] Other 6 (5.0) [1] 6 (5.0) [2} Pulmonary hemorrhage 1 (0.8) [0] Acute respiratory distress/failure 2 (1.7) [0] Cardiopulmonary failure 1 (0.8) [0] Infection due to aplasia 1 (0.8) [1] Severe pneumonia 1 (0.8) [0] Respiratory failure 1 (0.8) [0] Aplasia, fungal orbital cellulitis 1 (0.8) [0] Septic shock 1 (0.8) [0] Acute respiratory distress, aspergillosis 1 (0.8) [1] 5
Sepsis, multiple organ failure 1 (0.8) [0] Unknown cause 1 (0.8) [1] Conclusion: See publication below. Publications: Guilhot, F, Bouabdallah, R, Desablens, B, Guerci, A, Ferrant, A, Chopra, R., Amrein, P., Saba, H.,Dharan, B,,Gress, M.,Camlett, I. and Ross, G.: Topotecan, Cytosine arabinoside and G-CSF () versus Idarubicin, Cytosine arabinoside and G-CSF () in Patients with Myelodysplastic Syndrome (MDS) or MDS in Transformation. Blood 100: 98a, 2002 (abstr.). Date Updated: 13-Apr-2005 6