Bernd Kasper 1, Viktor Grünwald 2, Peter Reichardt 3, Sebastian Bauer 4, Florian Haller 5, Peter Hohenberger 1

Transcription

1 Clinical and translational research results of a phase II study evaluating imatinib to induce progression arrest in RECIST progressive desmoid tumors - a study of the German Interdisciplinary Sarcoma Group (GISG-01) Bernd Kasper 1, Viktor Grünwald 2, Peter Reichardt 3, Sebastian Bauer 4, Florian Haller 5, Peter Hohenberger 1 1 University of Heidelberg, Mannheim University Medical Center, Interdisciplinary Tumor Center Mannheim, Sarcoma Unit, Mannheim; 2 Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover; 3 HELIOS Klinikum Berlin-Buch, Sarcoma Center Berlin-Brandenburg, Berlin; 4 Sarcoma Center, West German Cancer Center, Essen; 5 University of Erlangen-Nuremberg, Institute of Pathology, Erlangen, Germany.

2 Background GISG-01 Desmoid tumors describe a rare monoclonal, fibroblastic proliferation characterized by a variable and often unpredictable clinical course. The incidence is < 3 % of all STS with a peak age around 30 years. There is no evidence-based therapy approach available as of today. Kasper B et Name al. Oncologist I Folie 1 I 2011; Datum 16:

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4 Study Rationale GISG-01 Initial data demonstrated a response in two patients with extraabdominal aggressive fibromatosis treated with imatinib 800 mg daily. 1 US study with 19 desmoid tumor patients treated with 800 mg imatinib daily 2 : - 3 PR and 4 SD (response rate = 16 %) - No mutations of KIT, PDGFRA or PDGFRB were found FSG presented a phase II study in 35 patients with 400 mg imatinib daily 3 : - 1 CR, 3 PR and 28 SD (response rate = 11 %) - Non-progression rates at 3, 6 and 12 months were 91 %, 80 % and 67 % - 2-years PFS and OS were 55 % and 95 % 1 Mace J et al. Cancer 2002; 95: Heinrich MC et al. J Clin Oncol 2006; 24: Penel N et al. Name Ann Oncol I Folie 2011; 1 I Datum 22:

5 Study Endpoints GISG-01 Primary endpoint: Non-progression rate after 6 months of treatment Secondary endpoints: Non-progression rate after 12 and 24 months of treatment Response rate (CR, PR, SD > 12 weeks) Progression-free survival (PFS) and overall survival (OS) Tolerability of the treatment and toxic effects Recording of patient quality of life at study baseline and end of study Statistical analysis: Simon 2-step design with an interim analysis at 17/37 patients Name I Folie 1 I Datum

6 Inclusion Criteria GISG-01 Patients with histological confirmed aggressive fibromatosis (desmoid tumor) Measurable disease according to RECIST 1.0 Evidence of relapse or disease progression within the last 6 months (based on RECIST 1.0) in computed tomography or magnetic resonance imaging No possibility of complete surgical resection or cases in which surgical therapy leaving a large tissue defect, functional deficit or disfigurement would be required No possibility of curative radiotherapy with acceptable toxicity and/or late morbidity Previous treatment of the tumor region by surgical intervention and/or radiotherapy and/or antihormonal therapy possible Age 18 years WHO PS 1 Effective contraception during study medication Signed informed consent form Name I Folie 1 I Datum

7 Exclusion Criteria GISG-01 Surgical intervention < 4 weeks Prior therapy with imatinib Pregnancy or lactation Severe hepatic dysfunction Known allergic reaction to imatinib or one of its components The following laboratory values: Absolute neutrophil count < 1.5 x 10 3 /mm 3 Platelets < /mm 3 Serum creatinine 2.5 mg/dl SGOT and/or SGPT > 2.5 x ULN (upper limit of normal) Total bilirubin > 1.5 x ULN Participation in another study (four weeks before and during the study) Prior malignancy apart from completely resected basal cell carcinoma of the skin or carcinoma in situ of the uterine cervix Name I Folie 1 I Datum

8 Treatment / TR GISG-01 Treatment: Imatinib 2 x 400 mg daily (start with 400 mg for up to 4 weeks; if well tolerated - escalation to 800 mg daily) Amendment: Nilotinib 2 x 400 mg, if PD or intolerance under therapy with imatinib (n = 9) Translational Research: Analysis of mutations in the beta-catenin gene CTNNB1 and correlation with patients progression-free survival Name I Folie 1 I Datum

9 Study Status GISG patients recruited between 7/2010-9/2013 in the following centers: Berlin n = 8 Essen n = 3 Hannover n = 9 Mannheim n = evaluable patients Final analysis for the primary endpoint was presented at ESMO Final analysis after two years of imatinib therapy is expected in Name I Folie 1 I Datum

10 Patients Characteristics GISG-01 (n = 37) Median age 40 years (range: 19-80) Gender (female/male) 26/11 70 % ECOG (0/1) 33/4 89 % Prior surgery (yes/no) 32/5 87 % R0 resection (yes/no) 4/27 13 % Prior radiotherapy (yes/no) 9/28 24 % Prior systemic therapy (yes/no) 11/26 30 % Site of primary tumor: Extremity % Chest 5 13 % Head & neck 1 3 % Abdomen 6 17 % Other 5 13 % Kasper B et al. Name Ann Oncol I Folie 2014: 1 I Datum 25 (suppl 4): iv494

11 Analysis Primary Endpoint GISG-01 Primary endpoint: Non-progression rate after 6 months of treatment Final analysis for the primary endpoint (9/2014): Positive study, if 11/37 patients are progression-free at 6 months 24 out of 37 patients had at least stable disease Response: 1 PR (3 %) and 23 SD (62 %) 13 non-successors : 10 PD, 1 toxicity, 2 withdrawals With a progression arrest rate of 65 % imatinib clearly exceeded the primary endpoint. Kasper B et al. Name Ann Oncol I Folie 2014: 1 I Datum 25 (suppl 4): iv494

12 Prospective Trials with Imatinib (n = 140) n Inclusion criteria Treatment dose [mg] Treatment duration Response rate [%] 6-month- PFS [%] 12-month- PFS [%] Heinrich et al. J Clin Oncol No PD required heavily pretreated patients days Penel et al. Ann Oncol No RECIST PD radiological evidence for PD year Chugh et al. Clin Cancer Res No PD required locally advanced disease BSA adjusted until PD 9 pts. > 3 years Kasper et al. Ann Oncol RECIST PD required years 3 65 n.e. Kasper B et al. Name Ann Oncol I Folie 2014: 1 I Datum 25 (suppl 4): iv494

13 TR Rationale GISG-01 Mutations in the CTNNB1 gene have been identified as molecular key events in the majority (~ 80 %) of sporadic desmoid tumors. Mutation frequencies are located at two specific amino acid positions: threonine 41 (T41, %) and serine 45 (S45, %). 1 Several studies reported on a more aggressive clinical course in desmoid tumors with the specific S45F mutation. 2,3,4 The aim of the current study was to analyze the CTNNB1 mutation status in the prospective trial evaluating imatinib in desmoid tumor patients. 1 Le Guellec S et al. Mol Pathol 2012; 25: Lazar AJ et al. Am J Pathol 2008; 173: Colombo C et al. Cancer 2013; 119: Name I Folie 1 I Datum Van Broekhoven DL et al. Ann Surg Oncol 2015; 22:

14 TR Methods GISG patients were evaluable for the primary endpoint. 33 (97 %) were successfully analyzed for CTNNB1 mutation status using Sanger sequencing. First prospective clinical trial reporting on the impact of CTNNB1 mutation status for the clinical course in desmoid tumor patients. Patients with mutations at position S45 were overrepresented in this trial recruiting RECIST progressive patients only, corresponding to their reported more aggressive clinical course. More details on TR data will be presented at the upcoming CTOS. Name I Folie 1 I Datum

15 Take-home-messages Prospective studies in this rare entity are feasible: 4 studies with n = 140 GISG-01 study is positive and met its primary endpoint. Imatinib is active with a progression arrest of 65 % at 6 months in the small subgroup of RECIST progressive patients. Selling points of the GISG study compared to previous trials: Inclusion of patients with RECIST progressive disease only Long treatment duration of 2 years Data on Translational Research results to be presented at CTOS. Name I Folie 1 I Datum

16 Discussion and Questions