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Update on clinical studies in Belgium Jacques De Grève MD, PhD Medical Oncology Oncologisch Centrum.

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Presentation on theme: "Update on clinical studies in Belgium Jacques De Grève MD, PhD Medical Oncology Oncologisch Centrum."— Presentation transcript:

1 Update on clinical studies in Belgium Jacques De Grève MD, PhD Medical Oncology Oncologisch Centrum

2 Observations Some academic, many “commercial” Profile similar between large community hospitals and academic hospitals, except for initiating translational studies Phase I-III and post-marketing  The latter are often (masked) drug-pushing studies Some increasing cross-center cooperation  Which is very good Very little non-drug research activity  Surgical or radiotherapy

3 Caution Confidential Biased overview  Information requested from 25 sources  Information obtained from 12 investigators/centers

4 Overview Prevention Surgical Neoadjuvant Adjuvant  Hormonal  HER2 positive  Chemotherapy  Molecular Metastatic  Hormonal  HER2 positive  Chemotherapy  Molecular

5 Prevention IBIS studies:  Role of AI in BC prevention in high risk profiles  Some scientific value, but impact on clinical practice improbable because of anticipated Financial+toxicity cost Efficacy = ASTRONOMICAL

6 Familial breast cancer Search for novel breast cancer predisposing genes Better method for counseling BARD 1 >1 J. De Grève et al, Current Opinion in Oncology, 11, 2008 UZBrussel

7 Copyright ©2004 BMJ Publishing Group Ltd. Sermijn, E et al. J Med Genet 2004;41:e23 Awareness of the existence of a BRCA mutation in the subject's own family Families ill-informed

8 Half of all pre-symptomatic mutation carriers do not engage in cancer prevention Screening 50% BSO (all) 57.2% PM (No BC) 18% Chemoprevention (No mastectomy) 8.4% No action (No BC) 50% Half of mutation carriers do nothing

9 Prospective study Organized an active information of relevant family members on existence of mutation and subsequent prevention Efficacy and psychological impact E.Sermijn/M. Goossens, UZBrussel

10 SURGERY

11 Surgery Pedicled Perforator Flaps Since 1989, major advance for reconstructive surgery Only skin and subcutaneous tissue is utilized for reconstruction of defects with preservation of fascia, muscles and nerves according to basic plastic surgical principle of ” replacing like with like “ Muscle left in its native place to serve its original function and minimize donor site morbidity

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13 Thoracodorsal artery perforator (TDAP) flap Second generation perforator flaps  Hamdi M, et al. Pedicled perforator flaps in breast reconstruction: a new concept. Br. J. Plast. Surg Sep; 57(6): Other  Thoracodorsal artery perforator (TDAP) flap  Intercostal artery perforator (ICAP) flap  Serratus anterior artery perforator (SAAP) flap  Superior epigastric artery perforator (SEAP) flap BJMO review (coming) UGent

14 Indications Immediate or delayed partial breast reconstruction following tumorectomy/ quadrantectomy Post-mastectomy breast reconstruction in combination with an implant Reconstruction of shoulder and thoracic defects after oncological resections Should replace the classical latissimus dorsi flap in many indications in breast surgery

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19 Satisfied women

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22 Adjuvant radiotherapy EORTC SUPREMO Phase III randomized trial Role of adjuvant chest wall irradiation in “intermediate risk” breast cancer following mastectomy D. Vanden Wyngaert, ZNA

23 Neoadjuvant

24 Aout 2008 FRAGRANCE TRIAL Postmenopausal patients (no age limits) Non-candidates for CT T  2 cm Stages I, II & III ER and/or PgR+ Letrozole 4 to 6 months SURGERYSURGERYSURGERYSURGERY Frozen Biopsy 1 D15D0 Frozen Biopsy 2 (optional) Frozen Biopsy 3 F. Cardoso Lab: M. Gloeckel, C. Desmedt, V. Durbecq, C. Sotiriou Biomarkers for response to AI

25 RANDOMIZERANDOMIZE NEO-ALTTO Stratification: —T 5 cm —ER or PgR + versus both ER and PgR – —N0-1 versus N ≥2 —Conservative surgery or not lapatinib trastuzumab lapatinib trastuzumab paclitaxel SurgerySurgery FEC  3 lapatinib trastuzumab lapatinib trastuzumab 18 weeks9 weeks34 weeks 52 weeks of anti-ErbB2 therapy Invasive breast cancer HER2+ T>2 cm (inflammatory BC excluded) LVEF  50% N=450 Biomarkers for response

26 Adjuvant

27 Adjuvant studies SOLE IBCSG / BIG 1-07 Postmenopausal women with HR positive, N+ early stage breast cancer Phase III trial of continuous letrozole versus intermittent letrozole following 4 to 6 years of prior adjuvant endocrine therapy N=4600 Guy Jerusalem, Liège

28 Rationale ER+ cancers relapse continuously Extended adjuvant results Adjuvant tamoxifen: 10 years is better than 5 years AI reimbursed for 5 years or extended adjuvant

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30 N+

31 Hormonal adjuvant EORTC 10031(SOFT) Premenopausal  35y Tamoxifen vs OFS + tamoxifen vs OFS + exemestane

32 Adjuvant studies ALTTO Lapatinib dual EGFR/HER2 neu inhibitor  EGFR effect irrelevant in BC  Good drug after H failure, especially with BM’s A randomised phase III comparison  Adjuvant lapatinib, trastuzumab, their sequence and their combination in patients with HER2/ErbB2 positive primary breast cancer Open Q how efficacies versus toxicities will differ BIG 2-06/N063D/DGF106708

33 Patients with ER or PgR-positive tumours receive endocrine therapy selected accordingly to menopausal status; endocrine therapy will be started after the end of chemotherapy, will be administered concurrently with targeted therapies and will be planned for at least 5 yearsPatients with ER or PgR-positive tumours receive endocrine therapy selected accordingly to menopausal status; endocrine therapy will be started after the end of chemotherapy, will be administered concurrently with targeted therapies and will be planned for at least 5 years Radiotherapy if indicated Radiotherapy if indicated DESIGN 1: Completion of ALL (neo)adjuvant chemotherapy prior to targeted therapy Trastuzumab3-weekly (For 52 weeks) Lapatinib TrastuzumabWeekly (For 12 weeks) Lapatinib 3-weekly 3-weekly+Trastuzumab (For 52 weeks) Centrally-determined HER2 + Surgery, complete (neo)adjuvant anthracycline-based chemotherapy (selected from an approved list) LVEF  50% Locally-determined HER2-positive invasive breast cancer Washout (6 weeks) Lapatinib (34 weeks) ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization) study

34 Locally-determined HER2-positive invasive breast cancer Centrally-determined HER2 + Surgery, complete (neo)adjuvant chemotherapy (selected from an approved list) (selected from an approved list) LVEF  50% 52 W EE KS Lapatinib+ Trastuzumab 3-weekly 40 weeks Lapatinib+TrastuzumabWeekly 12 weeks TrastuzumabWeekly Lapatinib 52 weeks 3-weekly Trastuzumab 40 weeks Lapatinib 34 weeks PaclitaxelWeekly 12 weeks  +/- Radio- therapy PaclitaxelWeekly 12 weeks  +/- Radio- therapy PaclitaxelWeekly 12 weeks  +/- Radio- therapy Washout 6 weeks DESIGN 2: Paclitaxel concurrent with targeted therapy after any A-based (neo)adjuvant CT PaclitaxelWeekly 12 weeks  +/- Radio- therapy TrastuzumabWeekly 12 weeks  ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) study

35 Adjuvant studies MINDACT EORTC BIG3-04  Fatima Cardoso/ Martine Piccart Can microarray expression profiling help avoid chemotherapy in N- disease? Phase III Compares the 70-gene expression signature with common clinical-pathological criteria in selecting patients for adjuvant chemotherapy in node- negative breast cancer

36 Aout 2008 Evaluate Clinical-Pathological risk and 70-gene signature risk Clinical-pathological and 70-gene both HIGH risk Discordant cases Clin-Path HIGH 70-gene LOW Clin-Path LOW 70-gene HIGH Clinical-pathological and 70-gene both LOW risk Use Clin-Path risk to decide Chemo or not Use 70-gene risk to decide Chemo or not 55% 32%13% R1 Chemotherapy N=3300 N=780 Endocrine therapy EORTC-BIG MINDACT TRIAL DESIGN 6,000 Node negative women N=1920 MD: M. Piccart; F. Cardoso;

37 HER2+ adjuvant BACH study Caelyx-endoxan-herceptin vs AC -> taxol-herceptin + cardiac substudy strain rate UZLeuven

38 Beatrice International multi-centre phase III trial of adjuvant Bevacizumab in triple negative breast cancer

39 Beatrice

40 Aout 2008 LOCAL RELAPSE [IBCSG 27-02, BIG 1-02] Chemotherapy for Radically Resected Loco-regional Relapse RANDOMIZERANDOMIZE SURGERYSURGERY Strata: - Prior CT - ER+ and/or PgR+ - Location of recurrence Observation (+/- Radiation Therapy) Chemotherapy (+/- Radiation Therapy) ER+ and/or PgR+: hormonal therapy Recrutement total prévu: 977 patientes (MD: F. Cardoso) « PSEUDO-ADJUVANT »

41 Metastatic

42 Hormones

43 HR+ MBC IGF1-receptor targeting IGF1R important co-regulator of other GF pathways and endocrine pathways, including causing resistance CP-751,871 = IGF1R Moab Pfizer Multiple myeloma:  9/ 27 RR in combination with dexamethasone  2 PR in dexa resistant patients

44 HR+ MBC IGF1-receptor targeting RANDOMIZED PHASE 2 in 1 st -line COMBINATION WITH EXEMESTANE vs EXEMESTANE ALONE AS FIRST LINE Hans Wildiers

45 Copyright ©2007 AlphaMed Press Stanway, S. J. et al. Oncologist 2007;12: Steroidogenesis in postmenopausal women and site of action of STX64 (BN83495) Steroid sulfatase (STS) activity much higher than aromatase activity in breast tumors High levels of STS mRNA associated with a poor prognosis STS hydrolyzes steroid sulfates, such as estrone sulfate and dehydroepiandrosterone sulfate (DHEAS), to estrone and DHEA, which can be converted to steroids with potent estrogenic properties, that is, estradiol and androstenediol, respectively.

46 Jan 2008 Steroid sulfatase inhibitor Post-menopausal with ER positive, LABC or MBC 2 nd line HT (adjuvant HT allowed but progressed > 12 ms) Only 1 prior CT and Herceptin (discontinued at least for 4 months prior) Measurable (RECIST) and non-measurable (only until OBD) Progressive CNS excluded METASTATIC SETTING: HR + Hormonal Therapy IPSEN BN83495 TRIAL (Phase 1) Bordet

47 HOBO-trial Phase II study in patients with hormone receptor positive breast cancer with Bortezomib (Velcade) in the reversal of endocrine resistance L. Dirix, Sint Augustinus Also many interesting translational studies in inflammatory breast cancer

48 HER2 positive disease

49 Metastatic disease (MBC) HER2-positive EGF Phase III study  Paclitaxel plus Trastuzumab plus Lapatinib vs  Paclitaxel plus Trastuzumab plus placebo

50 Aout 2008 Pfizer A : Herceptin + Sutent Phase II CT not indicated but Herceptin indicated Prior treatment with trastuzumab and/or lapatinib in the neoadjuvant, adjuvant or metastatic setting is permitted Pfizer A : Docetaxel + Herceptin + SU (Sutent) Phase II F. Cardoso METASTATIC SETTING HER-2  BC 1st Line

51 Aout 2008 METASTATIC SETTING HER-2  BC 2nd or more Line Local relapse and/or inflammatory MBC Lapatinib +/- Pazopanib Phase III randomised double blind Must have received CT and Trastuzumab Main endpoint: PFS Controlled CNS mets allowed GSK: VEG108838

52 HSP90

53 Metastatic studies HER2-positive MedImmune Protocol No. MI-CP153 Phase 2 Antitumor Activity and Safety of IPI-504,  Small Molecule Inhibitor of Heat Shock Protein 90 (Hsp90) Progressed on HER2-targeted Therapy Marleen Borms, AZ Groeninge UZLeuven

54 Aout 2008 METASTATIC SETTING HER-2  BC Herceptin + Velcade Bordet-sponsored trial and based on their prior preclinical experiments 1 Phase I No limit of previous lines of HT nor CT Previous Herceptin or lapatinib allowed All MBC HER-2  for whom Herceptin alone would be the choice F. Cardoso 1 Cardoso F, et al Bortezomib increases the efficacy of trastuzumab (Herceptin) in HER-2-positive breast cancer cells in a synergistic manner Mol Cancer Ther Dec;5(12):

55 Ertumaxomab Bispecific antibody targeting HER2/neu and CD3 Formation of a tri-cell complex tumour cell, T cell and accessory cell Antitumour efficacy against HER2/neu low-expressing tumours resistant to trastuzumab Phase I study in MBC : strong immune responses Phase II studies MBC even without HER2/neu gene amplification

56 Aout 2008 METASTATIC SETTING Biological Therapy Alone HR + & HER-2 1 or 2  /FISH  BC Ertumaxomab (trifunctional HER MoAb) (Fresenius) Phase II HR + but HT Resistant HER-2 + ou ++ but FISH neg F. Cardoso

57 Aout 2008 METASTATIC SETTING 1.Lapatinib + Temozolomide (LAPTEM) 2.Lapatinib + Capecitabine BRAIN METASTASES HER-2+ Bordet

58 Metastatic HER2 + BC 3144A1-203-WW HKI-272: irreversible inhibitor of EGFR/HER2neu Phase I/II study and after Herceptin failure HKI-272 with paclitaxel in subjects with solid tumours and breast cancer HKI-272 (Neratinib) + Vinorelbine AZ Groeninge en Bordet

59 Metastatic Triple Negative BC BIBW 2992 (Boehringer) Dual irreversible EGFR/HER2neu inhibitor Phase II HER-2 Neg, HR negative (Triple Negative) Asymptomatic brain mets allowed

60 Eribulin Synthetic analogue of halichondrin B Substance derived from a marine sponge (Lissodendoryx sp.) Binds to vinca domain of tubulin and inhibits the polymerization of tubulin Inhibition of mitotic spindle assembly, induction of cell cycle arrest at G2/M phase

61 MBC, 2 nd line E7389 (Eribulin) Phase 3, Multiple centers 1. Eribulin versus ‘treatment of physician’s choice’ in patients with locally recurrent or metastatic breast cancer, previously treated with at least two and maximum five prior chemotherapy regimens, including an anthracycline and a taxane 2. Eribulin versus Capecitabine in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines and taxanes and refractory to the most recent chemotherapy

62 Jan 2008 METASTATIC SETTING Triple Negative 1st Line MERCK BALI-1 Phase-II randomized WEEKLY CETUXIMAB + six 3-WEEKLY cycles of CISPLATIN Maximum of six 3-WEEKLY CYCLES OF CISPLATIN Main endpoint: RR Only 1 prior anthracycline or taxane (adjuvant or MBC) MD: A. Awada

63 IMC-1121B A multicenter phase III-study in first-line Anti-vascular endothelial growth factor receptor-2 (VEGFR-2) monoclonal antibody IMC-1121B plus Docetaxel vs placebo plus Docetaxel V. Cocquyt

64 SUCON trial SUtent CONsolidation A belgian multicenter phase II randomized trial in her2 negative metastatic breast cancer evaluating consolidation antiangiogenic therapy with SU11248 after response to taxane chemotherapy induction. H. Wildiers

65 SUCON trial

66 Biomarking in Top trial Anthracycline in triple negative: Looking for biomarkers for sensitivity/resistance  Expression profiling  Genetic predisposition genes  Epigenetic profiling Bordet-ULB-UCL-VUB

67 PARP1 inhibitor High activity in genetic ovarian cancer* Under study:  SA activity under study in genetic breast cancer  Activity with cisplatinum in breast cancer * AZD2281 (KU ), a PARP (poly ADP-ribose polymerase) inhibitor with single agent anticancer activity in patients with BRCA deficient ovarian cancer: Results from a phase I study. P. C. Fong, D. S. Boss, C. P. Carden, M. Roelvink, J. De Greve, et al J Clin Oncol 26: 2008 (May 20 suppl; abstr 5510)

68 L. D. Wood et al., Science 318, (2007) Future is: genomics

69 Thank you for the information Bordet: F. Cardoso AZ Groeninge: M. Borms Hasselt: J. Janssens UGent: H. Thierens, V.Cocquyt, M. Hamdi UZBrussel: C. Fontaine UZLeuven : H. Wildiers en P. Neven UZAntwerpen: W. Tjalma (overview) Klina: D. Verhoeven, OLV-Aalst Sint-Nicolaas ZNA (Vandenwyngaert)

70

71 Propidium iodide Annexin V Control Fulvestrant Estradiol B Estrogen Induces Apoptosis and Tumor Regression in a Breast Cancer Cell Line Resistant To Estrogen Deprivation AUTONOMOUS GROWTH ESTRADIOL FULVESTRANT A DNA (  g/well) Days G1-blockade Apoptosis Average tumour area (cm 2 ) Weeks AUTONOMOUS GROWTH FULVESTRANT ESTRADIOL C In vivo In vitro Lewis et al, J Natl Cancer Inst. 2005; 97:

72 Effect of intermittent letrozole treatment in MCF-7Ca xenografts Her-2 p-Her-2 p-MAPK MAPK Aromatase ERα ß-Actin Off Letrozole Letrozole Mean Tumor Volume (mm 3 ) Control Back on Letrozole Weeks Control Letrozole-22 wkLetrozole-33 wkOff – 28 wkOff – 33 wk Back On Letrozole 28 weeks Sabnis et al. Cancer Res. 2008;68,4518.

73 Patient Population Postmenopausal Disease-free after 4 to 6 years of prior adjuvant endocrine therapy (SERM and/or AI) Endocrine-responsive breast cancer at diagnosis Node-positive breast cancer at diagnosis S LE

74 10 of a total of 25 accepted sites in Belgium are actively recruting. Last month Belgium as a country take the lead compared to all other countries concerning the recrutment. The trial allows free drug access for all postmenopausal lymph node positive patients who are candidates for extended adjuvant treatment and who received an aromatase inhibitor within the first 5 years (and who consequently can not obtained a reimbursement for extended adjuvant treatment). Contact:

75 Patient Visit Schedule All patients will be followed every 6 months for years 1 to 5, and thereafter yearly for assessment of disease status and for survival data collection. S LE

76 Aout 2008 « EN PRATIQUE »: ADJUVANT Phase III trial (4800 pts): 5 years continuous letrozole vs of intermittent letrozole following 4 to 6 years of prior adjuvant HT (tam and/or AI) Postmenopausal women with HR positive; Node positive only Main endpoint: DFS; tumor block required; QoL substudy

77 Participating centers : 15 centres UZ Gasthuisberg Leuven (R Paridaens and H Wildiers and P Neven) AZ St-Augustinus Wilrijk (L Dirix) Imelda Bonheiden (W. Wynendaele) AZ St jan Brugge (E. Decuypere) ZOL (J Mebis, D Luyten, G Debrock) St-Elisabeth Turnhout (M Martens) St-Elisabeth Namen (P Vuylsteke and Jean-Charles Goemine) UZ Gent (H Denys and Dr V Cocquyt) UCL Brussels and Mont-Godinne (JP Machiels and J Kerger) Charleroi (JL Canon) UZBrussel (J De Greve) Liege (G Jerusalem) : 5 new centres Cliniques du Sud-Luxembourg, Arlon (P Glorieux) CHR de Huy (J Collignon, J Bury, M Reginster) CHC Clinique Saint Joseph (C Focan, M P Graas, F Kreutz) UCL Ottignies Louvain-la-Neuve (L Duck) AZ Nikolaas (W Lybaert, I Deleu, E Everaert)

78 Aout 2008 METASTATIC SETTING HER-2 Neg BC 1st Line MBC WX ‑ Capecitabine vs. Placebo + Capecitabine (Wilex) Phase II randomised Main endpoint: PFS Measurable disease (RECIST) Bone or skin only not allowed SNS mets not allowed F. Cardoso Serine protease inhibitor inhibits the uPA system


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