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WO 2010/135468 Al (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 25 November 2010 (25.11.2010) WO 2010/135468 Al (51) International Patent Classification: [US/ES]; C/ Rio EsIa 77 PO2 A Villamayor, E-37007 GOlN 33/50 (2006.01) Salamanca (ES). LAGO, Santiago [GB/ES]; C/ Fernando Camino 15 3-E, E-29016 Malaga (ES). MATOSES, (21) International Application Number: Maria [ES/ES]; C/ Los Cristos 1 1 C, E-29008 Malaga PCT/US2010/035474 (ES). SUAREZ, Lilia [ES/ES]; C/ Ancla, 27 Casa 13, (22) International Filing Date: E-29720 CaIa Del Moral (ES). SAPIA, Sandra [IT/ES]; 19 May 2010 (19.05.2010) C/ Zapateros, 2 2 C, E-29005 Malaga (ES). BOSAN- QUET, Andrew [GB/GB]; 4 The Brow, Church Road, English (25) Filing Language: Combe Down, BA2 5JL, Bath (GB). GOR- (26) Publication Language: English ROCHATEGUI, Julian [ES/ES]; C/Puerto de los Leones 5, Majadahonda, E-28220 Madrid (ES). (30) Priority Data: TUDELA, Consuelo [ES/ES]; Av. Juan Carlos I 23, M a 61/179,685 19 May 2009 (19.05.2009) US jadahonda, E-28220 Madrid (ES). HERNANDEZ, Pilar (71) Applicant (for all designated States except US): VIVIA [ES/ES]; C/Uruguay 16, E-37OO3 Salamanca (ES). BIOTECH S.L. [ES/ES]; C/ Menendez Pelayo 12, 3d, CAVEDA, Luis Ignacio [ES/ES]; Av. Valladolid 17, E-47001 Valladolid (ES). E-28008 Madrid (ES). (72) Inventors; and (74) Agent: MALLON, Joseph, J.; Knobbe Martens Olson & (75) Inventors/Applicants (for US only): BALLESTEROS, Bear LLP, 2040 Main Street, 14th Floor, Irvine, CA Juan [ES/ES]; C/ Espalter 8 - 7 B, E-28014 Madrid (ES). 92614 (US). BENNETT, Teresa [US/ES]; C/ Rio EsIa 77 PO2 A ViI- (81) Designated States (unless otherwise indicated, for every lamayor, E-37007 Salamanca (ES). PRIMO, Daniel [ES/ kind of national protection available): AE, AG, AL, AM, ES]; Avda. Italia 14 5 4 A, E-37007 Salamanca (ES). AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, ORFAO, Alberto [ES/ES]; C/ Faisanes 64, E-37194 CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, Santa Marta De Tormes (ES). JACKSON, Coyt DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, [Continued on next page] (54) Title: METHODS FOR PROVIDING PERSONALIZED MEDICINE TESTS EX VIVO FOR HEMATOLOGICAL NEO PLASMS (57) Abstract: Described herein are methods, devices, (µM) Fludarabine Cyclophosphamide Mitoxantrone and compositions for providing personalized medicine 1 1 30 1 tests for hematological neoplasms. In some embodiments, 2 0.33 10 0.33 the methods comprise measuring the efficacy of inducing 0.1 1 3.33 0.1 1 3 apoptosis selectively in malignant cells using any number 4 0.037 1.1 1 0.037 of potential alternative combination drug treatments. In some embodiments, the ex vivo testing is measured using a recently extracted patient hematological samples. In other embodiments, the efficacy is measured ex vivo u s ing an automated flow cytometry platform. For example, by using an automated flow cytometry platform, the eval uation of hundreds, or even thousands of drugs and com positions, can be made ex vivo. Thus, alternative poly- therapy treatments can be explored. Non- cytotoxic drugs surprisingly induce apoptosis selectively in malignant cells ex vivo. In some embodiments, the methods de scribed herein comprise evaluating non-cytotoxic drugs. Dose points FIG. 24 HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, LV, MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, GW, ML, MR, NE, SN, TD, TG). SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. Declarations under Rule 4.17: — of inventorship (Rule 4.1 7(iv)) (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, Published: GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, — with international search report (Art. 21(3)) ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, METHODS FOR PROVIDING PERSONALIZED MEDICINE TESTS EX VIVO FOR HEMATOLOGICAL NEOPLASMS RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Patent Application Serial No. 61/179685, filed on May 19, 2009, which is incorporated by reference herein in its entirety. BACKGROUND OF THE INVENTION [0002] This invention relates to the use of a screening platform to determine a cytotoxic drug sensitivity profile for multiple drugs and drug combinations using specimens from cancer patients. Described herein is a cell-based screening platform that incorporates both automated sample preparation and automated evaluation by flow cytometry that is useful as a personalized medicine test because of its rapid data acquisition, analysis, and reporting of results, even from very large numbers of drugs and drug combinations. Also disclosed are particular combinations of drugs useful in the treatment of proliferative lymphoid disease. Description of the Related Art [0003] There are many methods available to evaluate the cytotoxic drug sensitivity profiles of tumor cells in ex vivo samples taken from cancer patients. Ex vivo assays for detecting cell death in hematological neoplasms have been developed during the past 40 years, resulting in a number of assays to identify chemosensitivity. The term Individualized Tumor Response Test/Testing (ITRT) has recently been proposed for these methods to describe the "effect of anticancer treatments on whole living tumor cells freshly removed from cancer patients." (Bosanquet et al., G. J. Kaspers, B. Coiffier, M. C. Heinrich and E. H. Estey. New York, NY, 2008, Informa Healthcare: 23-44). Initial ITRTs designed to study the ability of a drug to slow or arrest neoplastic cell growth (e.g., clonogenic assays) did not work well. However, in the 1980s, a number of ITRTs of cell death were developed that have consistently shown good comparisons between assay results and clinical outcomes (i.e., clinical correlations). [0004] Even with good clinical correlations, currently available ITRTs of cell death suffer from undesirable limitations that restrict their use as personalized medicine tests. For example, clonogenic assays generally require weeks rather than days to generate results, restricting their clinical usefulness (Hamburger et al., Science 1911, 197:461-463; Marie et al., Br J Haematol 1983, 55:427-437; Selby et al., New Engl J Med 1983, 308:129-134). Also, the majority of ITRTs measure total cell death to evaluate the effect of incubating samples with drugs ex vivo. Measuring total cell death limits the ability of an ITRT to distinguish between a drug's effect on tumor cells versus normal cells. The ITRTs that are currently available differ from one another mainly with respect to the methodology used to determine the percentage of live cells or live tumor cells at the end of an assay. [0005] While some ITRTs measure cells directly, the majority evaluate cell death indirectly using surrogate markers. For example, the MTT (methyl-thiazolyl tetrazolium) assay estimates the number of live cells by measuring mitochondrial reduction of MTT to formazan, eliciting a change in color that can be quantified using a spectrophotometer (Pieters et al., Blood 1990, 76:2327-2336; Sargent et al., Br J Cancer 1989, 60:206-210; Carmichael et al., Cancer Res 1987, 47:936-942). Other ITRTs use fluorescein diacetate hydrolysis (e.g., the fluorometric microculture cytotoxicity assay (FMCA)) or cellular ATP levels as indirect markers of cellular viability (Rhedin et al., Leuk Res 1993, 17:271-276; Larsson et al., Int J Cancer 1992, 50:177-185). The DiSC (Differential Staining Cytotoxicity) assay and more recently, the TRAC (Tumor Response to Antineoplastic Compounds) assay use staining methods to determine live tumor cells by microscopy (Bosanquet et al., Br J Haematol 2009, 146:384-395; Bosanquet et al., Leuk Res 1996, 20:143-153; Weisenthal et al., Cancer Res 1983, 43:749-757). [0006] The above-mentioned ITRTs require incubation of a patient's neoplastic cells with cytotoxic drugs for a period of at least 4 to 5 days. However, hematological cells start to lose important properties after only 24 to 48 hours outside the human body. Shorter incubation periods would allow for the evaluation of ex vivo cytotoxicity profiles prior to the start of patient treatment, thereby increasing their clinical utility and allowing for a more effective application as personalized medicine tests. [0007] Cytotoxic drugs have been shown to eliminate malignant cells by inducing apoptosis (Aragane et al., / Cell Biol 1998, 140:171-182; Hannun et al., Blood 1997, 89:1845-1853). Apoptosis is a type of cellular death, commonly referred to in the art as "programmed cell death," which the art defines according to morphological and antigenic features. Apoptosis commonly starts within hours of a drug coming into contact with target cells (Del Bino et al., Cell Prolif 1999, 32:25-37). There are many assays for apoptosis based on markers that reflect different aspects of the apoptotic process, such as: 1) changes in the mitochondrial potential membrane using DiOC6 or JC-I (Tabrizi et al., Leukemia 2002, 16:1154-1159; Liu et al., Leukemia 2002, 16:223-232); 2) fragmentation of internucleosomic DNA identified by Tdt in the terminal deoxynucleotidyl transferase (TUNEL) assay (Liu et al., Leukemia 2002, 16:223-232) using electrophoresis or labeling with acridine orange (Tabrizi et al., Leukemia 2002, 16(6): 1154-9; Kim et al., Exp MoI Med 2000, 32:197-203; Konstantinov et al., / Cancer Res Clin Oncol 2002, 128:271-278; Ofir et al., Cell Death Differ 2002, 9:636-642); or 3) identification of proteolytic fragments of either poly-ADP-ribose polymerase (PARP) or caspase-3 using specific antibodies (Konstantinov et al., / Cancer Res Clin Oncol 2002 128(5):271-8; Ofir et al., Cell Death Differ 2002, 9(6):636-42; Byrd et al., Blood 2002, 99:1038-1043; Hasenjager et al., Oncogene 2004, 23:4523-4535; Prokop et al., Oncogene 2003, 22:9107-9120).
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