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Introduction: The biology of DLBCL is complex, with a number of clinicopathologic and molecular features impacting outcome. MCT-1 is an oncogene that promotes lymphomagenesis via enhanced cell survival signaling, increased G1 cyclin/CDK activity and overriding cell cycle checkpoints; its expression is substantially elevated in DLBCL without a clear difference in germinal center versus non-germinal center subtypes. Our preliminary studies showed that 1) 85% of DLBCL samples have strong or increased expression of MCT-1via IHC, 2) MCT-1 knockdown induces apoptosis in cell lines, and 3) mutant MCT-1 protein expression attenuates the malignant phenotype via translational changes. (Dai Ca Res 2009 69(19): p. 7835-43) MCT-1 levels are directly regulated by MEK/ERK signaling, providing a rationale to test MEK pathway inhibition as a therapeutic target in DLBCL. AZD-6244 (ARRY-142886, selumetinib) is a novel second generation oral small molecule MEK inhibitor that induces dose dependent apoptosis in DLBCL cell lines and attenuates tumor growth in xenograft models. (Bhalla Blood 2011 118(4): p. 1052-61) In patients with solid tumors, AZD-6244 75mg twice daily has been established as the recommended phase II dose (RP2D). (Adjei JCO 2008 26(13): p. 2139-46) Methods: Eligible relapsed/refractory (R/R) DLBCL patients received AZD6244 hydrogen sulfate at a dose of 75 mg by mouth twice daily continuously for up to eight 28-day cycles or until disease progression or unacceptable toxicity. The primary objective of the study was overall response rate (ORR) with secondary objectives including safety, progression free survival (PFS), overall survival (OS) and pharmacodynamic (PD) analyses. The statistical design used a Simon two-stage design. Due to excessive early toxicity, the protocol was amended to reduce the dose to 50mg twice daily. Results : Sixteen R/R DLBCL pts (9 male, 7 female) with a median age of 70 years (range, 29-86 yrs), median 3 prior regimens (range, 0-6) were enrolled. Cell-of-origin was not prospectively determined, but only 3/10 pts were CD10 positive and 5/9 were MUM1 positive. The median Lactate Dehydrogenase (LDH) at study entry was 483 (range, 194-1128). Two patients withdrew consent prior to treatment exposure. Of 14 patients receiving at least one dose of selumetinib, two had stable disease and the remainder progressed. The median number of treatment cycles was one (range, 1-5). This was partly due to toxicity causing frequent dose interruptions of AZD-6244. Grade ³3 toxicities were observed in 37.5% (15.2 - 64.6%) and included anemia (44%), thrombocytopenia (25%), diarrhea (31%), transaminitis 44%), fatigue (44%); other infrequent toxicities included AV block, LV dysfunction, anorexia and rash. Median progression-free survival (PFS) in all patients was 34 days [95% CI 14-73 days]. Median overall survival (OS) was 129 days [CI 58-134 days]; all but 3 patients (including one patient lost to follow-up) have expired. Conclusion: Despite excellent preclinical rationale to test selective MEK antagonism as a means of modulating MCT-1 and MEK/ERK in DLBCL, AZD-6244 was not well tolerated and had limited clinical activity. Other MEK/ERK inhibitors with a more favorable toxicity profile and/or use of rational synergistic combination therapy should be considered to further evaluate the role of MEC inhibition in this heavily pretreated patient population. (Patel Cancer 2014 19(4): p. 799-805 (Supported by NCI contract N01-CM-2011-00071C) Disclosures Petrich: Seattle Genetics: Consultancy, Honoraria, Research Funding. Westin:Spectrum: Research Funding. Gordon:Northwestern University: Employment; Dr Leo I. Gordon: Patents & Royalties: Patent for gold nanoparticles pending.

Introduction: Here we describe a novel signal-finding clinical trial protocol series, termed the Novartis “Signature” program. These are tissue-agnostic, genetic alteration (mutation, amplification, translocation, etc.) specific protocols that do not include pre-identified clinical trial sites. In part these are responsive to the increased frequency of molecular profiling in the oncology community, and the incidence of patients whose tumors are identified with actionable genetic alteration yet without automatic access to drugs targeting those alterations. As these patients are identified via standard of care physician-directed profiling, we bring the ‘Protocol to the Patient’, utilizing a rapid study start-up process, such that a de novo site can have one of these trials opened within weeks of the originating patient being identified. Currently the 8 open single agent protocols involve buparlisib (BKM120, PI3Ki), dovitinib (TKI258, multi-kinase inhibitor), binimetinib (MEK162, MEKi), encorafenib (LGX818, RAFi), LEE011 (CDK4/6i), BGJ398 (FGFRi), ceritinib (LDK378, ALKi) and sonidegib (LDE225; SMOi). Methods:Patients with advanced solid and hematologic cancers and no established standard therapy options are eligible. Patients are locally pre-identified with an actionable genetic alteration relevant to the particular compound being studied; a local test done in a CLIA laboratory is sufficient for eligibility. Central broad molecular profiling of patient’s tumors (including confirmatory analysis of inclusion genetic alteration) is performed post-hoc using a fresh or archived sample. The primary objective of these trials is to assess clinical benefit (SD or better for ≥ 16 weeks for solid tumors or appropriate hematologic criteria) associated with the study related compound. A novel statistical design is incorporated to adaptively cluster patients of like indications into cohorts for independent analysis for futility (minimum 10 patients) or efficacy (minimum 15 patients). Rare tumors of at least 4 patients can be clustered together into unique cohorts for determination of signals. To investigate mechanisms of resistance, an optional biopsy is taken upon progression for patients who have had a prior response to the study compound – these tissues are subjected to a broad molecular profiling analysis. Results: Between March 2013 - July 2014, 13 academic centers and another 74 unique community/network sites had screened 286 patients. On average the startup timelines were 5.2 weeks across the program. 147 patients with a genetic alteration received matched therapy and have been dosed: primarily colorectal (28; 19%), NSCLC (25; 17%), ovarian (13; 9%) and sarcoma (n=12; 8%). Rare tumors accrued include small intestine/duodenal (n=6), anal (n=3), thymus (n=2), cholangiocarcinoma (n=2) and appendix (n=2). The Signature program also accrued heme malignancies. Across the whole program, the identifying actionable alterations were mainly PIK3CA (35%), PTEN loss (23%), RAS (18%), NF1 (4.7%), and FGFR2 (3.5%), and also included BRAF, SMO, PTCH1, VEGFR2, RET, PDGFRa, PDGFRb, TRKa, FGFR3, MEK1 and FLT3. The median number of lines of prior treatment was 3 (mean = 3.4; range of 1 to 13), median patient age of 61 years (range of 22 to 82), 40.3 % male, ECOG PS of 0 in 38% of patients and ECOG PS of 1 in 61.5% of patients. Three patients with AML harboring RAS mutations and one patient with multiple myeloma with a BRAFV600E mutation were included in the binimetinib module. (3 female / 1 male; 1-6 prior lines of therapy; 31-80 years old. One AML patient received prior transplant). Additional data will be presented. Futility/Efficacy analyses for 5 cohorts (4 from buparlisib and 1 from binimetinib) are currently ongoing. Conclusions: This program effectively allows the enrollment of molecularly profiled patients with genetic alterations linked to cognate targeted agents. The cohort analysis will evaluate clinical activity in multiple tumor types in parallel. The Signature program could enable the identification of clinical signals using patient sparing designs, potentially leading to subsequent confirmatory trials. This trial model has successfully allowed enrollment of molecularly pre-selected rare tumors in a short timeline without pre-determined trial site selection. The next step of this model will include novel drug combination modules. Disclosures Giles: Novartis: Consultancy, Research Funding. Off Label Use: Ceritinib is approved for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC), who have progressed on or who are intolerant to crizotinib. Here, ceritinib is being evaluated in other tumor types that express ALK mutations. All other agents are investigational.. Braiteh:Bayer: Consultancy, Speakers Bureau; Agendia: Consultancy; Incyte: Consultancy, Speakers Bureau; Genomic Health: Consultancy, Speakers Bureau; Foundation Medicine: Consultancy; Celgene: Consultancy, Speakers Bureau; Caris Life Sciences: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Amgen/Onyxx: Consultancy, Speakers Bureau; INSYS: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Saladax: Consultancy; Sanofi: Consultancy, Speakers Bureau. Schwartzberg:Novartis: Honoraria, Speakers Bureau. Stein:Novartis: Employment, Equity Ownership. Salvado:Novartis: Employment. Lebedinsky:Novartis: Employment. Kang:Novartis: Employment. Slosberg:Novartis: Employment.