Supplemental Figure S1. Protein level changes induced by CUDC-907, panobinostat, or pictilisib in MYC-altered DLBCL cell lines; Supplemental Figure S2. CUDC-907 induced changes in WSU DLCL2 cells; Supplemental Figure S3. CUDC-907 changes the mRNA expression pattern of a subset of MYC target genes; Supplemental Figure S4. CUDC-907 does not induce significant body weight loss or obvious toxicity in human DLBCL cell line-derived xenograft models or Eμ-Myc transgenic tumor mouse syngeneic models of B-cell lymphoma; Supplemental Figure S5. CUDC-907 decreases MYC protein levels in cell line-derived Burkitt lymphoma xenograft tumors; Supplemental Figure S6. Protein level changes induced by CUDC-907, panobinostat, or pictilisib in MYC-dependent NMC cell lines; Supplemental Figure S7. CUDC-907 does not induce significant body weight loss or obvious toxicity in human NMC cell line-derived xenograft models; Supplemental Figure S8. Antitumor activity of CUDC-907 in human DLBCL cell line Karpas 422-derived xenograft model.

Supplemental Figure 1. Consort Diagram 03-311. Supplemental Figure 2. Consort Diagram 211B. Supplemental Figure 3. Subtype-specific changes in Immune Index upon brief-exposure to nab-paclitaxel in the 211B trial. Supplemental Figure 4. Evaluation of the Immune Index upon brief-exposure to trastuzumab in the 03-311 and 211B trials according to ER/PR status. Supplemental Figure 5. Evaluation of the Immune Index upon brief-exposure to nab-paclitaxel in the 211B trial according to ER/PR status. Supplemental Figure 6. Correlation between Immune Index and tumor content. Supplemental Figure 7. Association of CD4+ Th1 and Treg signatures with response. Supplemental Table 1. Immune Index genes discriminative of response at the post-exposure timepoint in the discovery (03-311) and validation (211B) datasets. Supplemental Table 2. Immune cell subset signatures discriminative of response at baseline and post-exposure timepoints in the discovery (03-311) and validation (211B) datasets. Supplemental Table 3. CD8+ T-cell cytolytic activity genes discriminative of response at the post-exposure timepoint in the discovery (03-311) and validation (211B) datasets.

Item response theory (IRT), which originated from psychometric theory, relates to latent variable models for psychological assessment . IRT's contributions have been less extensively studied in cancer research even though IRT has become prevalent in the measurement of ability and item parameters with respect to latent traits. Benefits of IRT include comprehensive analyses and reduction of measurement error, meaningful scaling of latent variables, evaluation of test and item bias, greater accuracy in the assessment of change due to therapeutic intervention, and evaluation of model and person fit. Advances in cancer biology and human genetics have resulted in the identification of driver events and critical biologic dependencies. These advances, together with the development of drugs for specific biologic targets hold promise for an era of personalized oncology treatment. Therefore, robust discovery of biomarkers associated with the biologic mechanisms that drive cancers could provide clinicians with the ability to tailor therapeutic strategies for individual patients, thus improving clinical outcomes. Incorporating biomarkers in clinical trials during drug development may also allow for determining the optimal patient population for a given drug, thus maximizing its efficacy. Thus, this chapter explores the application of different IRT models in the discovery of biomarkers and altered biologic processes in cancer. The utility and limitations of the IRT models in the discovery of biomarkers or biological mechanisms are highlighted through simulations and application to genome-scale molecular profiling studies of cancers.

Abstract Introduction Patients with relapsed or refractory (R/R) MYC-altered DLBCL have poor outcomes, and other than for a subset of patients who may benefit from chimeric antigen receptor T cell therapy, no treatment has shown a significant durable benefit or impact on survival outcomes. Fimepinostat is a first-in-class, well-tolerated, oral small molecule inhibitor of HDAC and PI3K enzymes. There is particular interest in evaluating fimepinostat in patients with MYC-dependent tumors as nonclinical studies demonstrated that fimepinostat inhibits transcription of MYC and a subset of MYC-associated genes. Additionally, MYC protein levels were downregulated by fimepinostat in part through inhibition of PI3K-mediated ubiquitination. Pharmacodynamic inhibition of HDAC and PI3K has also been demonstrated in human studies. Here we report the outcome of R/R DBLCL patients treated with fimepinostat in a Phase 1 and Phase 2 study, with an emphasis on outcomes for patients with MYC-altered disease. Patients and Methods A total of 105 R/R DLBCL patients were enrolled on the Phase 1 study CUDC-907-101 (n = 37) and the Phase 2 study CUDC-907-201 (n = 68). In CUDC-907-101, 14 patients were found to have MYC-altered disease, defined as presence of MYC rearrangement by either central or local testing by fluorescent in situ hybridization or MYC protein expression ≥40%) by immunohistochemistry (IHC). In CUDC-907-201, 46 patients had confirmed MYC-altered disease by central IHC testing. Across both studies, patients without available tissue or prior test results were deemed as MYC-status unknown (n = 23). Results A total of 19 responses (9 CR, 10 partial responses [PR]) were reported across both studies. The objective response rate (ORR) in MYC altered patients was 23.3% (14/60). Responses showed encouraging durability with a median duration of response of 13.6 months (range: 2.8 to Not Calculable [NC]). Five MYC-altered responses were ongoing as of the data-cut. Two MYC-altered patients achieving CR discontinued treatment early to pursue stem cell transplantation. Responses associated with fimepinostat often require multiple cycles of treatment to manifest (median time to first response = 2.5 months for MYC-altered patients), and of patients who were treated for ≥2 months, a large proportion (17/33; 52%) achieved a response. Patients with low disease burden at screening (tumor lesions diameters ≤ 5 cm and lactate dehydrogenase [LDH] < 1.5 x upper limit of normal [ULN]) generally continued treatment longer and were most likely to derive clinical benefit (Table 2). Conclusions The biologic rationale, tolerable safety profile, and evidence of durable anti-tumor activity in MYC-altered R/R DLBCL support the continued development of fimepinostat in this poor-prognosis patient population. Patients with low disease burden features may be more likely to have sufficient duration of drug exposure to allow clinical benefit. Future enrollment will focus on patients with screening characteristics most likely to derive the greatest benefit from fimepinostat treatment. Disclosures Landsburg: Takeda: Consultancy; Curis: Consultancy, Research Funding. Ramchandren:Seattle Genetics: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Merck: Research Funding; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Lugtenburg:Millennium/Takeda: Consultancy, Research Funding; Servier: Consultancy, Research Funding; Roche: Consultancy; BMS: Consultancy; Sandoz: Consultancy; Genmab: Consultancy. Younes:Takeda: Honoraria; Abbvie: Honoraria; BMS: Honoraria, Research Funding; Novartis: Research Funding; Curis: Research Funding; Incyte: Honoraria; Seattle Genetics: Honoraria; Janssen: Honoraria, Research Funding; Bayer: Honoraria; Sanofi: Honoraria; Astra Zeneca: Research Funding; Celgene: Honoraria; J&J: Research Funding; Pharmacyclics: Research Funding; Roche: Honoraria, Research Funding; Merck: Honoraria; Genentech: Research Funding. Tuck:Curis, Inc: Employment, Equity Ownership. Barta:Janssen: Membership on an entity's Board of Directors or advisory committees; Merck, Takeda, Celgene, Seattle Genetics, Bayer: Research Funding.

In the Phase 1 study CUDC-907-101, objective responses were reported in a number of patients with MYC-altered relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) treated with fimepinostat. The ongoing Phase 2 study CUDC-907-201 is designed to prospectively explore the efficacy of fimepinostat in this population.

Background: IRAK4 kinase activity is required for toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling in a variety of myeloid and lymphoid cell types. Recruitment of IRAK4 to these receptors and its subsequent activation is facilitated by the MYD88 adaptor protein. The MYD88-L265P activating mutation is prevalent in DLBCL (~30% in ABC subtype) and WM (>90%). MYD88- L265P leads to constitutive activation of NF-κB signaling that is associated with worse prognosis. In MCL, dysregulation of B-cell receptor (BCR) and TLR pathway components correlate with constitutive NF-κB signaling.

Abstract Upregulation of MYC is a common driver event in human cancers, and some tumors depend on MYC to maintain transcriptional programs that promote cell growth and proliferation. Preclinical studies have suggested that individually targeting upstream regulators of MYC, such as histone deacetylases (HDAC) and phosphoinositide 3-kinases (PI3K), can reduce MYC protein levels and suppress the growth of MYC-driven cancers. Synergy between HDAC and PI3K inhibition in inducing cancer cell death has also been reported, but the involvement of MYC regulation is unclear. In this study, we demonstrated that HDAC and PI3K inhibition synergistically downregulates MYC protein levels and induces apoptosis in “double-hit” (DH) diffuse large B-cell lymphoma (DLBCL) cells. Furthermore, CUDC-907, a small-molecule dual-acting inhibitor of both class I and II HDACs and class I PI3Ks, effectively suppresses the growth and survival of MYC-altered or MYC-dependent cancer cells, such as DH DLBCL and BRD–NUT fusion-positive NUT midline carcinoma (NMC) cells, and MYC protein downregulation is an early event induced by CUDC-907 treatment. Consistently, the antitumor activity of CUDC-907 against multiple MYC-driven cancer types was also demonstrated in animal models, including DLBCL and NMC xenograft models, Myc transgenic tumor syngeneic models, and MYC-amplified solid tumor patient-derived xenograft (PDX) models. Our findings suggest that dual function HDAC and PI3K inhibitor CUDC-907 is an effective agent targeting MYC and thus may be developed as potential therapy for MYC-dependent cancers. Mol Cancer Ther; 16(2); 285–99. ©2016 AACR.

IRAK4 kinase activity is required for toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling in a variety of myeloid and lymphoid cell types. Recruitment of IRAK4 to these receptors and its subsequent activation is facilitated by the MYD88 adaptor protein, which is mutated in ~22% of diffuse large B-cell lymphoma (DLBCL) cases. The MYD88- L265P activating mutation is found in ~30% of the activated B-cell (ABC) and ~6% of germinal center B-cell (GCB) subtypes of DLBCL and leads to constitutive activation of NF-κB signaling that is associated with worse prognosis. In Waldenstrom macroglobulinemia (WM), the MYD88- L265P activating mutation is present in >90% of cases. Thus, the development of small molecule inhibitors targeting IRAK4 is an attractive anticancer strategy for MYD88 mutation-containing cancers such as DLBCL and WM.

IRAK4 kinase activity is required for toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling in a variety of myeloid and lymphoid cell types. Recruitment of IRAK4 to these receptors and its subsequent activation is facilitated by the MYD88 adaptor protein, which is mutated in ~22% of DLBCL cases. The MYD88 L265P activating mutation is found in ~30% of the activated B-cell (ABC) and ~6% of germinal center B-cell (GCB) subtypes of DLBCL and leads to constitutive activation of NF-κB signaling that is associated with worse prognosis. Thus, the development of small molecule inhibitors targeting IRAK4 is an attractive anticancer strategy for MYD88 mutation-containing cancers such as DLBCL. We are developing an IRAK4 inhibitor, CA-4948, as a therapeutic agent for hematological cancers with dysregulated TLR/MYD88/IRAK4 signaling. CA-4948 (previously AU-4948) is a selective and potent IRAK4 kinase inhibitor with in vivo activity in a TLR4-induced cytokine release model. CA-4948 exhibits favorable DMPK properties, oral bioavailability, and is well tolerated in mice. Furthermore, CA-4948 was previously shown to exhibit dose-dependent efficacy in ABC-DLBCL MYD88-L265P xenograft tumor models using cell lines OCI-LY3 and OCI-LY10. Here, we report the efficacy results from testing CA-4948 in a panel of well characterized, patient-derived DLBCL tumor xenograft (PDX) mouse models. CA-4948 exhibited the greatest efficacy in four of the five ABC-DLBCL PDX models tested as compared to GBC-DLBCL and ABC/GCB DLBCL PDX models. Furthermore, CA-4948 was efficacious in ABC-DLBCL PDX tumors containing activating mutations in both TLR/IL-1R and BCR signaling pathways (MYD88 and CD79B double mutants). Interestingly, the one ABC-DLBCL PDX model that failed to respond to CA-4948 treatment contained a MYD88 L265P mutation as well as a BCL6 translocation. While this particular PDX model was resistant to CA-4948, and showed a weak anti-tumor response to single-agent ibrutinib, the combination treatment of ibrutinib and CA-4948 exhibited a synergistic tumor growth inhibition effect. In summary, CA-4948 exhibited anti-tumor activity in ABC-type DLCBL PDX tumor models including those containing combinations of activating mutations in the TLR/IL-1R and BCR signaling pathways. These results underscore the therapeutic potential of IRAK4 kinase inhibition by CA-4948, as a single-agent or in combination with BCR inhibitors, for the treatment of DLBCL. Citation Format: Robert N. Booher, Maria Elena Samson, Guang-Xin Xu, Hongsheng Cheng, David P. Tuck. Efficacy of the IRAK4 inhibitor CA-4948 in patient-derived xenograft models of diffuse large B cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1168. doi:10.1158/1538-7445.AM2017-1168

Abstract The clinical success of antibody-mediated immune checkpoint blockade therapies has transformed the cancer therapy paradigm by demonstrating that durable antitumor immune responses and long-term remissions may be achieved in a subset of patients across a diverse range of cancers. However, the majority of patients fail to respond to antibody therapies targeting single immune checkpoint pathways and antibodies exhibit a long in vivo half-life (>15-20 days with >70% target occupancy for months) which may contribute to the emergence of immune-related adverse events. Additionally, antibody therapies must be administered by intravenous infusion in a hospital or clinic which places an additional burden on patients who may have mobility challenges. Thus, there is a significant opportunity for a novel immune checkpoint therapy that can address the shortcomings associated with the current antibody therapies. CA-170 is a small molecule, orally bioavailable antagonist of the PD-L1, PD-L2 and VISTA/PD-1H immune checkpoint pathways which is currently undergoing Phase I clinical testing. In preclinical safety studies conducted in rodents and non-human primates, orally administered CA-170 shows no signs of toxicity when dosed up to 1000 mg/kg for 28 consecutive days. CA-170 exhibits an oral bioavailability of approximately 40% and <10% in mouse and monkey, respectively, and the plasma half-life ranges from approximately 0.5 hours for mouse to approximately 3.25-4.0 hours for cynomolgus monkey. The ability of CA-170 to disrupt the signaling of PD-1/PD-L1/2 or VISTA/PD-1H has been inferred though in vitro functional studies. CA-170 exhibits potent activity comparable to that of blocking PD-1 or VISTA antibodies when tested in cell culture assays to rescue the proliferation or IFN-γ secretion of lymphocytes stimulated in the presence of inhibitory PD-L1, PD-L2 or VISTA/PD-1H proteins. In mice, orally administered CA-170 inhibits the growth of syngeneic tumors, enhances peripheral T cell activation, and promotes the activation of tumor infiltrating CD8+ T cells in a dose dependent manner. These non-clinical data provide a strong rational for the continued Phase I clinical development of CA-170, the first oral, small molecule immune checkpoint antagonist for the treatment of advanced cancers. Citation Format: Adam S. Lazorchak, Troy Patterson, Yueyun Ding, Pottayil G. Sasikumar, Naremaddepalli S. Sudarshan, Nagaraj M. Gowda, Raghuveer K. Ramachandra, Dodheri S. Samiulla, Sanjeev Giri, Rajesh Eswarappa, Murali Ramachandra, David Tuck, Timothy Wyant. CA-170, an oral small molecule PD-L1 and VISTA immune checkpoint antagonist, promotes T cell immune activation and inhibits tumor growth in pre-clinical models of cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A36.

This report is a summary of 'New Cancer Immunotherapy Agents in Development' program, which took place in association with the 31st Annual Meeting of the Society for Immunotherapy of Cancer (SITC), on November 9, 2016 in National Harbor, Maryland. Presenters gave brief overviews of emerging clinical and pre-clinical immune-based agents and combinations, before participating in an extended panel discussion with multidisciplinary leaders, including members of the FDA, leading academic institutions and industrial drug developers, to consider topics relevant to the future of cancer immunotherapy.

CUDC-907 is a first-in-class, oral small molecule inhibitor of both HDAC (class I and II) and PI3K (class Iα, β, and δ) enzymes, with demonstrated anti-tumor activity in multiple pre-clinical models, including MYC-driven ones. In this report, we present the safety and preliminary activity results of CUDC-907, with and without rituximab, in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), with a particular focus on those with MYC-altered disease. Thirty-seven DLBCL patients were enrolled, 14 with confirmed MYC-altered disease. Twenty-five patients received monotherapy treatment, and 12 received the combination of CUDC-907 with rituximab. CUDC-907 monotherapy and combination demonstrated similar safety profiles consisting primarily of Grade 1/2 hematologic and gastrointestinal events. The most frequently reported Grade ≥3 treatment-related events were thrombocytopenia, neutropenia, diarrhea, fatigue, and anemia. Eleven responses (5 complete responses and 6 partial responses) were reported, for a response rate of 37% (11 out of 30) in evaluable patients [30% (11 out of 37) including all patients]. The objective response rate in evaluable MYC-altered DLBCL patients was 64% (7 out of 11; 4 complete responses and 3 partial responses), while it was 29% (2 out of 7) in MYC unaltered, and 17% (2 out of 12) in those with unknown MYC status. Median duration of response was 11.2 months overall; 13.6 months in MYC-altered patients, 6.0 months in MYC unaltered, and 7.8 months in those with MYC status unknown. The tolerable safety profile and encouraging evidence of durable anti-tumor activity, particularly in MYC-altered patients, support the continued development of CUDC-907 in these populations of high unmet need. (clinicaltrials.gov identifier: 01742988).

TPS3099 Background: Programmed-death 1 (PD-1) and V-domain Ig suppressor of T-cell activation (VISTA) are independent immune checkpoints that negatively regulate T-cell function and are implicated in various malignancies. Preclinical studies have demonstrated that dual blockade of these pathways is synergistic. CA-170 is a first-in-class oral small molecule that directly targets both PD-1/PD-L1 and VISTA pathways and has shown anti-tumor activity in multiple preclinical models. Methods: The dose escalation phase has a target enrollment of 50 pts with advanced solid tumors or lymphomas onto escalating doses; the first four single-pt cohorts are accelerated titration but then switch to 3+3 design. The dose expansion phase has a target enrollment of 250 pts with select tumor types known to be responsive to anti-PD-1/L1 inhibitors and/or known to express PD-L1 or VISTA. Key eligibility criteria include: age ≥ 18 years, ECOG ≤1, adequate organ function, and ineligible for/did not respond to standard therapy including anti-PD-1/L1 inhibitors, where available. Primary objectives of this first-in-human study: safety, maximum tolerated dose, and recommended phase 2 dose. Secondary objectives: pharmacokinetics (PK) and anti-tumor activity. Exploratory endpoints: biomarkers and pharmacodynamic (PD) effects, which include changes in immune cell and peripheral cytokine populations in tumor (IHC/mRNA) and blood (flow cytometry/mRNA). Oral CA-170 is administered once daily in 21-day cycles. Response will be evaluated every other cycle per RECIST (v1.1) and Immune-related Response Criteria or by Cheson criteria (2007). Patients who discontinue treatment for reasons other than progressive disease will be followed for progression-free survival. Serial plasma, blood, and tumor samples will be collected for PK and PD evaluation. Clinical trial identifier: Clinical trial information: NCT02812875.

CUDC-907 is a first-in-class, oral, dual inhibitor of Class I and II HDAC, as well as Class I PI3K enzymes. Specifically, CUDC-907 is designed to inhibit HDACs 1, 2, 3, 6 and 10 and PI3K-alpha, delta and beta isoform. Preclinical studies demonstrate that CUDC-907 has potent effects on acetylated histone-regulated genes and PI3K signaling. CUDC-907 showed potent antitumor activity in multiple preclinical tumor models as well as in patients with relapsed or refractory diffuse large B-cell lymphoma (RR DLBCL), with objective responses reported in multiple patients, including complete responses. It is currently being investigated in a Phase 2 study in patients with RR DLBCL, including those with MYC-alterations. Preclinical studies of CUDC-907 in combination with chemotherapeutic and targeted agents are in progress. Venetoclax, a BH3 mimetic and selective BCL2 inhibitor, was recently approved for the treatment of patients with chronic lymphocytic leukemia (CLL) whose tumors had a 17p deletion. Results from a Phase 1 study of venetoclax monotherapy in patients with relapsed or refractory non-Hodgkin lymphoma showed that patients with DLBCL exhibited short-lived responses to venetoclax. Thus, combination approaches may be required to achieve durable responses to venetoclax in DLBCL. In our preclinical studies, we examined the combination of venetoclax and CUDC-907 in DLBCL cell lines. Interestingly, the combination exhibited the most synergy, as measured by fold-improvement over predicted additive effect, in cell lines insensitive to venetoclax. For example, OCI-Ly3 cells were insensitive to single agent venetoclax with an IC50 >10uM; however, in combination with a fixed dose (12nM) of CUDC-907, venetoclax resulted in >10000-fold improvement in potency with a combination IC50 of 0.001uM. Synergy was also observed in tumor growth inhibition studies in xenograft models. Western blot analysis showed that single-agent CUDC-907 simultaneously increased pro-apoptotic BIM protein and decreased anti-apoptotic BCL2 protein levels. Interestingly, the low nano-molar concentrations of CUDC-907 that were shown to regulate the BCL-2 family member proteins could also potentiate pro-apoptotic effects of venetoclax when used together in combination in WSU-DLCL2 cell line which carries MYC and BCL2 translocations. Thus, the effect of CUDC-907 on BCL2 family members appears to be the basis for the observed synergy with venetoclax, which functions to displace BIM from BCL2. These results provide a mechanistic rationale for the use of CUDC-907 in combination with venetoclax for the treatment of patients with DLBCL. Disclosures Sun:Curis: Employment, Equity Ownership. Atoyan:Curis: Employment, Equity Ownership. Borek:Curis: Employment, Equity Ownership. Dellarocca:Curis: Employment, Equity Ownership. Rhyasen:Curis: Employment, Equity Ownership. Fattaey:Curis: Employment, Equity Ownership. Tuck:Curis, Inc.: Employment, Equity Ownership.

### P189 Rational combinations of intratumoral T cell and myeloid agonists mobilize abscopal responses in prostate cancer #### Casey Ager1, Matthew Reilley2, Courtney Nicholas1, Todd Bartkowiak1, Ashvin Jaiswal1, Michael Curran1 ##### 1Department of Immunology, University of Texas MD Anderson

MYC family genes are among the most frequently deregulated oncogenic drivers in human cancer. Pharmacologic inhibition of HDAC activity and blockade of the PI3K pathway have both been shown to suppress MYC-induced transcription. HDAC activity is critical for MYC gene regulation, as MYC represses transcription of target genes through recruitment of HDACs. HDAC inhibitors have been shown to restore expression of genes suppressed by MYC family members and to induce rapid downregulation of expression of MYC itself. The PI3K pathway plays a central role in regulating MYC at the post-transcriptional level. Activation of PI3K signaling leads to activation of AKT, which phosphorylates and inhibits GSK3β. As GSK3β normally phosphorylates MYC which facilitates the degradation of MYC, activation of PI3K signaling leads to increased stability of MYC, whereas PI3K inhibitors decrease MYC stability. A recent study has demonstrated addiction to MYC signaling and hypersensitivity to PI3K inhibition in PTEN-deficient diffuse large B-cell (DLBCL) cell lines, suggesting that MYC-driven cancers may be particularly sensitive to PI3K inhibition. As HDACs and PI3K regulate MYC protein levels and functions through nonoverlapping mechanisms, simultaneous HDAC and PI3K inhibition may further enhance MYC suppression. CUDC-907 is an orally bioavailable, small-molecule dual HDAC and PI3K inhibitor that primarily inhibits class I and II HDACs and the PI3Kα, β, and δ isoforms. CUDC-907 shows greater anti-tumor activity in vitro than single-target HDAC or PI3K inhibitors, especially in MYC-dependent cell types, such as DLBCL and NUT midline carcinoma (NMC). In preclinical testing, CUDC-907 treatment leads to a dose-dependent decrease in MYC protein levels, and is also more potent in decreasing MYC than the HDAC inhibitor panobinostat and the pan-PI3K inhibitor pictilisib alone or in combination. Significant antitumor effects have been consistently observed in MYC-driven DLBCL xenograft and genetically engineered mouse models exposed to CUDC907. In particular, certain MYC translocation (Daudi), double-hit (concurrent MYC and BLC2 translocation, WSUDLCL2 and DOHH2), double-expresser (expression of MYC and BCL2 proteins, U2932) xenograft models, and the Eμ-Myc transgenic mouse model achieve tumor growth inhibition of 100%, 69%, 56%, 97% and 72%, respectively. These findings raise the possibility that hematologic and solid tumors driven by aberrant overexpression of MYC family genes (e.g., MYC-altered DLBCL and NMC) might be more responsive to simultaneous HDAC and PI3K inhibition with CUDC-907 than they are to single-target therapy. Clinical Phase 1 studies are currently testing CUDC-907 in patients with relapsed/refractory (R/R) DLBCL and advanced MYC-aberrant solid tumors. Preliminary data are encouraging and support the planned Phase 2 study in R/R MYC-altered DLBCL, as well as further testing in other MYC-driven malignancies. Citation Format: Kaiming Sun, Ruzanna Atoyan, Mylissa A. Borek, Steven Dellarocca, Maria E. Samson, Anna W. Ma, Guangxin Xu, Troy Patterson, David P. Tuck, Jaye L. Viner, Ali Fattaey, Jing Wang. Novel dual HDAC & PI3K inhibitor, CUDC-907, for MYC-driven malignancies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4634.