AXL Inhibitors in Oncology Clinical Trials: A Review

<div>Abstract<p><b>Purpose:</b> To determine whether combination therapy with NHS-muIL12 and the anti-programmed death ligand 1 (PD-L1) antibody avelumab can enhance antitumor efficacy in preclinical models relative to monotherapies.</p><p><b>Experimental Design:</b> BALB/c mice bearing orthotopic EMT-6 mammary tumors and μMt<sup>−</sup> mice bearing subcutaneous MC38 tumors were treated with NHS-muIL12, avelumab, or combination therapy; tumor growth and survival were assessed. Tumor recurrence following remission and rechallenge was evaluated in EMT-6 tumor-bearing mice. Immune cell populations within spleen and tumors were evaluated by FACS and IHC. Immune gene expression in tumor tissue was profiled by NanoString® assay and plasma cytokine levels were determined by multiplex cytokine assay. The frequency of tumor antigen–reactive IFNγ-producing CD8<sup>+</sup> T cells was evaluated by ELISpot assay.</p><p><b>Results:</b> NHS-muIL12 and avelumab combination therapy enhanced antitumor efficacy relative to either monotherapy in both tumor models. Most EMT-6 tumor–bearing mice treated with combination therapy had complete tumor regression. Combination therapy also induced the generation of tumor-specific immune memory, as demonstrated by protection against tumor rechallenge and induction of effector and memory T cells. Combination therapy enhanced cytotoxic NK and CD8<sup>+</sup> T-cell proliferation and T-bet expression, whereas NHS-muIL12 monotherapy induced CD8<sup>+</sup> T-cell infiltration into the tumor. Combination therapy also enhanced plasma cytokine levels and stimulated expression of a greater number of innate and adaptive immune genes compared with either monotherapy.</p><p><b>Conclusions:</b> These data indicate that combination therapy with NHS-muIL12 and avelumab increased antitumor efficacy in preclinical models, and suggest that combining NHS-IL12 and avelumab may be a promising approach to treating patients with solid tumors. <i>Clin Cancer Res; 23(19); 5869–80. ©2017 AACR</i>.</p></div>

Purpose: To determine whether combination therapy with NHS-muIL12 and the anti-programmed death ligand 1 (PD-L1) antibody avelumab can enhance antitumor efficacy in preclinical models relative to monotherapies.Experimental Design: BALB/c mice bearing orthotopic EMT-6 mammary tumors and μMt- mice bearing subcutaneous MC38 tumors were treated with NHS-muIL12, avelumab, or combination therapy; tumor growth and survival were assessed. Tumor recurrence following remission and rechallenge was evaluated in EMT-6 tumor-bearing mice. Immune cell populations within spleen and tumors were evaluated by FACS and IHC. Immune gene expression in tumor tissue was profiled by NanoString® assay and plasma cytokine levels were determined by multiplex cytokine assay. The frequency of tumor antigen-reactive IFNγ-producing CD8+ T cells was evaluated by ELISpot assay.Results: NHS-muIL12 and avelumab combination therapy enhanced antitumor efficacy relative to either monotherapy in both tumor models. Most EMT-6 tumor-bearing mice treated with combination therapy had complete tumor regression. Combination therapy also induced the generation of tumor-specific immune memory, as demonstrated by protection against tumor rechallenge and induction of effector and memory T cells. Combination therapy enhanced cytotoxic NK and CD8+ T-cell proliferation and T-bet expression, whereas NHS-muIL12 monotherapy induced CD8+ T-cell infiltration into the tumor. Combination therapy also enhanced plasma cytokine levels and stimulated expression of a greater number of innate and adaptive immune genes compared with either monotherapy.Conclusions: These data indicate that combination therapy with NHS-muIL12 and avelumab increased antitumor efficacy in preclinical models, and suggest that combining NHS-IL12 and avelumab may be a promising approach to treating patients with solid tumors. Clin Cancer Res; 23(19); 5869-80. ©2017 AACR.

<div>Abstract<p><b>Purpose:</b> To determine whether combination therapy with NHS-muIL12 and the anti-programmed death ligand 1 (PD-L1) antibody avelumab can enhance antitumor efficacy in preclinical models relative to monotherapies.</p><p><b>Experimental Design:</b> BALB/c mice bearing orthotopic EMT-6 mammary tumors and μMt<sup>−</sup> mice bearing subcutaneous MC38 tumors were treated with NHS-muIL12, avelumab, or combination therapy; tumor growth and survival were assessed. Tumor recurrence following remission and rechallenge was evaluated in EMT-6 tumor-bearing mice. Immune cell populations within spleen and tumors were evaluated by FACS and IHC. Immune gene expression in tumor tissue was profiled by NanoString® assay and plasma cytokine levels were determined by multiplex cytokine assay. The frequency of tumor antigen–reactive IFNγ-producing CD8<sup>+</sup> T cells was evaluated by ELISpot assay.</p><p><b>Results:</b> NHS-muIL12 and avelumab combination therapy enhanced antitumor efficacy relative to either monotherapy in both tumor models. Most EMT-6 tumor–bearing mice treated with combination therapy had complete tumor regression. Combination therapy also induced the generation of tumor-specific immune memory, as demonstrated by protection against tumor rechallenge and induction of effector and memory T cells. Combination therapy enhanced cytotoxic NK and CD8<sup>+</sup> T-cell proliferation and T-bet expression, whereas NHS-muIL12 monotherapy induced CD8<sup>+</sup> T-cell infiltration into the tumor. Combination therapy also enhanced plasma cytokine levels and stimulated expression of a greater number of innate and adaptive immune genes compared with either monotherapy.</p><p><b>Conclusions:</b> These data indicate that combination therapy with NHS-muIL12 and avelumab increased antitumor efficacy in preclinical models, and suggest that combining NHS-IL12 and avelumab may be a promising approach to treating patients with solid tumors. <i>Clin Cancer Res; 23(19); 5869–80. ©2017 AACR</i>.</p></div>

Treatment with poxvirus-based active immunotherapies shows evidence of robust immune responses against a variety of tumor-associated antigens in preclinical and clinical studies. Poxvirus-based immunotherapies in development include PSA-targeted PROSTVAC, now in Phase 3 clinical development; CV-301 (targeting CEA and MUC-1); as well as MVA-BN-HER2 and MVA-BN-Brachyury (targeting HER-2 and the transcription factor Brachyury, respectively). Evidence of robust and productive anti-tumor efficacy in preclinical models was accompanied by treatment-emergent infiltration of tumors by activated cytotoxic CD8 T cells producing high amounts of IFNγ. Treatment with immune checkpoint inhibitors such as anti-PD-1 antibodies is showing significant clinical benefit by re-activating dormant tumor-specific T cells. Furthermore, preclinical studies have shown further synergistic efficacy by combining PD-1 blockade with inhibition of LAG-3, which acts independently of PD-1 to modulate T cell function. We hypothesized that poxvirus-based active immunotherapy may provide even greater improvements to patient outcome when used in combination with immune checkpoint blockade, by inducing new productive tumor-specific responses. This may be especially important in patients lacking an endogenous T cell response against their tumors. In therapeutic CT26-HER2 solid and metastatic tumor models, mice were administered MVA-BN-HER2 immunotherapy alone or in combination with anti-PD-1 and/or anti-LAG-3 antibodies. Synergistic benefit for anti-tumor efficacy was observed when combining MVA-BN-HER2 immunotherapy with anti-PD-1 alone, while combination with anti-LAG-3 alone had little effect. Notably, a further enhancement occurred when MVA-BN-HER2 immunotherapy was combined with PD-1 and LAG-3 blockade as shown by complete tumor regression in 20/20 mice. Subsequent rejection of HER-2 negative tumors 6 months after the original challenge revealed that immune responses were durable and included antigen spread to additional tumor antigens. Flow cytometric analysis demonstrated that tumor infiltrating lymphocytes (TILs) in untreated tumors were PD-1hi and LAG-3+, a more exhausted phenotype. Poxvirus-based immunotherapy led to the induction of activated TILs characterized by low to mid-levels of PD-1 expression. While PD-1 blockade prevented binding to PD-L1 it also caused an increase in LAG-3 expression on T cells. Together these data provide further rationale for why combination therapy of poxvirus-based immunotherapy with inhibition of PD-1 plus LAG-3 resulted in synergistic efficacy in preclinical tumor models. Overall these data demonstrate that combining complementary immune-based therapies such as poxvirus-based active immunotherapy and PD-1 plus LAG-3 immune checkpoint blockade result in synergistic anti-tumor efficacy. Citation Format: Barbara Sennino, Susan P. Foy, Ryan B. Rountree, Tracy dela Cruz, Evan J. Gordon, Veronica Xavier, Felicia Kemp, Alex Franzusoff, James Breitmeyer, Stefanie J. Mandl. Poxvirus-based active immunotherapy synergizes with PD-1 plus LAG-3 immune checkpoint inhibition to enhance antitumor efficacy in preclinical models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-234. doi:10.1158/1538-7445.AM2015-LB-234

Therapeutic Targeting of Nuclear Export Inhibition in Lung Cancer

ONC201 Depletes Cancer Stem Cells in Refractory Cancer Patient Samples

Preclinical Efficacy of Decoy-Resistant IL-18 in Hematological Malignancies

Background: PIK3CA mutation is associated with a lower pCR rate in primary HER2+ breast cancer (BC) treated with trastuzumab and lapatinib in addition to chemotherapy (from five clinical trials, PMID: 27177864). The BOLERO-1 study showed that the efficacy of a combination of mTOR inhibitor (everolimus) plus trastuzumab (T) and paclitaxel was not very efficacious with HER2+ advanced BC patients except for HER2+/ER- BC patients (PMID: 26092818). In the same line, BOLERO 3 trial data showed the same combination (T + everolimus + vinorelbine) is also not efficacious in T-resistant, HER2+ advanced breast cancer women (median PFS 7 months with everolimus and 5.78 months with placebo, HR: 0.78) (PMID: 24742739). T-DM1 does not have typical adverse events of chemotherapy. Therefore, there has been interest in combining it with other targeted agent. Here we tested the efficacy of a combination of T-DM1 plus GDC-0980 (a dual PI3K/mTOR inhibitor) in HER2+/T-resistant BC cell lines in vitro and in vivo. Methodology: Here we have studied the in vitro and in vivo effects of GDC-0980 along with T-DM1 in HER2+/T-sensitive (BT474), HER2+/T-resistant (BT474HerR), and HER2+/PIK3CA (HCC1954, MDA-MB453) mutated models. We assessed in vitro anti-proliferative, pro-apoptotic and activation status of the PI3K-AKT-mTOR signaling pathway following the combination of GDC-0980 plus T-DM1 in HER2+ BC cell lines. We next evaluated the impact of GDC-0980 plus T-DM1 on tumor growth and angiogenesis using xenograft models. Results: 1) GDC-0980 inhibited downstream activation of the PI3K-mTOR signaling pathway effectors, p-AKT (Ser473, The308), p-P70S6K, p-S6RP and p-4EBP1, and this inhibition was more pronounced when GDC-0980 was combined with T-DM1, 2) similarly the anti-proliferative activity of a combination of GDC-0980 plus T-DM1 was significantly higher by 3D-ON-TOP clonogenic assay following heregulin stimulation, 3) consistent with anti-proliferative effects of GDC-0980, the proportion of cells in the G1 phase of the cell cycle increased in HER2+ cell lines with a concomitant decrease in the S phase of their treatment with GDC-0980, 4) the initiation of apoptotic activity (annexin V) of GDC-0980 was significantly superior to that of an allosteric inhibitor of mTOR, RAD001. GDC-0980 also induced apoptotic markers like cleaved CASPASE3, cleaved PARP1, BIM in HER2+ BC cells and 5) a combination of GDC-0980 plus T-DM1 significantly blocked tumor growth to tumor regression in the HER2+/T-sensitive, HER2+/T-resistant and HER2+/PIK3CA mutated BC xenograft models. Along with its anti-tumor effect, this combination effectively decreased tumor angiogenesis (tumor micro-vessel density via CD31 staining). Conclusions: A combination of GDC-0980 plus T-DM1 significantly blocked in vitro and in vivo HER2+ breast tumor cells growth irrespective of PIK3CA mutation status. This strategy warrants further clinical investigation. Citation Format: De PK, Carlson JH, Sun Y, Lin X, Friedman L, Dey N, Leyland-Jones B. A combination of dual inhibition in HER2-network by T-DM1 and GDC-0980 provides maximal antitumor efficacy in preclinical model of HER2+ breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-03-01.

TIGIT (T-cell immunoglobulin and ITIM domain) has emerged as a promising target in cancer immunotherapy. It is an immune “checkpoint” inhibitor primarily expressed on activated T cells, NK cells and Tregs. Engagement of TIGIT to its ligands PVR and PVR-L2 leads to inhibitory signaling in T cells, promoting functional exhaustion of tumor-infiltrating T lymphocytes. Here, we described the pre-clinical characterization of Ociperlimab (BGB-A1217), a novel humanized IgG1 anti-TIGIT antibody (mAb), and systemically evaluated the contribution of Fc functions in the TIGIT mAb-mediated anti-tumor activities. BGB-A1217 binds to the extracellular domain of human TIGIT with high affinity (KD = 0.135 nM) and specificity, and efficiently blocks the interaction between TIGIT and its ligands PVR or PVR-L2. Cell-based assays show that BGB-A1217 significantly enhances T-cell functions. In addition, BGB-A1217 induces antibody dependent cellular cytotoxicity (ADCC) against Treg cells, activates NK cells and monocytes, and removes TIGIT from T cell surfaces in an Fc-dependent manner, In vivo, BGB-A1217, either alone or in combination with an anti-PD-1 mAb elicits strong immune responses and potent anti-tumor efficacy in pre-clinical models. Moreover, the Fc effector function is critical for the anti-tumor activity of BGB-A1217 in a syngeneic human TIGIT-knock-in mouse model. The observed anti-tumor efficacy is associated with a pharmacodynamic change of TIGIT down-regulation and Treg reduction. These data support the selection of BGB-A1217 with an effector function competent Fc region for clinical development for the treatment of human cancers.

Background: TIGIT (T-cell immunoglobulin and ITIM domain) is a “checkpoint” inhibitory receptor, which is primarily expressed on activated and “exhausted” T and NK cells. Engagement of TIGIT to its ligands (i.e., PVR and PVR-L2) leads to inhibitory signaling in T cells, promoting functional exhaustion of tumor-infiltrating T lymphocytes. BGB-A1217 is a novel humanized IgG1 anti-TIGIT antibody under clinical development. The immunomodulatory activity of BGB-A1217 was evaluated both in vitro and in vivo. Materials and methods: BGB-A1217 was generated through hybridoma fusion, humanized by CDR grafting and structural simulation. The binding affinity and specificity were studied by FACS and SPR. The immunomodulatory functions of BGB-A1217 were evaluated using primary immune cells as well as using animal models. Results: BGB-A1217 binds to the extracellular domain of human TIGIT with high affinity (KD = 0.135 nM) and specificity. In a competition assay, BGB-A1217 efficiently blocks the interaction between TIGIT and PVR. In vitro, BGB-A1217 significantly enhances T-cell functions and induces potential ADCC against TIGITHi targets. In a human T-cell assay, BGB-A1217 enhances IFN-γ production of CMV-specific T cells. In a PBMC assay, BGB-A1217 augments T cell response, either alone or in combination with an anti-PD-1 antibody BGB-A317. Besides blocking TIGIT signaling, BGB-A1217 can also remove TIGIT from cell surface through trogocytosis. This activity is Fc-dependent. In vivo, the Fc effector function is critical for the activity of BGB-A1217 against CT26WT tumor implanted in humanized TIGIT knock-in mice. The observed anti-tumor efficacy is associated with pharmacodynamic change of TIGIT down-regulation, CD226 upregulation and Treg depletion at 48hrs after first dosing. Conclusions: BGB-A1217, either alone or in combination with anti-PD-1 mAb promotes immune cell activation both in vitro and in vivo, supporting its clinical development for the treatment of human cancers. Citation Format: Xin Chen, Liu Xue, Xiao Ding, Qi Liu, Jing Zhang, Lei Jiang, Sha Liu, Hongjia Hou, Qing Zhu, Bin Jiang, Lijie Zhang, Xiaosui Zhou, Jie Ma, Yucheng Li, Wei Jin, Min Wei, Zhirong Shen, Mike Liu, Kang Li, Tong Zhang. A Fc-competent anti-human TIGIT blocking antibody BGB-A1217 elicits strong immune responses and potent anti-tumor efficacy in pre-clinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1854.

Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) play a fundamental role in tumor growth and angiogenesis. Signalling through VEGF/VEGFR not only induces cancer angiogenesis but also affects immune cells, making VEGF/VEGFR a pair of well-documented cancer therapeutic targets. Recently more and more studies have focused on combination of anti-VEGF/VEGFR agents and immune checkpoint inhibitors in preclinical and clinical settings. BD0801 is a humanized rabbit anti-VEGF monoclonal antibody currently in clinical development stage. In this study, we have revealed that BD0801 presents more potent activity than Bevacizumab in blockade of VEGF/VEGFR2 binding (IC50=275 ng/ml for BD0801; IC50=1451 ng/ml for Bevacizumab) and VEGFR2 activation in HUVEC assays. BD0801 also showed enhanced inhibitory effects on the proliferation (IC50=87 ng/ml for BD0801; IC50=476 ng/ml for Bevacizumab) and migration of the HUVECs, compared to Bevacizumab. We found that BD0801 exhibits dose-dependent tumor growth inhibitory activities in both lung cancer PC9 xenograft and lung cancer 3LL murine syngeneic tumor models. In addition, we obtained PK parameters of BD0801 using lung cancer PC9 tumor bearing mice and successfully made correlations between the in vitro function, PK profile and in vivo efficacy of BD0801. Notably, combination of BD0801 with either anti-PD-1, or anti-PD-L1 antibodies showed synergistic anti-tumor efficacy in both lung and colorectal cancer mouse models. Mechanistic studies were conducted to reveal possible mechanism of actions (MOA) underlying the modification in tumor microenvironment. Our data demonstrated that the MOA of the anti-tumor synergy may involve enhanced T-cell mediated immunity, including increased tumor infiltration of CD8+ and CD4+ T cells and reduced double positive CD8+PD-1+ T cells, as well as improved vasculature normalization. Taken together, these data provide a foundation for combining BD0801 with immunotherapy for cancer treatment and support further clinical development plans for BD0801 toward this direction. Citation Format: Liting Xue, Haoyu Zhang, Qian Wang, Feng Li, Xinxin Li, Xiaohong Yu, Zhihong Lu, Yue Huang, Wenqing Yang. Combination of an anti-angiogenic antibody with PD1/PDL1 blockade agents produces synergistic anti-tumor efficacy in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2651.

IBI379, a novel B cell maturation antigen/CD3 bispecific T-cell engager, displays high antitumor efficacy in preclinical models of multiple myeloma

<div>Abstract<p><b>Purpose:</b> This clinical trial investigated the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profile of CHR-3996, a selective class I histone deacetylase inhibitor.</p><p><b>Patients and Methods:</b> CHR-3996 was administered orally once a day. This phase I trial used a 3+3 dose-escalation design. PK profiles were analyzed by liquid chromatography–tandem mass spectroscopic methods and PD studies were conducted using ELISA studying histone H3 acetylation in peripheral blood mononuclear cells.</p><p><b>Results:</b> Thirty-nine patients were treated at dose levels of 5 mg (<i>n</i> = 3), 10 mg (<i>n</i> = 4), 20 mg (<i>n</i> = 3), 40 mg (<i>n</i> = 10), 80 mg (<i>n</i> = 10), 120 mg (<i>n</i> = 4), and 160 mg (<i>n</i> = 5) administered orally once daily. The dose-limiting toxicities seen were thrombocytopenia (160 mg), fatigue (80 and 120 mg), plasma creatinine elevation (80 and 120 mg), and atrial fibrillation (40 mg). The area under the curve was proportional to the administered dose and a maximal plasma concentration of 259 ng/mL at a dose of 40 mg exceeded the concentrations required for antitumor efficacy in preclinical models. Target inhibition measured by quantification of histone acetylation was shown at doses of 10 mg/d and was maximal at 40 mg. A partial response was seen in one patient with metastatic acinar pancreatic carcinoma.</p><p><b>Conclusions:</b> Taking the toxicity and PK/PD profile into consideration, the recommended phase II dose (RP2D) is 40 mg/d. At this dose, CHR-3996 has a favorable toxicologic, PK, and PD profile. CHR-3996 has shown preliminary clinical activity and should be evaluated in further clinical trials. <i>Clin Cancer Res; 18(9); 2687–94. ©2012 AACR.</i></p></div>

This clinical trial investigated the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profile of CHR-3996, a selective class I histone deacetylase inhibitor. CHR-3996 was administered orally once a day. This phase I trial used a 3+3 dose-escalation design. PK profiles were analyzed by liquid chromatography-tandem mass spectroscopic methods and PD studies were conducted using ELISA studying histone H3 acetylation in peripheral blood mononuclear cells. Thirty-nine patients were treated at dose levels of 5 mg (n = 3), 10 mg (n = 4), 20 mg (n = 3), 40 mg (n = 10), 80 mg (n = 10), 120 mg (n = 4), and 160 mg (n = 5) administered orally once daily. The dose-limiting toxicities seen were thrombocytopenia (160 mg), fatigue (80 and 120 mg), plasma creatinine elevation (80 and 120 mg), and atrial fibrillation (40 mg). The area under the curve was proportional to the administered dose and a maximal plasma concentration of 259 ng/mL at a dose of 40 mg exceeded the concentrations required for antitumor efficacy in preclinical models. Target inhibition measured by quantification of histone acetylation was shown at doses of 10 mg/d and was maximal at 40 mg. A partial response was seen in one patient with metastatic acinar pancreatic carcinoma. Taking the toxicity and PK/PD profile into consideration, the recommended phase II dose (RP2D) is 40 mg/d. At this dose, CHR-3996 has a favorable toxicologic, PK, and PD profile. CHR-3996 has shown preliminary clinical activity and should be evaluated in further clinical trials.

<div>Abstract<p><b>Purpose:</b> This clinical trial investigated the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profile of CHR-3996, a selective class I histone deacetylase inhibitor.</p><p><b>Patients and Methods:</b> CHR-3996 was administered orally once a day. This phase I trial used a 3+3 dose-escalation design. PK profiles were analyzed by liquid chromatography–tandem mass spectroscopic methods and PD studies were conducted using ELISA studying histone H3 acetylation in peripheral blood mononuclear cells.</p><p><b>Results:</b> Thirty-nine patients were treated at dose levels of 5 mg (<i>n</i> = 3), 10 mg (<i>n</i> = 4), 20 mg (<i>n</i> = 3), 40 mg (<i>n</i> = 10), 80 mg (<i>n</i> = 10), 120 mg (<i>n</i> = 4), and 160 mg (<i>n</i> = 5) administered orally once daily. The dose-limiting toxicities seen were thrombocytopenia (160 mg), fatigue (80 and 120 mg), plasma creatinine elevation (80 and 120 mg), and atrial fibrillation (40 mg). The area under the curve was proportional to the administered dose and a maximal plasma concentration of 259 ng/mL at a dose of 40 mg exceeded the concentrations required for antitumor efficacy in preclinical models. Target inhibition measured by quantification of histone acetylation was shown at doses of 10 mg/d and was maximal at 40 mg. A partial response was seen in one patient with metastatic acinar pancreatic carcinoma.</p><p><b>Conclusions:</b> Taking the toxicity and PK/PD profile into consideration, the recommended phase II dose (RP2D) is 40 mg/d. At this dose, CHR-3996 has a favorable toxicologic, PK, and PD profile. CHR-3996 has shown preliminary clinical activity and should be evaluated in further clinical trials. <i>Clin Cancer Res; 18(9); 2687–94. ©2012 AACR.</i></p></div>