ENMD-2076 is a novel orally active, small molecule kinase inhibitor with a mechanism of action involving several pathways key to tumor growth and survival: angiogenesis, proliferation, and the cell cycle. ENMD-2076 has selective activity against the mitotic kinase Aurora A, as well as kinases involved in angiogenesis (VEGFRs, FGFRs). ENMD-2076 inhibited the growth in vitro of a wide range of human solid tumor and hematopoietic cancer cell lines with IC 50 values ranging from 0.025 to 0.7 mmol/L. ENMD-2076 was also shown to induce regression or complete inhibition of tumor growth in vivo at well-tolerated doses in tumor xenograft models derived from breast, colon, melanoma, leukemia, and multiple myeloma cell lines. Pharmacodynamic experiments in vivo showed that in addition to inhibiting Aurora A, single doses of ENMD-2076 had sustained inhibitory effects on the activation of Flt3 as well as the angiogenic tyrosine kinases, VEGFR2/KDR and FGFR1 and 2. ENMD-2076 was shown to prevent the formation of new blood vessels and regress formed vessels in vivo at doses equivalent to those that gave substantial activity in tumor xenograft models. These results indicate that ENMD-2076 is a well-tolerated, orally active multitarget kinase inhibitor with a unique antiangiogenic/antiproliferative profile and provides strong preclinical support for use as a therapeutic for human cancers. Several phase 1 studies involving ENMD-2076 have been recently completed, and the compound is currently being evaluated in a phase 2 clinical trial in patients with platinumresistant ovarian cancer.

BACKGROUND: CFI-400945 is a first-in-class oral inhibitor of polo-like kinase 4 (PLK4) that regulates centriole duplication. Primary objectives of this first-inhuman phase 1 trial were to establish the safety and tolerability of CFI-400945 in patients with advanced solid tumours. Secondary objectives included pharmacokinetics, pharmacodynamics, efficacy, and recommended phase 2 dose (RP2D). METHODS: Continuous daily oral dosing of CFI-400945 was evaluated using a 3+3 design guided by incidence of dose-limiting toxicities (DLTs) in the first 28-day cycle. Safety was assessed by CTCAE v4.0. ORR and CBR were evaluated using RECIST v1.1. RESULTS: Forty-three patients were treated in dose escalation from 3 to 96 mg/day, and 9 were treated in 64 mg dose expansion. After DLT occurred at 96 and 72 mg, 64 mg was established as the RP2D. Neutropenia was a common high-grade (19%) treatment-related adverse event at ≥ 64 mg. Half-life of CFI-400945 was 9 h, with C max achieved 2-4 h following dosing. One PR (45 cycles, ongoing) and two SD ≥ 6 months were observed (ORR = 2%; CBR = 6%). CONCLUSIONS: CFI-400945 is well tolerated at 64 mg with dose-dependent neutropenia. Favourable pharmacokinetic profiles were achieved with daily dosing. Response rates were low without biomarker pre-selection. Disease-specific and combination studies are ongoing.

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This study was designed to investigate Bad phosphorylation at several of its key regulatory Ser residues in cytokine-dependent hemopoietic cells. These studies were initiated in light of numerous studies that have reported a key role for phosphorylated Bad in preventing apoptosis. One key question is whether the survival signaling effect of the PI 3-kinase pathway is mediated by PKB phosphorylation of Bad. We confirm previous reports that if Bad is overexpressed or if active PKB is overexpressed, then the increased phosphorylation of Bad at Ser136 is apparent. However, we were unable to detect phosphorylation of endogenous Bad at Ser136 in the MC/9 mast cell line or in murine bone marrow-derived macrophages. On the other hand, phosphorylation of Bad at Ser112 and Ser155 was observed in response to IL-3 or GM-CSF, which activate the MEK/erk pathway, but not with IL-4, which activates the PI 3-kinase, but not the MEK/erk pathway, and also promotes cell survival. In contrast to previous reports, we found that ceramide had no effect on the phosphorylation status of Bad. In summary, our results suggest that Bad phosphorylation at any of the three major sites is not a required event for cytokine-dependent cell survival, and in particular, the activation of PI 3-kinase/PKB pathway can be dissociated from phosphorylation of Bad at Ser136.

Background: TTK (also known as Mps1), a dual-specificity serine-threonine kinase, is critical for the spindle assembly checkpoint (SAC), chromosome alignment and error correction in mitosis. Inhibition of TTK causes premature mitotic exit with unattached chromosomes, resulting in chromosomal missegregation, aneuploidy and cell death. CFI-402257 is a potent (Ki = 0.09 nM, IC50 = 1.2 nM), highly selective and orally active inhibitor of TTK. Robust suppression of tumor growth was achieved upon oral dosing of single agent CFI-402257 in ER+/HER2- and triple negative breast cancer (TNBC) cell line and patient derived xenograft models. CFI-402257 demonstrated enhanced cytotoxicity in CDK4/6 inhibitor resistant ER+ breast cancer cell line models compared to parental cell lines, including those with RB1 loss. Methods: This multi-center Phase I dose escalation study (3+3 design) was designed to determine the safety, tolerability and maximum tolerated dose (MTD) of CFI-402257 and evaluate anti-tumor activity at the RP2D. CFI-402257 was dosed once daily on a continuous schedule in 28-day cycles at a starting dose of 5mg based on preclinical toxicology. Dose escalation included patients with advanced solid tumors and dose expansion at the RP2D into three expansion cohorts - Cohort A advanced solid tumors, Cohort B advanced ER+ or TNBC with 1-4 prior lines of chemotherapy for metastatic disease and Cohort C ER+/HER2- breast cancer in combination with Fulvestrant (500mg IM Day 1, 15 and 29 and then every 28 days) who have had prior treatment with an aromatase inhibitor in combination with a CDK4/6 inhibitor (>= 3 months) and =<1 prior chemotherapy for metastatic disease. Results: As of May 25, 2021, 66 patients had been enrolled, majority (76%) of patients received >3 prior therapies before study entry and 37% of patients’ (23/66) primary malignancy was breast cancer. The maximum administered dose was 294 mg and the study has continued enrolling at the recommended phase 2 dose of 168 mg with grade 3 Neutropenia, grade 3 Febrile Neutropenia and grade 3 Colitis as the dose limiting toxicities. Only 1/6 patients experienced a DLT at 168 mg (grade 3 Neutropenia, >7 days) The most common treatment emergent AEs (Gd3, >5%) were Neutropenia (15.6%), Anaemia (7.8%), Hypophosphataemia and Febrile Neutropenia (6.3%). PR’s confirmed by the Investigator have been seen to date in 33% of the cohort C subjects (2/6 patients), with an additional two cPR’s seen in the breast cancer population (ER+/HER2-) from the expansion cohorts. Conclusion: CFI-402257 is generally well tolerated and continues to enroll at 168mg daily with a manageable AE profile and early signs of anti-tumor activity. Enrollment in the expansion cohorts is ongoing and updated safety and efficacy data for the previously treated ER+/HER2- population will be presented at the time of the meeting. A multi-center phase II clinical trial is planned. Citation Format: John Hilton, Daniel J Renouf, David W Cescon, Aaron R Hansen, Albiruni RA Razak, Lee-Anne Stayner, Trisha Denny, Graham Fletcher, Tak W Mak, Mark Bray, Philippe L Bedard. Phase I study of cfi-402257, an oral ttk inhibitor, in patients with advanced solid tumors with breast cancer expansion cohorts [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-17.

Supplementary Table 1, Supplementary Figures 1-4 from ENMD-2076 Is an Orally Active Kinase Inhibitor with Antiangiogenic and Antiproliferative Mechanisms of Action

<div>Abstract<p>ENMD-2076 is a novel orally active, small molecule kinase inhibitor with a mechanism of action involving several pathways key to tumor growth and survival: angiogenesis, proliferation, and the cell cycle. ENMD-2076 has selective activity against the mitotic kinase Aurora A, as well as kinases involved in angiogenesis (VEGFRs, FGFRs). ENMD-2076 inhibited the growth <i>in vitro</i> of a wide range of human solid tumor and hematopoietic cancer cell lines with IC₅₀ values ranging from 0.025 to 0.7 μmol/L. ENMD-2076 was also shown to induce regression or complete inhibition of tumor growth <i>in vivo</i> at well-tolerated doses in tumor xenograft models derived from breast, colon, melanoma, leukemia, and multiple myeloma cell lines. Pharmacodynamic experiments <i>in vivo</i> showed that in addition to inhibiting Aurora A, single doses of ENMD-2076 had sustained inhibitory effects on the activation of Flt3 as well as the angiogenic tyrosine kinases, VEGFR2/KDR and FGFR1 and 2. ENMD-2076 was shown to prevent the formation of new blood vessels and regress formed vessels <i>in vivo</i> at doses equivalent to those that gave substantial activity in tumor xenograft models. These results indicate that ENMD-2076 is a well-tolerated, orally active multitarget kinase inhibitor with a unique antiangiogenic/antiproliferative profile and provides strong preclinical support for use as a therapeutic for human cancers. Several phase 1 studies involving ENMD-2076 have been recently completed, and the compound is currently being evaluated in a phase 2 clinical trial in patients with platinum-resistant ovarian cancer. <i>Mol Cancer Ther; 10(1); 126–37. ©2010 AACR</i>.</p></div>