Background: TT-00420, a multikinase inhibitor, targets cell proliferation, angiogenesis, and immunomodulatory pathways by inhibiting the mitotic kinases Aurora A/B, Janus kinases (JAK) involved in cytokine signalling, and receptor tyrosine kinases involved in angiogenesis (FGFRs and VEGFRs). These pathways are important in the pathogenesis of triple negative breast cancer (TNBC) and TT-00420 has shown preclinical efficacy against multiple subtypes of TNBC.

Methods: This phase I, open-label, first-in-human study is enrolling adult patients with advanced or metastatic TNBC and other advanced solid tumors. The study contains a dose escalation phase (N=22), followed by dose expansion in two parallel cohorts, a TNBC cohort (N=22) and a selected advanced tumor (SAT) cohort (N=22). The provisional dose range for dose escalation is 1 mg/d to 20 mg/d. Dose escalation is guided by Bayesian modeling with overdose control until a dose recommended for dose expansion is determined. Adverse events (AE) are evaluated per CTCAE v5.0 criteria, and tumor response is evaluated per RECIST v1.1 criteria. Patients receive a single daily oral administration of TT-00420 continuously for 28-day cycles. The primary endpoint is to evaluate dose limiting toxicity (DLT) and identify a maximum tolerated dose (MTD). Secondary objectives include evaluating the efficacy and pharmacokinetic profile of TT-00420.

Results: As of the data cut-off date on September 26, 2019, 11 patients have received TT-00420 treatment in 4 dose levels, 1 mg/d (N=1), 3 mg/d (N=1), 5 mg/d (N=3), and 8 mg/d (N=6). No DLTs have been observed at any of the tested dose levels. Commonly reported suspected AEs across all tested dose levels were grades 1 or 2 diarrhea (n=4, 36.4%), myalgia (n=2, 18.2%) and hypertension (n=2, 18.2%). Two suspected serious adverse events reported were grade 2 hypertension (8 mg/d) and grade 3 nausea (5 mg/d). No grade 3 AEs have occurred in more than one subject. Stable disease has been observed in 4 patients, including a metastatic TNBC patient treated at 8 mg/d, who received 9 lines of prior antineoplastic therapy. Per RECIST v1.1 criteria, this TNBC patient had a 21% decrease in target lesions observed on restaging after two cycles of TT-00420 treatment. Interestingly, significant clinical improvement in the skin lesions were observed as well. More detailed data from this TNBC patient and other patients treated in the study will be presented. Enrollment in dose escalation is currently ongoing. Clinical trial information: NCT03654547

Citation Format: Sarina A. Piha-Paul, Ecaterina Ileana-Dumbrava, Filip Janku, Daniel D. Karp, Funda Meric-Bernstam, Jordi Rodon, Brenda Ngo, Peng Peng, Frank Wu. Phase I study of TT-00420, a multiple kinase inhibitor, in patients with triple negative breast cancers and other advanced solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3011.