Phase I study of TT-00420, a multiple kinase inhibitor, as a single agent in advanced solid tumors.
Authors: Sarina Anne Anne Piha-Paul, Binghe Xu, Filip Janku, Ecaterina Elena Dumbrava, Siqing Fu, Daniel D. Karp, Funda Meric-Bernstam, David S. Hong, Jordi Rodon Ahnert, Apostolia Maria Tsimberidou, Milind M. Javle, Ying Fan, Peng Peng, Wendy J. Levin, Brenda Ngo, Hui Wang, Caixia Sun, Qinhua Cindy Ru, Frank Wu
Journal: Journal of Clinical Oncology (2021)

3090 Background: TT-00420 is a spectrum-selective multi-kinase inhibitor that targets cell proliferation, angiogenesis, and immune-oncology pathways by inhibiting Aurora kinases A/B and Janus kinases (JAK) involved in cytokine signaling and receptor tyrosine kinases (FGFRs and VEGFRs) involved in the tumor microenvironment. TT-00420 has demonstrated anti-tumor activity in both in vitro and in vivo preclinical models of solid tumors, including triple-negative breast cancer (TNBC) and cholangiocarcinoma (CCA). Methods: The phase I, first-in-human dose escalation and expansion study of TT-00420 is enrolling adult patients with advanced or metastatic solid tumors. TT-00420 capsules in 1 mg or 5 mg formulation are administered orally once daily in 28-day cycles. Dose escalation is guided by Bayesian modeling with overdose control. The primary safety endpoints are to determine dose limiting toxicities (DLTs) and a dose recommended for dose expansion (DRDE). Secondary endpoints include pharmacokinetics (PK) and preliminary efficacy evaluated per RECIST v1.1 criteria. Results: As of February 17, 2021, 40 advanced solid tumor patients were enrolled in dose escalation cohorts and received at least one dose of TT-00420 in 7 dose levels: 1 mg q.d. (N=1), 3 mg q.d. (N=1), 5 mg q.d. (N=4), 8 mg q.d. (N=10), 10 mg q.d. (N=6), 12 mg q.d. (N=12), and 15 mg q.d. (N=6). DLTs were observed in 3 out of 32 DLT-evaluable patients, including 1 patient at 8 mg q.d. who had grade (Gr) 3 palmar-plantar erythrodysaesthesia syndrome and 2 patients at 15 mg q.d. who both had Gr 3 hypertension. Suspected adverse events (AEs) reported in ≥ 20% of patients across all tested dose levels include hypertension (any grade: n=17, 42.5%; Gr 3: n=8, 20.0%), diarrhea (n=10, 25.0%; Gr 3: n=1, 2.5%), vomiting (n=9, 22.5%; Gr 3: n=0), palmar-plantar erythrodysaesthesia syndrome (n=9, 22.5%; Gr 3: n=1, 2.5%), and nausea (n=8, 20.0%; Gr 3: n=1, 2.5%). No Gr 4 AEs, regardless of causality, were reported. Out of 26 patients who had at least one post-baseline scan, 4 (15.4%) had a best overall objective response of partial response (PR) and 13 (50.0%) had stable disease (SD). Of the patients who achieved PRs are 2 CCA patients (8 mg q.d., n=1; 10 mg q.d., n=1), 1 HER2-negative breast cancer patient (12 mg q.d.), and 1 TNBC (10 mg q.d.). Both CCA patients with PRs had disease control for ≥ 8 months. Of the patients who achieved SD, 1 salivary gland patient (5 mg q.d.) and 1 CCA patient (10 mg q.d.) had disease control for 8 months, and 2 TNBC patients (5 mg q.d., n=1; 8 mg q.d., n=1) had disease control for 6 months prior to disease progression. Conclusions: Toxicities observed in dose escalation cohorts were manageable with concomitant treatment and/or dose interruptions of TT-00420. 12 mg p.o. q.d. was recommended as the dose for dose expansion cohort for further safety and efficacy evaluation of TT-00420 capsules with focus on enrollment of TNBC and CCA patients. Clinical trial information: NCT03654547.