First-in-human, phase I study of TT-00420, a multiple kinase inhibitor, as a single agent in advanced solid tumors.
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Published:2022-06-01
Issue:16_suppl
Volume:40
Page:3013-3013
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ISSN:0732-183X
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Container-title:Journal of Clinical Oncology
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language:en
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Short-container-title:JCO
Author:
Piha-Paul Sarina Anne1, Xu Binghe2, Raghav Kanwal Pratap Singh1, Meric-Bernstam Funda1, Janku Filip1, Dumbrava Ecaterina Elena1, Fu Siqing1, Karp Daniel D.1, Rodon Ahnert Jordi1, Conley Anthony Paul3, Mott Frank1, Ajani Jaffer A.1, Hong David S.1, Fan Ying2, Peng Peng4, Levin Wendy J.5, Ngo Brenda5, Ru Qinhua Cindy5, Wu Frank4, Javle Milind M.1
Affiliation:
1. The University of Texas MD Anderson Cancer Center, Houston, TX; 2. Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; 3. University of Texas MD Anderson Cancer Center, Department of Sarcoma Medical Oncology, Houston, TX; 4. TransThera Sciences (Nanjing), Inc., Nanjing, China; 5. CRC Oncology Corp, San Diego, CA;
Abstract
3013 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: This phase I, first-in-human, dose escalation and expansion study of TT-00420 ( NCT03654547 ) enrolled adult patients with advanced or metastatic solid tumors. Capsules in 1 mg or 5 mg formulation were administered orally once daily in 28-day cycles. Dose escalation was guided by Bayesian modeling with overdose control. The primary safety endpoints were to determine dose limiting toxicities (DLTs) and a dose recommended for dose expansion (DRDE). Secondary endpoints included pharmacokinetics (PK) and preliminary efficacy evaluated per RECIST v1.1 criterion. Results: As of February 7, 2022, 48 advanced solid tumor patients were enrolled in the study, 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 = 20), and 15 mg q.d. (N = 6). DLTs were observed in 3 out of 40 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. Among the twenty (20) safety evaluable patients treated at 12 mg, the DRDE, drug-related TEAEs included hypertension (n = 11, 55.0%; Gr 3: n = 6, 30%); diarrhea (n = 7, 35%, Gr 3: n = 1, 5%); mucosal inflammation (n = 7, 35%; Gr 3: n = 1, 5%); palmar-plantar erythrodysaesthesia syndrome (n = 6, 30%; Gr 3: n = 0, 0%); and vomiting (n = 4, 20%; Gr 3: n = 0, 0%). No grade 4 suspected adverse events were reported. Out of 42 patients who had at least one post-baseline scan, 7 (16.7%) had a best response of partial response (PR) and 22 (52.4%) had stable disease (SD). Among 7 PRs, 3 were CCA patients (one for each treated at 8 mg, 10 mg, or 12 mg), 2 were TNBC patients (one for each at 10 mg, or 12 mg), 1 was HER2-negative BC patient at 12 mg, and 1 was CRPC patient at 12 mg. Sustainable stable disease for six months or longer was observed in patients with colon cancer (n = 1), head and neck cancer (n = 1), and peritoneal mesothelioma (n = 1). Conclusions: TT-00420 monotherapy was well tolerated and had favorable PK characteristics. The TEAEs observed in dose escalation and dose expansion cohorts were manageable with concomitant treatment and/or dose interruptions of TT-00420 and reversible upon the discontinuation of TT-00420 treatment. Taking safety, efficacy and clinical PK into consideration, 10 mg p.o. q.d. was recommended for phase II study of TT-00420 in patients with advanced CCA. Clinical trial information: NCT03654547.
Funder
TransThera Sciences (Nanjing), Inc.
Publisher
American Society of Clinical Oncology (ASCO)
Subject
Cancer Research,Oncology
Cited by
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