The Lynx Group
Cholangiocarcinoma News

FDA Grants TT-00420, a Multi-Kinase Inhibitor, Fast-Track Review for Cholangiocarcinoma

Web Exclusives — November 9, 2021

On November 3, 2021, TransThera Sciences announced that the FDA granted its investigational drug, TT-00420, a spectrum-selective multi-kinase inhibitor, a fast-track designation for the treatment of patients with cholangiocarcinoma (CCA) who have no available standard treatment options.1 In preclinical studies, TT-00420 has shown high activity in a variety of FGFR mutations.1

In November 2019, the FDA granted TT-00420 an orphan drug designation for CCA.1 TT-00420 targets cell proliferation, angiogenesis, and immune pathways by inhibiting kinases that are “involved in cytokine signaling and receptor tyrosine kinases (FGFRs and VEGFRs) involved in the tumor microenvironment.”2

The new FDA designation is based on the results of a phase 1, first-in-human dose-escalation clinical trial that evaluated TT-00420 in patients with several advanced or metastatic solid tumors, including triple-negative breast cancer and CCA. The primary end point was dose escalation. Secondary end points were pharmacokinetics and preliminary efficacy.2

As of February 17, 2021, 40 patients were enrolled in dose-escalation cohorts, including 9 patients with CCA, of whom at least 7 patients had ≥1 posttreatment efficacy assessments. Among the evaluable patients with CCA, 5 had an FGFR fusion or rearrangement, as well as resistance to treatment with a previous FGFR inhibitor.

The patients received 1 of 7 doses of TT-00420, including 1 mg, 3 mg, 5 mg, 8 mg, 10 mg, 12 mg, and 15 mg daily. In all, 2 patients with CCA achieved a partial response to TT-00420 therapy that lasted ≥8 months, and 2 patients had stable disease that lasted ≥6 months.1,2 In addition, 1 patient with CCA achieved a partial response within approximately 10 months, and 1 patient who responded to TT-00420 had an 8-month progression-free survival; another patient with CCA but with no FGFR alteration reached stable disease, with a reduction in the tumor size.1,2

“We have been and will continue to actively work with the FDA, expediting the clinical development of TT-00420 in the CCA field,” said Frank Wu, PhD, Chief Executive Officer at TransThera, in the press release.1

TT-00420 has demonstrated high potency in several cancers with FGFR2 mutation. Its molecular profile and mechanism of action facilitate the treatment of patients with heterogeneous tumors, including those who do not have a clear biomarker.

The most common adverse effects of any grade included hypertension (42.5%), diarrhea (25%), vomiting (22.5%), palmar-plantar erythrodysesthesia syndrome (22.5%), and nausea (20%). The most common grade 3 events were hypertension (20%), diarrhea (2.5%), palmar-plantar erythrodysesthesia syndrome (2.5%), and nausea (2.5%).

References

  1. PR Newswire. TransThera receives fast track designation from FDA for its core product TT-00420 to treat cholangiocarcinoma. November 3, 2021. www.prnewswire.com/news-releases/transthera-receives-fast-track-designation-from-fda-for-its-core-product-tt-00420-to-treat-cholangiocarcinoma-301415291.html. Accessed November 8, 2021.
  2. Piha-Paul SAA, Xu B, Janku F, et al. Phase I study of TT-00420, a multiple kinase inhibitor, as a single agent in advanced solid tumors. J Clin Oncol. 2021;39(15_suppl):Abstract 3090. doi: 10.1200/JCO.2021.39.15_suppl.3090.

Related Items

Phase 1 Results of Gunagratinib in Patients with Advanced Solid Tumors Harboring FGFR Pathway Alterations
2021 Year in Review: Cholangiocarcinoma
A phase 1/2a, first-in-human clinical study demonstrated that the highly selective, irreversible pan-FGFR inhibitor gunagratinib was safe and well-tolerated in patients with advanced solid tumors, including CCA.
Prognostic Value of FGFR2 Alterations in Patients Receiving Systemic Chemotherapy for Intrahepatic CCA
2021 Year in Review: Cholangiocarcinoma
A retrospective analysis indicated the prognostic value of FGFR2 fusions/rearrangements in patients with intrahepatic CCA receiving systemic chemotherapy, which warrants additional study.
FGFR2 Fusion and/or Rearrangement Profiling in Chinese Patients with Intrahepatic CCA
2021 Year in Review: Cholangiocarcinoma
Epidemiologic data assessed the incidence rate of FGFR2 gene fusion or rearrangement in Chinese patients with intrahepatic CCA, including those with heterogeneous FGFR2 partner genes.
A Comprehensive Genomic and Immune Profiling Study of IDH1- and IDH2-Driven Intrahepatic CCA
2021 Year in Review: Cholangiocarcinoma
A comprehensive genomic and immune characterization of IDH-mutated and wild-type intrahepatic CCA revealed significant differences in genetic alterations.
Characteristics of IDH Mutations in Bile Duct Carcinoma in a Chinese Population
2021 Year in Review: Cholangiocarcinoma
A retrospective analysis in a large Chinese patient cohort with bile duct carcinoma indicated that activating IDH1/2 mutations occurred at a lower rate compared with that previously reported in the global population.
Silmitasertib (CX-4945) plus Gemcitabine and Cisplatin as First-Line Treatment for Patients with Locally Advanced or Metastatic CCA
2021 Year in Review: Cholangiocarcinoma
Preliminary evidence suggests that combination treatment with silmitasertib plus gemcitabine/cisplatin as first-line therapy has promising efficacy and a favorable safety profile in patients with locally advanced or metastatic CCA.
Targeted Therapies in CCA: Assessment of US Oncologist Practice Patterns
2021 Year in Review: Cholangiocarcinoma
Findings from a clinical practice assessment identified gaps in knowledge, competence, and confidence regarding testing and the use of targeted therapies in patients with unresectable CCA, underscoring the important role of education in overcoming these gaps.
First-Line Toripalimab plus Lenvatinib in Combination with GemOx Chemotherapy for Advanced Intrahepatic CCA
2021 Year in Review: Cholangiocarcinoma
Results of a phase 2 study indicate that toripalimab and lenvatinib in combination with GemOx chemotherapy provide antitumor activity and reasonable tolerability in patients with advanced intrahepatic CCA.
Comparative Landscape of Actionable Somatic Alterations in Advanced CCA from Circulating Tumor and Tissue-Based DNA Profiling
2021 Year in Review: Cholangiocarcinoma
Findings from a retrospective analysis support the use of both tissue and liquid biopsy biomarker testing to guide therapy selection in patients with advanced CCA, particularly when tissue may not be readily available.
Tibsovo (Ivosidenib) FDA Approved for Advanced or Metastatic Cholangiocarcinoma and IDH1 Mutation
By Loretta Fala
2021 Year in Review: Cholangiocarcinoma
Cholangiocarcinoma (CCA) is an aggressive cancer of the bile duct that forms inside the liver (ie, intrahepatic) or outside the liver (ie, extrahepatic, including perihilar and distal tumors). Individuals with colitis or certain liver diseases may have an increased risk for CCA. Although the precise incidence of CCA is unknown, an estimated 8000 new cases of CCA are diagnosed annually in the United States. It is likely, however, that this number is higher, because CCA is difficult to diagnose and may be misclassified at times.

Subscribe to CCA News

Stay up to date with personalized medicine by subscribing to receive the free CCA News print publication or weekly e‑Newsletter.

I'd like to receive: