A phase 1/2a safety, pharmacokinetics, and efficacy study of the novel nucleoside analog FF-10502-01 for the treatment of advanced solid tumors

Filip Janku; Milind M Javle; Shiraj Sen; Shubham Pant; Lindsay G Bramwell; Vivek Subbiah; Tracey Way; David S Wages; Catherine A Wheeler; Takeaki Suzuki; Kazunori Saeki; Ruth Ann Subach; Timothy Madden; Gary Maier; Mary J Johansen; Kin Cheung; Gerald S Falchook

doi:10.1002/cncr.34709

A phase 1/2a safety, pharmacokinetics, and efficacy study of the novel nucleoside analog FF-10502-01 for the treatment of advanced solid tumors

Cancer. 2023 May 15;129(10):1537-1546. doi: 10.1002/cncr.34709. Epub 2023 Mar 7.

Authors

Filip Janku¹, Milind M Javle², Shiraj Sen³, Shubham Pant², Lindsay G Bramwell³, Vivek Subbiah¹, Tracey Way³, David S Wages⁴, Catherine A Wheeler⁴, Takeaki Suzuki⁴, Kazunori Saeki⁵, Ruth Ann Subach⁴, Timothy Madden⁴, Gary Maier⁴, Mary J Johansen⁴, Kin Cheung⁴, Gerald S Falchook³

Affiliations

¹ Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
² Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
³ Sarah Cannon Research Institute at HealthONE, Denver, Colorado, USA.
⁴ FUJIFILM Pharmaceuticals U.S.A., Inc., Cambridge, Massachusetts, USA.
⁵ FUJIFILM Corporation, Tokyo, Japan.

PMID: 36882377
DOI: 10.1002/cncr.34709

Abstract

Background: The nucleoside FF-10502-01, structurally similar to but with different biologic effects than gemcitabine, shows promising activity both alone and combined with cisplatin in preclinical gemcitabine-resistant tumor models. We conducted an open-label, single-arm, 3 + 3 first-in-human trial to explore the safety, tolerability, and antitumor activity of FF-10502-01 in patients with solid tumors.

Methods: Patients with inoperable metastatic tumors refractory to standard therapies were enrolled. Escalating intravenous FF-10502-01 doses (8-135 mg/m² ) were administered weekly for 3 weeks in 28-day cycles until progressive disease or unacceptable toxicity was observed. Three expansion cohorts were subsequently evaluated.

Results: A phase 2 dose of 90 mg/m² was determined after evaluating 40 patients. Dose-limiting toxicities included hypotension and nausea. Phase 2a enrolled patients with cholangiocarcinoma (36), gallbladder cancer (10), and pancreatic/other tumors (20). Common adverse events were grade 1-2 rash, pruritus, fever, and fatigue. Grade 3 or 4 hematologic toxicities were observed at low incidences, including thrombocytopenia (5.1%) and neutropenia (2%). Confirmed partial responses (PRs) occurred in five patients with gemcitabine-refractory tumors, including three with cholangiocarcinoma and one each with gallbladder and urothelial cancer. Median progression-free and overall survival rates in patients with cholangiocarcinoma were 24.7 and 39.1 weeks, respectively. Prolonged progression-free survival in patients with cholangiocarcinoma was associated with BAP1 and PBRM1 mutations.

Conclusion: FF-10502-01 was well tolerated with manageable side effects and limited hematologic toxicity. Durable PRs and disease stabilizations were observed in heavily pretreated biliary tract patients who had received prior gemcitabine. FF-10502-01 is distinct from gemcitabine and may represent an effective therapy.

Keywords: BAP1; FF-10502-01; PBRM1; antimetabolite; cholangiocarcinoma; nucleoside; solid tumors.

Publication types

Clinical Trial, Phase I
Clinical Trial, Phase II
Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Combined Chemotherapy Protocols / adverse effects
Bile Duct Neoplasms*
Bile Ducts, Intrahepatic
Cholangiocarcinoma* / drug therapy
Deoxycytidine
Gallbladder Neoplasms*
Gemcitabine
Humans

Substances

Deoxycytidine
Gemcitabine