Background: FF10502-01 is a synthetic pyrimidine nucleoside analogue that is structurally similar to gemcitabine with a substitution of sulfur for oxygen in the pentose ring. FF-10502-01 showed potent anti-tumor activity in preclinical studies. In Capan-1 and SUIT-2 pancreatic ca xenograft models, FF-502-01 achieved superior tumor growth suppression and survival, respectively, compared to gemcitabine (gem), with less toxicity at clinically relevant doses. In gem-resistant pancreatic PDX models, FF-10502-01, alone and in combination with nab-paclitaxel (nab-pac), had higher efficacy and tolerability than gem/gem+nab-pac.

Methods: We conducted a standard 3+3, dose-escalation phase 1 trial with FF-10502-01 to determine safety, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD) i.e. FF-10502 incorporation into peripheral blood cellular DNA, and preliminary antitumor activity. Eligibility criteria included age >18 years, solid tumors refractory to standard treatment and adequate organ function. FF-10502-01 was administered IV over 60 minutes on days 1, 8, and 15 every 4 weeks. Planned dosing cohorts included 8, 12, 18, 27, 40, 60, 90, 135 and 200 mg/m2. Supportive medications such as anti-nausea prophylaxis were allowed.

Results: 22 patients (pts) have been treated in 6 dose cohorts of 8-60 mg/m2. The median number of cycles received was 2 (range 1 to >12). Pts with the following cancers were enrolled: pancreatic (5 pts); ovarian and cholangiocarcinoma (3 each); parotid gland, prostate, and sarcoma (2 each); and endometrial, squamous cell carcinoma of the head and neck, anal, colon-neuroendocrine, and unknown primary (1 pt each). 11 pts were male and 11 female, median age 63 years (range 21-80), average number of prior cytotoxic therapies 3 (range 1-7) and 9 pts with prior gemcitabine therapy. Common related adverse events were Gr 1/2 nausea (43%), rash (38%), fever (29%), fatigue (19%), and vomiting despite prophylactic ondansetron and dexamethasone (14%). One pt had Gr 3 nausea (a DLT). Cytopenias have been minimal: 2 pts with Gr 1 and 2 anemia; with no neutropenia or thrombocytopenia. No pts have required dose reduction for toxicity. To date, an MTD has not been identified and enrollment continues. A pt with chondroblastic osteogenic sarcoma (18 mg/m2) achieved an unconfirmed partial response (73% decrease) in a maxillary mass but developed progressive disease at another site. 3 currently active patients (1 each of acinar pancreatic, prostate, parotid gland), demonstrated durable stable disease for > 48, 40 and 28 weeks, respectively, at doses ranging from 8 to 27 mg/m2. FF-10502 plasma concentrations increased with dose. Additional PK and PD data will be presented.

Conclusions: The pyrimidine nucleoside antimetabolite FF-10502-01 is well tolerated with prophylactic anti-emetics and demonstrated preliminary antitumor activity in heavily pretreated patients.

Citation Format: Gerald Steven Falchook, Lindsay Bramwell, Lori Hannan, Deeksha Vishwamitra, Takayuki Yamada, Michele Rosner, David Wages, Thomas Myers, Linda Paradiso, Filip Janku. First-in-human phase 1 trial of pyrimidine anti-metabolite FF-10502-01 in patients with advanced cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT100. doi:10.1158/1538-7445.AM2017-CT100