TAS-106 IN COMBINATION WITH CARBOPLATIN IS ACTIVE IN PATIENTS WITH REFRACTORY NON-SMALL CELL LUNG CANCER AND OVARIAN CANCER

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Abstract

Background

TAS-106 is a nucleoside 3′-C-ethynylcytidine that inhibits RNA polymerases I, II and III. Preclinical studies have shown that TAS-106 acts synergistically in combination with a platinum agent. We designed a 3 + 3 dose-finding trial of TAS-106 and carboplatin to assess toxic effects, maximum tolerated dose (MTD) and activity.

Methods

This phase I trial was comprised of a regimen of a 60-minute IV infusion of carboplatin on day 1 of each 21-day cycle followed by a 24-hour infusion of TAS-106, also on day 1 of each cycle. The combination was administered at different dose levels as shown in table.

Results

39 patients were treated (male 21, female 18, median age = 62 yrs, range 21–80). Median number of prior therapies is 4.Twenty eight patients had received prior platinum. Diagnoses included: non-small cell lung cancer (NSCLC, n = 13), colorectal (n = 10), squamous cell carcinoma (n = 4), breast (n = 3), adenocystic carcinoma (n = 2), ovarian cancer (n = 2), neuroendocrine (n = 1), endometrial (n = 1), pancreatic (n = 1), Merkel cell (n = 1), and basal cell carcinoma (n = 1). Grade 3 & 4 drug-induced toxic effects included neutropenia (n = 20), thrombocytopenia (n = 4) and anemia (n = 5). Dose-limiting toxic effects were neutropenia and thrombocytopenia, with and without growth factor support. Stable disease >4 months was seen in NSCLC (n = 3) for 5, 5 and 10 months, ovarian cancer (n = 1) for 8 months, basal cell cancer (n = 1) for 6 months, and colorectal cancer (n = 1) for 6 months. Four of 6 patients with SD = or >4 months had previous exposures to a platinum compound.

Conclusions

TAS-106 in combination with carboplatin was well tolerated. MTD was TAS-106 3 mg/m2 and carboplatin AUC 4. SD = or >4 months was seen in different tumor types, suggesting that further study is warranted for this combination in advanced cancer.

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