Initial signals of efficacy in cholangiocarcinoma from a phase Ib trial of varlitinib in combination with doublet chemotherapy (cisplatin + 5-fluororacil or capecitabine).

Abstract

e15671 Background: Varlitinib (ASLAN001) is a potent, reversible, small molecule pan-HER inhibitor that selectively binds to HER1 (IC50 7nM), HER2 (IC50 2nM) and HER4 (IC504nM). Clinical data in cholangiocarcinoma, gastric cancer, colorectal cancer and breast cancer indicate that varlitinib is a safe and well tolerated inhibitor of tumor growth and survival. Here we conducted a phase Ib trial to determine the safety and early efficacy signals of varlitinib in combination with cisplatin (CIS) and 5-fluorouracil (5-FU) or CIS and capecitabine (CAP). Methods: Eligible patients had metastatic solid tumors. Doses of varlitinib were escalated in a standard 3+3 design with corresponding chemotherapy for 6 cycles after which patients remained on varlitinib montherapy. Responses were defined using RECIST 1.1 criteria. Results: To date, 27 patients have been enrolled. Most common treatment related adverse events ( > 10%) were nausea (56%; ≥G3 4%), vomiting (48%; ≥G3 4%), decreased appetite (44%; ≥G3 7%), diarrhea (37%; ≥G3 11%), anemia (26%; ≥G3 11%), fatigue (22%; ≥G3 0%), creatinine increase (19%; ≥G3 4%), stomatitis (15%; ≥G3 4%), acute kidney injury (11%; ≥G3 11%), bilirubin increase (11%; ≥G3 7%), leukopenia (11%; ≥G3 7%), abdominal pain (11%; ≥G3 0%), and neutropenia (11%; ≥G3 0%). All patients with diarrhea, including those with G3 diarrhea were well controlled with standard doses of loperamide. Of 15 patients evaluable for response, three had partial response (20%), ten had stable disease (67%), and two had progressive disease (13%). Of note were strong and durable responses in cholangiocarcinoma. One cholangiocarcinoma patient demonstrated an 87% reduction in liver tumor size by cycle 2 and a complete resolution in one liver lesion by cycle 4. Another cholangiocarcinoma patient without measurable lesions in the liver or biliary tract achieved long-term disease control for a total of 15.2 months with good tolerability on varlitinib as monotherapy. Conclusions: The combination of varlitinib and CIS + 5-FU or CAP doublet chemotherapy is safe, well tolerated and has demonstrated strong efficacy signals in cholangiocarcinoma. Clinical trial information: NCT02648425.