An open label phase I dose escalation study of ADH-1 in combination with chemotherapy in subjects with N-Cadherin expressing solid tumors

Abstract

14529 Background: Malignant transformation and invasive capacity is highly correlated with the expression on tumor cells of N-cadherin (N- cad), a cell signaling and adhesion molecule. ADH-1, a cyclic pentapeptide (CHAVC), is a functional inhibitor of N-cad, and produces apoptosis and tumor vascular disruption in preclinical models. We report results from a phase 1, multicenter, dose-escalation study of ADH-1 in combination with either 1) carboplatin (C) or 2) docetaxel (T) or 3) capecitabine (CAPE) in subjects with N-cad positive, advanced solid tumors. Methods: 35 patients whose tumors expressed N-cad by IHC and had advanced solid tumors with measurable disease (per RECIST criteria) for which treatment with either C, T, or CAPE was appropriate were enrolled. Most patients were heavily pre-treated (57% had received at least 5 previous antineoplastic agents). A 3+3 rule of dose escalation was used to determine the maximum tolerated dose (MTD). ADH-1 dose levels were 1.0 gm, 2.0 gm and 4.0 gm in succeeding cohorts. C was concurrently administered at a dose of AUC 5 on day 1 of each 28 day cycle with ADH-1 administrations on days 1, 8, 15, and 22. 75 mg/m^2 of T was concurrently administered on day 1 of each 21 day cycle with ADH-1 administrations on days 1, 8, and 15. 1000 mg/m^2 of CAPE was administered po bid on days 1–14 of each 21 day cycle with ADH-1 administrations on days 1, 8, and 15. Results: 10 patients have been enrolled on the C arm (6 - 1gm, 4 - 2gm), 11 on the T arm (3 - 1 gm, 3 - 2gm, 5 - 4gm), and 14 (3 - 1gm, 6 - 2gm, 5 - 4gm) on the CAPE arm. The MTD of T in combination with ADH-1 is 2.0 gm. The MTD for the CAPE and C arms has not, as yet, been reached. 2 partial responses (CAPE arm) and 4 stable diseases that lasted at least 2 cycles (3 on T arm and 1 on CAPE arm) were documented. The DLTs consisted of grade 4 febrile neutropenia, grade 3 mucositis, grade 2 and 3 nausea/vomiting, grade 3 thrombocytopenia, and grade 3 hand/foot syndrome. No pharmacokinetic data were collected during this study. Conclusions: ADH-1 was generally well tolerated and there was some evidence of antitumor activity in heavily pretreated patients in combination with docetaxel and capecitabine. The DLT of ADH-1 in combination with docetaxel was myelosuppression. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Adherex Adherex Adherex Technologies Adherex Technologies Adherex Technologies