The aim of this study was to determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic profile of E7107 in patients with advanced solid tumors. Patients in this phase I, open-label, single-arm, dose-escalation study had metastatic or locally advanced solid tumors and received E7107 as a 30-minute intravenous infusion at doses of 0.6, 1.2, 1.8, 2.4, 3.2, 4.3, and 5.7 mg/m(2). Twenty-six patients were enrolled in the study. At 5.7 mg/m(2), two patients experienced dose-limiting toxicities including diarrhea, vomiting, dehydration, and myocardial infarction on Days 1-3 following E7107 administration. Three additional patients were recruited at the lower dose and all six patients tolerated E7107 4.3 mg/m(2) with no dose-limiting toxicities. The maximum tolerated dose of E7107 was therefore 4.3 mg/m(2). The most common drug-related adverse events were nausea, vomiting, and diarrhea. Vision loss was experienced by two patients at Cycles 2 and 7, each patient receiving 3.2 mg/m(2) and 4.3 mg/m(2), respectively. This resulted in the study being put on clinical hold. Pharmacokinetic analysis showed that E7107 was rapidly distributed with a moderate elimination half-life (6-13 h) and high clearance. Exposure to E7107 was dose-related. The best tumor response was stable disease in eight patients. E7107 is a unique first-in-class molecule. The incidence of two cases of vision loss probably related to E7107 led to study discontinuation.

BACKGROUND Galectin‐3 is a carbohydrate‐binding protein whose level of expression has been shown to be correlated with metastatic potential in a number of different tumor types. The purpose of this investigation was to examine galectin‐3 expression in several tumorigenic and nontumorigenic prostate cell lines and prostate tissue samples. METHODS The expression of galectin‐3 in cell lines and tissue samples was evaluated by tissue immunohistochemistry and Western blot analysis. RESULTS Human cell lines PC‐3M, PC‐3, DU‐145, PrEC‐1, and MCF10A demonstrated the presence of galectin‐3. Galectin‐3 was not detected in TSU‐pr1 and LNCaP by Western blot analysis. We furthered our studies by examining a series of human prostate tissue samples for expression of galectin‐3. Overall, approximately 60–70% of the normal tissue examined demonstrated heterogenous expression of galectin‐3. In stage II tumors, however, there was a dramatic decrease in galectin‐3 expression in both PIN and tumor sections, with only 10.5% (2/19) of these samples expressing this protein. Stage III tumors also demonstrated a decreased expression of galectin‐3, although this downregulation was not as dramatic, with 35% of PIN samples and 52% of tumor tissue expressing galectin‐3 (P < 0.01). CONCLUSIONS These data demonstrate that galectin‐3 is downregulated in prostate cancer. The altered downregulation pattern of galectin‐3 observed between tumor stages suggests different roles for galectin‐3 in the progression of prostate cancer. Prostate 44:118–123, 2000. © 2000 Wiley‐Liss, Inc.

Background Poly (ADP-ribose) polymerase (PARP) is essential for recognition and repair of DNA damage. In preclinical models, PARP inhibitors modulate topoisomerase I inhibitor-mediated DNA damage. This Phase I study determined the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics (PK) and pharmacodynamics (PD) of veliparib, an orally-bioavailable PARP 1/2 inhibitor, in combination with irinotecan. Methods Patients with advanced solid tumors were treated with 100 mg/m2 irinotecan on days 1 and 8 of a 21-day cycle. Twice-daily (BID) oral dosing of veliparib (10–50 mg) occurred days 3–14 (Cycle 1) and days −1–14 (subsequent cycles) followed by a 6-day rest. PK studies were conducted with both agents alone and in combination. Paired tumor biopsies were obtained after irinotecan alone and veliparib/irinotecan to evaluate PARP1/2 inhibition and explore DNA damage signals (nuclear γ-H2AX and pNBS1). Results Thirty-five patients were treated. DLTs included fatigue, diarrhea, febrile neutropenia, and neutropenia. The MTD was 100 mg/m2 irinotecan (days 1, 8) combined with veliparib 40 mg BID (days −1–14) on a 21-day cycle. Of 31 response-evaluable patients there were 6 (19%) partial responses. Veliparib exhibited linear PK, and there were no apparent PK interactions between veliparib and irinotecan. At all dose levels, veliparib reduced tumor poly(ADP-ribose) (PAR) content in the presence of irinotecan. Several samples showed increases in γ-H2AX and pNBS1 after veliparib/irinotecan compared to irinotecan alone. Conclusions Veliparib can be safely combined with irinotecan at doses that inhibit PARP catalytic activity. Preliminary antitumor activity justifies further evaluation of the combination.