Background: Chemoresistance may occur through acidification of the tumor microenvironment, impaired uptake and the inhibition of autophagy. PTP is a proton pump inhibitor that reduces gastric acidification in peptic ulcer disease. Our preclinical studies demonstrate that high dose intravenous (IV) PTP increases the nuclear localization and anti-tumor activity of DOX in xenografts, suggesting It may represent a novel approach to increasing tumor sensitivity. The primary objective of this phase 1 trial is to evaluate the recommended phase II dose and safety profile of IV PTP in combination with DOX; secondary objectives are to assess the preliminary anti-tumor activity, evaluate pharmacokinetics (PK) and to evaluate the influence of PTP on DOX distribution in tumor tissue.

Methods: Patients are eligible with advanced solid tumors with no further standard treatment options, an ejection fraction 50% and prior exposure of 240 mg/m2 DOX or 300 mg/m2 of epirubicin. Treatment is with DOX 60mg/m2 with PTP at 4 predetermined dose levels on a 3 weekly schedule using a 3+3 design. The dose limiting toxicity (DLT) period is 21 days. A DLT is defined as CTCAE v4 grade (g) 4 thrombocytopenia; g4 neutropenia 7 days; g3 febrile neutropenia; g3 infection with g3 neutropenia 7 days; g3 nonhematologic toxicities; and any toxicity resulting in the inability to administer day 1 of a planned cycle within 14 days. Study assessments include weekly hematology and biochemistry (C1, 2) then q3wkly (C3); clinical assessment q3wkly, CT imaging q9wkly and cardiac function q6wkly. Plasma samples for DOX PK analysis are collected post dose at 0, 1, 2, 4, 8, 24, 48 and 72 hours.

Results: As of August 2011, a total of 9 patients have been treated at 80 (DL1), 160 (DL2) and 240 mg (DL3) PTP dose levels. The median age was 61 years (42–73), ECOG PS 1, median treatment time 3 cycles (1,8). Treatment related g 3 toxicities are shown (Table 1). Partial response by RECIST v1.1 was achieved in 1 pt and stable disease in 4 pts. Preliminary data demonstrated no effect of pantoprazole on DOX PKs. Mean Cmax at 240mg PTP correlated to levels observed to enhance chemotherapy in our mice xenografts.

Conclusions: The combination is well tolerated and adverse events were consistent with toxicity profile for DOX alone. Objective antitumor activity was seen. Dose escalation is ongoing.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C25.