BACKGROUND:Methylnaltrexone has been shown to be effective for treating opioid-induced constipation (OIC) in chronic settings, but its effects on acute OIC have not been studied.

Although the efficacy of methylnaltrexone in reducing the duration of postoperative ileus was not demonstrated in these studies, intravenous methylnaltrexone at doses of 12 mg and 24 mg was safe, in general, and well tolerated in postcolectomy patients. The utility of intravenous methylnaltrexone in treating postoperative ileus remains unproven.

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4662 Background: The abundant expression of prostate specific membrane antigen (PSMA) type II transmembrane glycoprotein on prostate cancer cells provides a rationale for antibody therapy. PSMA ADC, a fully humanized antibody to PSMA linked to the potent antitubulin agent monomethyl auristatin E (MMAE), binds PSMA and is internalized within the prostate cancer cell where cleavage by lysosomal enzymes and releases free MMAE, causing cell cycle arrest and apoptosis. We report results from an ongoing phase 1 dose escalation study of PSMA ADC in subjects with taxane-refractory mCRPC. Methods: Eligibility requirements include progressive mCRPC following taxane-containing chemotherapy and ECOG status of 0 or 1. PSMA ADC was administered by IV infusion Q3W for up to 4 cycles. Adverse events, pharmacokinetics (PK), PSA, circulating tumor cells, clinical disease progression and immunogenic response to PSMA ADC were assessed. Serum PSMA ADC and total antibody were measured by ELISA, and free MMAE was measured by LC/MS/MS.The dosing cohorts range from 0.4 mg/kg to 2.8 mg/kg, with dose escalation continuing. Results: 40 subjects have been dosed in nine dose levels (0.4, 0.7, 1.1, 1.6, 1.8, 2.0, 2.2, 2.5, 2.8 mg/kg). To date, PSMA ADC has been well tolerated with the most commonly seen adverse events being anorexia and nausea, and the most common laboratory abnormalities being reversible hematologic parameters and liver function tests. Antitumor activity has been manifested as reductions either in PSA or circulating tumor cells in the higher dose cohorts. Exposure to PSMA ADC increased with dose and was ~1,000-fold greater than MMAE exposure. Similar PK metrics were observed after the first and third doses. Dosing at the 2.8 mg/kg cohort is continuing and an MTD has not yet been reached. Conclusions: PSMA ADC is generally well tolerated in subjects with mCRPC, previously treated with taxane in doses up to 2.8 mg/kg. Antitumor activity at higher dose levels has been observed. The MTD has not yet been reached and enrollment is ongoing at higher dose levels.

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