Tina E. Wood

Gemcitabine Plus nab-Paclitaxel Is an Active Regimen in Patients With Advanced Pancreatic Cancer: A Phase I/II Trial

PURPOSE The trial objectives were to identify the maximum-tolerated dose (MTD) of first-line gemcitabine plus nab-paclitaxel in metastatic pancreatic adenocarcinoma and to provide efficacy and safety data. Additional objectives were to evaluate positron emission tomography (PET) scan response, secreted protein acidic and rich in cysteine (SPARC), and CA19-9 levels in relation to efficacy. Subsequent preclinical studies investigated the changes involving the pancreatic stroma and drug uptake. PATIENTS AND METHODS Patients with previously untreated advanced pancreatic cancer were treated with 100, 125, or 150 mg/m(2) nab-paclitaxel followed by gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 every 28 days. In the preclinical study, mice were implanted with human pancreatic cancers and treated with study agents. RESULTS A total of 20, 44, and three patients received nab-paclitaxel at 100, 125, and 150 mg/m(2), respectively. The MTD was 1,000 mg/m(2) of gemcitabine plus 125 mg/m(2) of nab-paclitaxel once a week for 3 weeks, every 28 days. Dose-limiting toxicities were sepsis and neutropenia. At the MTD, the response rate was 48%, with 12.2 median months of overall survival (OS) and 48% 1-year survival. Improved OS was observed in patients who had a complete metabolic response on [(18)F]fluorodeoxyglucose PET. Decreases in CA19-9 levels were correlated with increased response rate, progression-free survival, and OS. SPARC in the stroma, but not in the tumor, was correlated with improved survival. In mice with human pancreatic cancer xenografts, nab-paclitaxel alone and in combination with gemcitabine depleted the desmoplastic stroma. The intratumoral concentration of gemcitabine was increased by 2.8-fold in mice receiving nab-paclitaxel plus gemcitabine versus those receiving gemcitabine alone. CONCLUSION The regimen of nab-paclitaxel plus gemcitabine has tolerable adverse effects with substantial antitumor activity, warranting phase III evaluation.

Phase I Trial of Weekly Tigatuzumab, an Agonistic Humanized Monoclonal Antibody Targeting Death Receptor 5 (DR5)

BACKGROUND TRA-8 is a murine agonist monoclonal antibody to death receptor 5 (DR5), which is able to trigger apoptosis in DR5 positive human tumor cells without the aid of crosslinking. It has demonstrated cytotoxicity in vitro and in vivo antitumor efficacy to a wide range of solid tumors in murine xenograft models. Tigatuzumab is a humanized IgG1 monoclonal antibody derived from TRA-8. METHODS A phase I trial of tigatuzumab in patients with relapsed/refractory carcinomas (n = 16) or lymphoma (n = 1) was designed to determine the maximal tolerated dose (MTD), pharmacokinetics, immunogenicity, and safety. Three to six (3-6) patients were enrolled in successive escalating cohorts at doses ranging from 1 to 8 mg/kg weekly. RESULTS Seventeen (17) patients enrolled, 9 in the 1-, 2-, and 4-mg/kg dose cohorts (3 in each cohort) and 8 in the 8-mg/kg dose cohort. Tigatuzumab was well tolerated with no DLTs observed, and the MTD was not reached. There were no study-drug-related grade 3 or 4, renal, hepatic, or hematologic toxicities. Plasma half-life was 6-10 days, and no anti-tigatuzumab responses were detected. Seven (7) patients had stable disease, with the duration of response ranging from 81 to 798 days. CONCLUSIONS Tigatuzumab is well tolerated, and the MTD was not reached. The high number of patients with stable disease suggests antitumor activity.

Peripheral neuropathy associated with capecitabine.

5-Fluorouracil (5-FU)-associated peripheral neuropathy is an uncommon event. Capecitabine (CAP) is a pro-drug of 5-FU and peripheral neuropathy associated with CAP has not been reported. During analysis of 28 patients receiving CAP with concomitant radiation (XRT) for pancreatic cancer (resected or locally advanced), two patients developed signs and symptoms consistent with peripheral neuropathy. Patients received CAP 1200–1600 mg/m2 in two divided doses with XRT (total 5040–5400 Gy)×6 weeks, followed by 4 weeks rest, then 6 cycles of CAP 2000–2500 mg/m2 in two divided doses×14 days every (q) 3 weeks. Patients were assessed weekly during CAP-XRT and q 3 weeks during CAP alone. Patient A reported right leg weakness (foot drop) during week 4 of CAP-XRT (1600 mg/m2). Patient B developed perioral and upper extremity paresthesias during the fourth cycle of CAP alone (2500 mg/m2). Dihydropyrimidine dehydrogenase (DPD) activity was measured by radioisotopic assay using lysates of peripheral blood mononuclear cells. Neurologic examination revealed right foot drop in Patient A and was unremarkable in Patient B. Central nervous system imaging was negative. Electromyogram and nerve conduction studies showed sensorimotor peripheral neuropathy in both patients. DPD activity was normal in both patients. There was no evidence of disease progression. Neurologic symptoms resolved after stopping CAP for 4 weeks in Patient A, with no recurrence after reinitiating CAP alone at 2000 mg/m2. Patient B continued at 80% of standard dose (2000 mg/m2) and symptoms resolved without further intervention. We conclude peripheral neuropathy with 5-FU is rare. Neurotoxicity occurs most often with intermittent high dose 5-FU as bolus injection or 24- to 48-h infusions. The etiology of neurotoxicity in our two patients remains unclear; however, as CAP is rapidly metabolized to 5-FU in patients with normal liver function, it is likely that 5-FU or its active metabolites (fluoro-&bgr;-alanine) were contributing factors. Knowledge regarding potential adverse effects of CAP is paramount and dose modification is indicated with development of neurotoxicity.

CA19-9 decrease at 8 weeks as a predictor of overall survival in a randomized phase III trial (MPACT) of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic pancreatic cancer

Any CA19-9 decline at week 8 and radiologic response by week 8 each predicted longer OS in both treatment arms. In the nab-P + Gem arm, the higher proportion of patients with week 8 CA19-9 decrease [82% (206/252); median OS 13.2 months] than a RECIST-defined response [16% (40/252); median OS 13.7 months] suggests that CA19-9 decline is a predictor of OS applicable to a larger population.