Safety and Efficacy of Andecaliximab (GS-5745) Plus Gemcitabine and Nab-Paclitaxel in Patients with Advanced Pancreatic Adenocarcinoma: Results from a Phase I Study.

BACKGROUND: Matrix metalloproteinase 9 (MMP9) expression in the tumor microenvironment is implicated in multiple protumorigenic processes. Andecaliximab (GS-5745), a monoclonal antibody targeting MMP9 with high affinity and selectivity, was evaluated in combination with gemcitabine and nab-paclitaxel in patients with advanced pancreatic adenocarcinoma. PATIENTS AND METHODS: This phase I study was completed in two parts: part A was a dose-finding, monotherapy phase that enrolled patients with advanced solid tumors, and part B examined andecaliximab in combination with chemotherapy in specific patient cohorts. In the cohort of patients with pancreatic adenocarcinoma (n = 36), andecaliximab 800 mg every 2 weeks was administered in combination with gemcitabine and nab-paclitaxel. Patients were treated until unacceptable toxicity, withdrawal of consent, disease progression, or death. Efficacy, safety, and biomarker assessments were performed. RESULTS: Andecaliximab combined with gemcitabine and nab-paclitaxel appeared to be well tolerated and did not demonstrate any unusual toxicities in patients with pancreatic adenocarcinoma. The most common treatment-emergent adverse events were fatigue (75.0%), alopecia (55.6%), peripheral edema (55.6%), and nausea (50.0%). Median progression-free survival was 7.8 months (90% confidence interval, 6.9-11.0) with an objective response rate of 44.4% and median duration of response of 7.6 months. Maximal andecaliximab target binding, defined as undetectable, andecaliximab-free MMP9 in plasma, was observed. CONCLUSION: Andecaliximab in combination with gemcitabine and nab-paclitaxel demonstrates a favorable safety profile and clinical activity in patients with advanced pancreatic adenocarcinoma. IMPLICATIONS FOR PRACTICE: The combination of andecaliximab, a novel, first-in-class inhibitor of matrix metalloproteinase 9, with gemcitabine and nab-paclitaxel in patients with advanced pancreatic adenocarcinoma provided a median progression-free survival of 7.8 months and objective response rate of 44.4%. The majority of systemic biomarkers related to matrix metalloproteinase 9 activity and immune suppression increased at 2 months, whereas biomarkers related to tumor burden decreased. Although this study demonstrates promising results with andecaliximab plus chemotherapy in patients with advanced pancreatic adenocarcinoma, andecaliximab was not associated with a survival benefit in a phase III study in patients with advanced gastric/gastroesophageal junction carcinoma.

Phase III safety study of rituximab administered as a 90-minute infusion in patients with previously untreated diffuse large B-cell and follicular lymphoma.

This phase III, multicenter, single-arm trial investigated the impact of 90 min rituximab infusions on infusion-related reactions (IRRs) in patients with untreated diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL). Patients received six or eight cycles of rituximab plus cyclophosphamide, vincristine, doxorubicin and prednisone for DLBCL or plus cyclophosphamide, vincristine and prednisolone for FL. A total of 425 patients received the first rituximab infusion per standard guidelines; median duration 240 min. Patients who did not experience grade ≥ 3 IRRs received subsequent infusions over 90 min (363 patients). A total of 303 patients received ≥ 6 cycles of rituximab. Fifty-three patients withdrew after cycle 1; 10 for grade 3 or 4 IRRs and one for a grade 3 adverse event. During cycle 2, 139 patients had IRRs, including four grade 3 IRRs. A 90 min rituximab infusion is well tolerated and feasible for patients with DLBCL or FL who tolerate the first standard rate infusion.