Background A single center phase Ib/II study of gemcitabine, nab-paclitaxel, and pembrolizumab (GNP) to evaluate the safety and efficacy in metastatic pancreatic adenocarcinoma (PDAC) was conducted (NCT02331251). Methods PDAC patients (pts) with measurable disease, biopsy proven metastasis, adequate laboratory tests, and KPS ≥ 70% received GNP until progression or toxicity. Safety monitoring, RECIST 1.1, and irRECIST assessments were conducted. Response imaging was performed prior to cycle 4, then every 3 months. Changes in tumor cell-free DNA copy number instability (CNI) was retrospectively evaluated. Results 17 pts. with a median age of 56 were treated. 11 were women and all had a KPS of at least 80%. Grade 3 events occurred in 53% of patients. The phase II portion was completed for chemotherapy naïve PDAC pts. Of the 11 evaluable chemotherapy naïve PDAC, the disease control rate (partial response [PR] + stable disease[SD]) was 100%. There were 3 with PR on treatment for 8+, ~11, and 15 months; respectively. The primary endpoint of >15% complete response was not met. The median progression-free survival (PFS) and overall survival (OS) was 9.1 and 15.0 months for chemotherapy naïve treated patients. Of 9 patients evaluable for CNI change, a greater reduction in CNI correlated with longer PFS and improved OS. Conclusions GNP can be safely given to chemotherapy naïve PDAC patients. Efficacy appears to be slightly improved over previously reported results for standard weekly × 3 every 28 day gemcitabine and nab-paclitaxel dosing. CNI change may be prognostic for OS.
Background:Pembrolizumab (P) is an anti-PD-1 antibody that blocks the interaction between programmed cell death protein 1 (PD-1) on T-cells and PD-L1 and PD-L2 on tumour cells. A phase Ib trial of P plus chemotherapy was undertaken to evaluate the safety and efficacy.Methods:Patients with advanced, metastatic solid tumours were enrolled onto one of six treatment arms. Pembrolizumab was given: with gemcitabine (G), G+docetaxel (D), G+nab-paclitaxel (NP), G+vinorelbine (V) or irinotecan (I) until progression or toxicity, or with liposomal doxorubicin (LD) for up to 15 cycles, progression or toxicity. Safety monitoring and response assessments were conducted.Results:Forty-nine patients were enrolled and treated. The most common adverse events were transaminitis, cytopenias, rash, diarrhoea, fatigue, nausea and vomiting. Arm 2 was closed due to poor accrual. The recommended phase II dose (RP2D) was determined for Arms 1, 3a, 4, 5 and 6. There were eight partial responses across multiple tumour types.Conclusions:Standard dose P can be safely combined with G, G+NP, G+V, I and LD. Efficacy was observed in multiple tumour types and evaluation to determine if response and duration of response are more robust than what would be expected for chemotherapy or immunotherapy alone requires further validation.
Purpose: Study objectives included evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of VX15/2503 in advanced solid tumor patients.Experimental Design: Weekly i.v. doses were administered on a 28-day cycle. Safety, immunogenicity, PK, efficacy, T-cell membrane-associated SEMA4D (cSEMA4D) expression and saturation, soluble SEMA4D (sSEMA4D) serum levels, and serum biomarker levels were evaluated.Results: Forty-two patients were enrolled into seven sequential cohorts and an expansion cohort (20 mg/kg). VX15/2503 was well tolerated. Treatment-related adverse events were primarily grade 1 or 2 and included nausea (14.3%) and fatigue (11.9%); arthralgia, decreased appetite, infusion-related reaction, and pyrexia were each 7.3%. One pancreatic cancer patient (15 mg/kg) experienced a Grade 3 dose-limiting toxicity; elevated g-glutamyl transferase.Complete cSEMA4D saturation was generally observed at serum antibody concentrations !0.3 mg/mL, resulting in decreased cSEMA4D expression. Soluble SEMA4D levels increased with dose and infusion number. Neutralizing anti-VX15/2503 antibodies led to treatment discontinuation for 1 patient. VX15/2503 C max and AUC generally increased with dose and dose number. One patient (20 mg/kg) experienced a partial response, 19 patients (45.2%) exhibited SD for !8 weeks, and 8 (19%) had SD for !16 weeks. Subjects with elevated B/T lymphocytes exhibited longer progression-free survival.Conclusions: VX15/2503 was well tolerated and produced expected PD effects. The correlation between immune cell levels at baseline and progression-free survival is consistent with an immune-mediated mechanism of action. Future investigations will be in combination with immunomodulatory agents. Clin Cancer Res; 22(4); 827-36. Ó2015 AACR.
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