A phase 1 clinical trial of ASG-5ME, a novel drug-antibody conjugate targeting SLC44A4, in patients with advanced pancreatic and gastric cancers.

Purpose ASG-5ME is an antibody-drug conjugate (ADC) targeting SLC44A4, a novel cell surface target expressed on most pancreatic and gastric cancers. This first-in-human study of ASG-5ME evaluated safety, pharmacokinetics, and preliminary activity of ASG-5ME in advanced pancreatic and gastric cancer patients. Experimental Design This phase 1, dose-escalation, multicenter study determined the maximum tolerated dose (MTD) and assessed safety and antitumor activity. The dose-escalation portion enrolled metastatic pancreatic adenocarcinoma patients; gastric adenocarcinoma patients were included in the dose-expansion portion. Patients received ASG-5ME intravenously on Days 1, 8, and 15 of 28-day cycles. Results Thirty-five pancreatic cancer patients (median age 63 years; performance status 0 [40 %] or 1 [60 %]) were treated at doses of 0.3 to 1.5 mg/kg (median duration 8.1 weeks). The MTD was exceeded at 1.5 mg/kg (n = 7) with 1 dose-limiting toxicity (DLT) of Grade 4 gastrointestinal hemorrhage. Four patients experienced non-DLT Grade 3 or 4 neutropenia. Fifteen gastric cancer patients (median age 59 years; performance status 0 [33 %] or 1 [67 %]) were treated at the identified MTD of 1.2 mg/kg (median duration 8.7 weeks). Common drug-related adverse events included fatigue (29 %), nausea (23 %), and vomiting (23 %) for pancreatic cancer patients and fatigue (33 %) and decreased appetite (33 %) for gastric cancer patients. Best clinical response was 1 partial response in each cohort. Disease-control rates of 33 % (pancreatic) and 47 % (gastric) were observed at the MTD. All patient biopsies (23 pancreatic, 15 gastric) expressed the SLC44A4 antigen. Conclusions ASG-5ME treatment was generally well tolerated with limited evidence of antitumor activity.

Phase I dose-escalation study of SGN-75 in patients with CD70-positive relapsed/refractory non-Hodgkin lymphoma or metastatic renal cell carcinoma.

PURPOSE: This first-in-human study evaluated the CD70-targeted antibody-drug conjugate SGN-75 in patients with relapsed or refractory CD70-positive non-Hodgkin lymphoma (NHL) or metastatic renal cell carcinoma (RCC). Methods SGN-75 was administered intravenously to 58 patients (39 RCC, 19 NHL) every 3 weeks (Q3Wk; doses escalated from 0.3 to 4.5 mg/kg) or on Days 1, 8, and 15 of 28-day cycles (weekly; doses of 0.3 or 0.6 mg/kg). Dose-limiting toxicities were evaluated during Cycle 1; treatment response was monitored every 2 cycles. RESULTS: The maximum tolerated dose of SGN-75 in RCC patients was 3 mg/kg Q3Wk. Due to toxicity concerns (idiopathic thrombocytopenic purpura in 2 NHL patients treated weekly), dose escalation in the weekly schedule was terminated; no regimen was recommended for NHL patients. The most common adverse events reported in patients treated Q3Wk (N = 47) were fatigue (40%), dry eye (32%), nausea (30%), and thrombocytopenia (26%). The nadir for thrombocytopenia typically occurred during Cycle 1. Ocular adverse events (e.g., corneal epitheliopathy, dry eye) were reported for 57% of patients treated Q3Wk and were generally reversible. Antitumor activity in patients treated Q3Wk included 1 complete response, 2 partial responses, and 20 stable disease. SGN-75 exposures were approximately dose proportional, with a mean terminal half-life of 10 days. Substantial depletions of CD70-positive peripheral blood lymphocytes were observed after SGN-75 treatment. CONCLUSIONS: Modest single-agent activity and generally manageable adverse events were observed in heavily pretreated RCC and NHL patients. Administration Q3Wk was better tolerated than weekly dosing. Targeted ablation of CD70-positive lymphocytes was demonstrated.

A phase II study of dacetuzumab (SGN-40) in patients with relapsed diffuse large B-cell lymphoma (DLBCL) and correlative analyses of patient-specific factors.

BACKGROUND: Patients with DLBCL who are ineligible for or have relapsed after aggressive salvage chemotherapy have a poor prognosis. CD40 is expressed on multiple B-cell neoplasms including DLBCL and is a potential target for immunotherapy. Dacetuzumab (SGN-40), a non-blocking, partial agonist, humanized IgG1, anti-CD40 monoclonal antibody, has previously demonstrated anti-lymphoma activity in a phase I study. METHODS: A phase II study was undertaken to evaluate the rate and duration of objective responses and safety of single-agent dacetuzumab in relapsed DLBCL. Forty-six adult patients with relapsed/refractory DLBCL received up to 12 cycles of intravenous dacetuzumab using intrapatient dose-escalation to a target dose of 8 mg/kg/week in an initial 5-week cycle, followed by 4-week cycles of 8 mg/kg/week. Study endpoints included rate and duration of objective responses, safety, survival, pharmacokinetics, immunogenicity, and exploratory correlative studies. RESULTS: Overall response rate was 9% and disease control rate (complete remission + partial remission + stable disease) was 37%. Common non-hematologic adverse events (AEs) included fatigue, headache, chills, fever, and nausea. The most frequent Grade 3-4 non-hematologic AE was deep venous thrombosis (3 patients). Grade 3-4 lymphopenia (41%), neutropenia (13%), or thrombocytopenia (19%) occurred without associated infection or bleeding. Reversible ocular events, including conjunctivitis and ocular hyperemia, occurred in 8 patients (17%). Patient-specific factors, including Fc-gamma-RIIIa polymorphism, did not appear to correlate with antitumor activity. CONCLUSIONS: Single-agent dacetuzumab has modest activity and manageable toxicity in unselected patients with relapsed DLBCL. Combination regimens and robust methods of patient selection may be necessary for further development. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00435916.

Pilot study of dacetuzumab in combination with rituximab and gemcitabine for relapsed or refractory diffuse large B-cell lymphoma.

Dacetuzumab, a CD40-targeted, humanized antibody, mediates antitumor activity through effector cell functions and direct apoptotic signal transduction. Preclinical studies demonstrated synergistic activity between dacetuzumab, gemcitabine and rituximab against non-Hodgkin lymphoma in vivo. A phase 1b safety/efficacy study of dacetuzumab in combination with rituximab and gemcitabine was conducted in relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Patients received dacetuzumab at doses of 8 or 12 mg/kg IV weekly with rituximab (375 mg/m(2) IV weekly in cycle 1, then every 28 days) and gemcitabine (1000 mg/m(2) IV, days 1, 8 and 15, or days 1 and 15). Thirty-three patients with a median age of 67 years were enrolled. Common adverse events (≥ 15%) were grade 1/2 cytokine release syndrome, nausea, fatigue, thrombocytopenia, headache, decreased appetite, dyspnea, neutropenia, pyrexia, anemia, diarrhea, edema, constipation and cough. Dacetuzumab-related grade 3/4 adverse events occurred infrequently. Six of 30 evaluable patients achieved a complete response (CR) and eight a partial response (PR) per investigator assessment for an overall response rate (ORR) of 47%.