Disease	Advanced cancer/solid tumor only
Stage of Disease/Treatment	Metastatic/advanced
Prior Therapy	1 prior regimen
Type of Study	Phase I, 3+3
Primary Endpoint	Safety
Secondary Endpoint	Pharmacodynamics, other
Additional Details of Endpoints or Study Design
This multicenter, open‐label, phase I dose‐escalation study enrolled 46 patients with advanced solid tumors from February 23, 2017 to March 8, 2019. It was designed to evaluate the safety and tolerability of SGN‐2FF, identify the MTD or optimal biological dose of SGN‐2FF, and characterize the PK, PD, and antitumor activity of SGN‐2FF as monotherapy and in combination with pembrolizumab.
This study consisted of four parts including dose‐escalation, dose finding, and biopsy (part A) and expansion (part B) cohorts for SGN‐2FF monotherapy, and dose‐escalation (part C) and expansion (part D) cohorts for SGN‐2FF in combination with pembrolizumab. The monotherapy and combination therapy dose‐escalation parts were conducted using a standard 3+3 design to determine a dose that demonstrated a dose‐limiting toxicity (DLT) rate less than 33%.
Patients enrolled in part A and part B had histologically or cytologically confirmed, locally advanced, or metastatic solid malignancy that was relapsed, refractory, or progressing after prior systemic therapy, and for which no standard therapy was available. Eligible diagnoses for patients in parts A and B were non‐small cell lung cancer, squamous cell carcinoma of the head and neck, breast carcinoma, urothelial carcinoma, colorectal carcinoma, and renal cell carcinoma. Patients enrolled in part C had a histologically confirmed, advanced solid malignancy for which pembrolizumab treatment is approved. Part D did not enroll any patients.
Key inclusion criteria were age ≥ 18 years, Eastern Cooperative Oncology Group performance status 0–1, adequate hematologic and end organ function, and measurable disease. After thromboembolic events occurred in five patients (16%) in part A of the trial, the eligibility criteria were updated on September 17, 2018, to require that patients with a history of prior deep vein thrombosis (DVT) but no evidence of clot per screening ultrasound, as well as those with a history of pulmonary embolism (PE) ≥4 weeks prior to the first dose of SGN‐2FF, be receiving therapeutic anticoagulation to decrease the risk of a recurrent thromboembolic event (TE). Subsequently, to further protect patient safety, all patients except for those who were already receiving therapeutic anticoagulation were mandated as of September 17, 2018, to receive prophylaxis with LMWH. At the same time, D‐Dimer testing and reflexive Doppler ultrasound were added as required baseline screening procedures for all newly enrolled patients and the presence of DVT was added as an exclusion criterion.
Adverse events (AEs) were graded using the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.03. The DLT evaluation period for part A was 28 days from the first dose of SGN‐2FF. A DLT was defined as any of the following: grade 5 toxicity; any grade 3 or grade 4 nonhematologic toxicity (excluding nausea, vomiting, and/or diarrhea lasting ≤3 days and reversible with medical intervention); any grade 3 or grade 4 nonhematologic laboratory value that did not downgrade to grade 2 within 3 days after onset despite optimal medical management; grade 4 hematologic toxicity lasting ≥7 days; or grade ≥ 3 febrile neutropenia.
Antitumor activity was assessed by radiographic imaging at protocol‐specified time points and based on objective response assessments as defined by RECIST version 1.1 and irRECIST [2, 3].
Blood samples for PK assessments were collected at 12 selected time points in cycle 1 on days 1, 4, 8, and 15. PD biomarker assessments included complete blood count, IgG fucosylation, and lectin binding of peripheral blood leukocytes. Fucosylated and nonfucosylated IgG1 and IgG2 were quantified using liquid chromatography‐tandem mass spectrometry to evaluate IgG fucosylation levels.
Investigator's Analysis	Demonstration of PD target inhibition of fucosylation and preliminary antitumor activity.