Daiichi Sankyo Company, Limited announced that the first patient has been dosed in a first-in-human global phase 1 study evaluating DS-1055, a GARP directed immuno-oncology therapy, in patients with advanced or metastatic solid tumors who have progressed on standard treatments including checkpoint inhibitors.
Immune checkpoint inhibitors have significantly impacted the treatment paradigm for several cancers over the past decade with improved survival for subsets of patients, but the majority of patients do not respond to current therapies or eventually develop resistance. GARP is highly expressed on activated regulatory T cells (Tregs) and contributes to their immunosuppressive activity. Research suggests that targeting GARP on Tregs may be a promising new immune intervention strategy. There are no GARP directed therapies currently approved for cancer treatment.
“We are pleased to initiate clinical development to further evaluate the novel mechanism behind DS-1055, which was specifically designed to decrease the number of GARP expressing regulatory T cells and restore antitumor immune response,” said Arnaud Lesegretain, vice president, Global Oncology Development, Alpha Portfolio, Daiichi Sankyo. “Evidence suggests that DS-1055 could serve as a new type of immune-based therapy for patients with various cancers, including those resistant or refractory to checkpoint inhibitors.”
The first-in-human, global, multi-center, open-label phase 1 dose escalation study will evaluate the safety, tolerability and preliminary efficacy of DS-1055 in adult patients with relapsed/refractory advanced or metastatic head and neck, gastric and esophageal cancers and other tumor types. The purpose of this study is to determine the maximum tolerated dose and recommended dose of DS-1055 for further study.
The study will evaluate safety endpoints including dose-limiting toxicities and adverse events. Efficacy endpoints include objective response rate, disease control rate, duration of response, time to response, progression-free survival and overall survival. Pharmacokinetic, immunogenicity and biomarker endpoints will also be assessed.
DS-1055 is a monoclonal antibody designed to target GARP (Glycoprotein-A Repetitions Predominant), a transmembrane protein expressed on the surface of activated Tregs in the tumor microenvironment. DS-1055 was designed to promote antitumor immunity through the depletion of GARP positive Tregs.
Tregs are involved in immune tolerance and have strong immunosuppressive activity. Tregs are accumulated in the tumor microenvironment, where they are activated and inhibit antitumor immunity through various mechanisms leading to suppression of effector T cells with antitumor activity. Tregs also cause resistance to immune checkpoint inhibitors. High Treg presence in the tumor microenvironment is associated with poor prognosis in various types of cancer.
Targeting GARP, which is selectively expressed on activated Tregs and contributes to the function of Tregs, may be a way to decrease the number of functional Tregs in the tumor microenvironment and restore antitumor immunity. Preclinical evidence has shown that depletion of Tregs results in antitumor activity.
Daiichi Sankyo Company announced that the first patient was dosed in a phase 2 study to evaluate the safety and efficacy of pexidartinib, a CSF-1R inhibitor, in Japanese patients with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitation and not amenable to improvement with surgery.
TGCT, also referred to as pigmented villonodular synovitis (PVNS) or giant cell tumor of the tendon sheath (GCT-TS) is a rare, typically non-malignant tumor that can be locally aggressive. TGCT affects the synovium-lined joints, bursae and tendon sheaths, resulting in reduced mobility in the affected joint or limb. For most patients, the current standard of care for TGCT is surgery; however, in more severe cases, the tumor may be difficult to remove and/or may not improve with surgery. Multiple surgeries can lead to significant joint damage, debilitating functional impairments, and reduced quality of life, and amputation may be considered.
“We are committed to continuing to explore the clinical benefit of pexidartinib in patients with TGCT, a disease which can be associated with severe morbidity, functional limitations and may not be amenable to improvement with surgery,” said Wataru Takasaki, PhD, Executive Officer, Head of R&D Division in Japan, Daiichi Sankyo. “This study will further serve to inform our development path forward in Japan and provide additional research insights to better understand this debilitating disease and the role pexidartinib may potentially play in Japanese patients with TGCT who are in need of alternative treatment options.”
This phase 2, multicenter, two-part, open-label, single-arm study will evaluate the safety and efficacy of pexidartinib in Japanese patients with symptomatic TGCT associated with severe morbidity or functional limitation and not amenable to improvement with surgery.
Approximately 18 patients will be enrolled into the two-part study. In the first part, pexidartinib 800 mg/day (400 mg twice a day on an empty stomach) will be administered to evaluate the tolerability and pharmacokinetics of pexidartinib to determine the initiation of the second part of the study. In the 2 second part, pexidartinib 800 mg/day (400 mg twice a day on an empty stomach) will be administered and efficacy, safety, and pharmacokinetics of pexidartinib will be evaluated.
The primary trial endpoints are dose-limiting toxicity, an analysis of pharmacokinetics and objective response rate (ORR), assessed by RECIST Version 1.1. Key secondary endpoints include ORR by tumor volume score, range of motion, patient reported outcomes, and treatment-emergent adverse events.
TGCT, also referred to as pigmented villonodular synovitis (PVNS) or giant cell tumor of the tendon sheath (GCT-TS), is a rare, typically non-malignant tumor that can be locally aggressive.
The current standard of care for TGCT is surgical resection. However, in patients with diffuse-type TGCT, the tumor may wrap around bone, tendons, ligaments and other parts of the joint. In these cases, the tumor may be difficult to remove and/or may not be amenable to improvement with surgery. Multiple surgeries for more severe cases can lead to significant joint damage, debilitating functional impairments and reduced quality of life, and amputation may be considered.
Pexidartinib is an oral small molecule that inhibits CSF-1R (colony stimulating factor-1 receptor), which is a primary growth driver of abnormal cells in the synovium that cause TGCT. Pexidartinib also inhibits KIT and FLT3-ITD. Pexidartinib was discovered by Plexxikon Inc., the small molecule structure-guided R&D center of Daiichi Sankyo.
