(P 401) A PHASE 3 MULTI-CENTER, RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL TO ASSESS THE EFFICACY AND SAFETY OF EMACTUZUMAB IN PATIENTS WITH TENOSYNOVIAL GIANT CELL TUMOR (TANGENT)

Objective: Tenosynovial giant cell tumor (TGCT), is a rare, locally aggressive tumor of the synovium, primarily affecting knee, hip, and ankle joints. There are 2 distinct types of TGCT: localized and diffuse. Localized TGCT generally affects smaller joints such as digits and parts of the foot, and diffuse TGCT mostly involves larger joints, such as the knee.
TGCT is caused by excessive production of colony stimulating factor 1 (CSF-1), a cytokine that plays an essential role in the proliferation, differentiation, and survival of monocytes and macrophages. It is a chronically debilitating disease causing loss of function of the affected joints, pain, stiffness, and limited range of motion. The worldwide incidence rate in digits, localized, and diffuse TGCT is about 29, 10, and 4 per million person-years, respectively (1).
TGCT can result in important functional impairments, significant joint damage, and decline in quality of life for. Surgery is regarded as the main treatment option for TGCT patients, but there is a high rate of tumor recurrence, particularly in diffuse TGCT, and risk for damage and degeneration of the affected joint and surrounding tissues or structures (2). This can lead to significant disability or amputation.

TANGENT is a Phase 3, global, double-blind, randomised, placebo-controlled study to evaluate the efficacy and safety of fixed infusions of emactuzumab in patients with TGCT (ClinTrials.gov ID: NCT05417789). The study design is depicted in Figure 1.
The objectives are to confirm the efficacy and safety of emactuzumab in patients with TGCT that are not amenable for surgery. The primary endpoint is the efficacy of emactuzumab assessed as the Objective Response Rate (ORR) at 6 months using Response Evaluation Criteria in Solid Tumours (RECIST 1.1) by MRI. Key secondary endpoints involve change in patient-reported outcomes (PROMIS-PF), range of motion, pain and stiffness, other antitumor activity (DoR, DCR, TTP, TVS) and surgical intervention rate.

Methods: The study consists of two Parts. In Part 1, eligible subjects will be assigned in a 2:1 ratio to receive either emactuzumab 1000 mg or matching placebo in a double-blind fashion, administered in total 5 times as an intravenous (i.v.) infusion once every 2 weeks (Q2W) for a maximum treatment period of 10 weeks. This will be followed by an observation period of 3 months, leading to a total duration of 6 months. Part 2 is a long-term double-blind follow-up phase of the subjects on emactuzumab or placebo.
Study participants whose TGCT condition worsens during the study may be eligible for treatment with emactuzumab in an open-label phase.
Several assessments will be carried out during the study, including tumor evaluation, physical examination, vital signs, electrocardiograms, questionnaires, and blood tests for hematology and biochemistry, urinalysis, and pharmacokinetics (PK) of emactuzumab.
Safety will be assessed by evaluation of the incidence and severity of AEs according to Common Terminology Criteria for Adverse Events [CTCAE] version 5.0.

Results: Emactuzumab is a novel monoclonal antibody and highly potent and specific CSF-1 receptor (CSF-1R) antagonist, that causes apoptosis of CSF-1R positive M2-like macrophages in the tumor environment, thereby inhibiting tumor growth (Figure 2).
In an earlier study, emactuzumab treatment, administered as a single agent during a limited number of cycles, demonstrated good tolerability with absence of any concerning liver toxicity with a pronounced and durable response (Objective Response Rate (ORR) of 71% across all dose-levels; Figure 3), and was associated with symptomatic improvement in patients with diffuse TGCT (3).
Emactuzumab was granted an Orphan Drug Designation (ODD) by the European Medicines Agency (EMA) in March 2022. The study is submitted to regulatory bodies and approvals have been obtained. The first patient is expected to be enrolled soon.

Conclusion: There are currently no worldwide approved systemic therapies available for the treatment of patients with TGCT. Emactuzumab demonstrated a favorable risk-benefit profile in early phase clinical studies without the need of chronic and/or daily treatment, which has been recognized to be important for the future treatment of TGCT. The efficacy and safety of emactuzumab in patients with TGCT will be further assessed in the Phase 3 TANGENT trial.

References:
1. Mastboom JL et al. Higher incidence rates than previously known in tenosynovial giant cell tumors. Acta Orthopaedica, 2017; 88: 688–694.
2. Staals EL et al. Diffuse-type tenosynovial giant cell tumour : Current treatment concepts and future perspectives. European Journal of Cancer, 2016; 63: 34-40.
3. Cassier PA et al. Long-term clinical activity, safety and patient-reported quality of life for emactuzumab-treated patients with diffuse-type tenosynovial giant-cell tumour. European Journal of Cancer, 2020; 141: 162-170.