Study of Emactuzumab for Tenosynovial Giant Cell Tumor (TGCT)

Study Overview
=================
Brief Summary
-----------------
This is a multicenter, Phase 3, randomised, double-blind, placebo-controlled study, which aims to evaluate the efficacy and safety of the investigational drug emactuzumab for the treatment of patients with localized or diffuse TGCT where surgical removal of the tumor is not viewed as an option. The study consists of two parts. In Part 1, eligible subjects will be assigned in a 2:1 ratio to receive either emactuzumab or matching placebo in a double-blind fashion, that will be administered in total 5 times as an intravenous (i.v.) infusion once every 2 weeks. This will be followed by an observation period of 3 months leading to a total duration of 24 weeks in Part 1. A number of assessments will be carried out during the course of the study, including physical examinations, blood tests, imaging studies, electrocardiograms, and questionnaires. Part 2 is a long-term double-blind follow-up phase of the subjects on emactuzumab or placebo. Subjects assigned to placebo in Part 1 have the option to crossover under certain circumstances to receive open-label emactuzumab in Part 2.

Official Title
-----------------
A Phase 3, Randomized, Placebo-controlled, Double-Blind Study of Emactuzumab to Assess Efficacy and Safety in Subjects With Tenosynovial Giant Cell Tumor (TANGENT)

Conditions
-----------------
TGCT

Intervention / Treatment
-----------------
* Drug: Emactuzumab
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age >12 years Biopsy-confirmed (standard of care diagnosis history) local or diffuse TGCT where surgical resection would be associated with predicted worsening functional limitations through surgical joint damage, and/or subject has an anticipated high risk of early recurrence as determined by a multidisciplinary tumour board or equivalent, or any other morbidity associated with the surgery, and/or surgical treatment is not expected to improve the clinical outcomes of the subject. Adequate organ and bone marrow function If a woman of childbearing potential (WOCBP), must have a negative pregnancy test prior to starting treatment and agree to use a highly effective method of contraception Participants must have written consent Exclusion Criteria: If a female, the subject is pregnant or breast feeding. Medical conditions, including auto-immune, requiring systemic immunosuppression. Any systemic treatment for these conditions (eg, glucocorticoids) is not allowed within 4 weeks of Screening and during the study. Known metastatic TGCT or other active cancer that requires concurrent or planned treatment Received therapy for TGCT within 4 weeks prior to screening and 3 months prior to screening for pexidartinib Unresolved clinically significant toxicity from a previous treatment or any history of serious liver toxicity. Current or chronic history of liver disease. Inadequate renal and liver function Systemic antiretroviral therapy within 3 months of baseline Within 6 months of baseline has experienced: clinically significant myocardial infarction, severe/unstable angina pectoris, congestive heart failure New York Heart Association (NYHA) Class III or IV, or pulmonary disease (NYHA Criteria 1994)

Ages Eligible for Study
-----------------
Minimum Age: 12 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 in Part 1/Part 2: Emactuzumab<br>Group 1: Subjects receiving emactuzumab administered on Day(D)1 and repeated once every two weeks (Q2W) for a total of 5 times, followed by an observation period of 3 months leading to a total period of 24 weeks in Part 1 and continued with a follow-up phase in Part 2. | Drug: Emactuzumab<br>* Emactuzumab administered once every 2 weeks (q2w)<br>|
| Placebo Comparator: Group 2 in Part 1 and Part 2: Placebo<br>Group 2: Subjects receiving placebo administered as iv infusion on D1 and repeated once every two weeks (Q2W) for 5 times followed by an observation period of 3 months to a total period of 24 weeks in Part 1 will have the option to crossover under certain circumstances to open-label emactuzumab once every 2 weeks (Q2W) for a total of 5 times in Part 2. | Drug: Placebo<br>* Matching placebo administered once every 2 weeks (q2w)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | Objective Response Rate (ORR = complete response [CR] + partial response [PR]) by 6 months from initiation of therapy assessed by central read using Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 | Day 0 - Day 180 (6 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Physical Function | Change in Patient-Reported Outcomes Measurement Information System Physical Function (PROMIS-PF) TGCT from baseline to 6 months | up to 24 months | 
| Range of Motion (ROM) | Mean change from baseline in active ROM of the joint over time | up to 24 months | 
| Worst Stiffness | Mean change from baseline in the Worst Stiffness Numeric Rating Scale (NRS) score over time | up to 24 months | 
| Worst Pain | Mean change in Pain Numerical Rating Scale (NRS) from baseline over time | up to 24 months | 
| Quality of Life (QoL) | Change in EuroQol 5-dimension, 5-level questionnaire (EQ-5D-5L) | up to 24 months | 
| Duration of response (DoR) | Duration of response (DoR) as measured by RECIST version 1.1 | up to 24 months | 
| Tumour volume score (TVS) | Change in Tumour volume score (TVS) | up to 24 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
TGCT, Tenosynovial Giant Cell Tumour, PVNS, Pigmented Villonodular Synovitis, Synovitis, Emactuzumab, Local TGCT, Diffuse TGCT