A Study to Evaluate Safety and Efficacy of AMB-05X Injections in Subjects With TGCT

Study Overview
=================
Brief Summary
-----------------
AMB-051-07 is an Open-Label, Adaptive, Dose-Ranging Study with Long-Term Extension which will enroll approximately 48 adult subjects with TGCT for IA doses over a 24-week dosing period (Part 1) with a Part 2 OLE of 6 treatment and/or observational cycles of 12 weeks each followed by 12 weeks of follow-up.

Official Title
-----------------
A Phase 2, Open-Label, Adaptive, Dose-Ranging Study With Long-Term Extension to Evaluate the Safety, Tolerability, Efficacy, and Pharmacokinetics of Intra Articular AMB-05X Injections in Subjects With Tenosynovial Giant Cell Tumor

Conditions
-----------------
Pigmented Villonodular Synovitis, TGCT, Tenosynovial Giant Cell Tumor

Intervention / Treatment
-----------------
* Biological: AMB-05X


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subject ≥ 18 years TGCT with only 1 joint involvement Symptomatic Measurable disease of at least 1 cm based on RECIST v1.1 Stable prescription of analgesic regimen Agrees to follow contraception guidelines Women of childbearing potential must have a negative pregnancy test Adequate hematologic, hepatic, and renal function Exclusion Criteria: Prior investigational drug use within 4 weeks or 5 half-lives of Baseline Previous use of therapeutics targeting CSF1 or CSF1R or oral tyrosine kinase inhibitors within 3 months prior to Baseline History of extensive or reconstructive surgery on the affected joint Active cancer (either currently or within 3 mo before Baseline) that requires/required therapy (e.g., surgery, chemotherapy, or radiation therapy) Metastatic or malignant transformation of TGCT Hepatitis C virus (HCV) or hepatitis B virus (HBV) or human immunodeficiency virus (HIV) Known active tuberculosis Significant concomitant arthropathy in the affected joint, serious illness, uncontrolled infection, or a medical or psychiatric history Women who are breastfeeding A screening Fridericia-corrected QT interval (QTcF) ≥ 450 ms (men) or ≥ 470 ms (women) MRI contraindications (e.g., pacemaker, loose metallic implants) History of hypersensitivity to any ingredient of the study drug History of drug or alcohol abuse within 3 months before baseline Any other severe acute or chronic medical or psychiatric condition or clinically significant laboratory abnormality that may increase the risk associated with study participation/treatment or interfere with interpretation of study results and, in the Investigator's opinion, make the subject inappropriate for this study Subjects who, in the Investigator's opinion, should not participate in the study for any reason, including if there is a question about their ability to comply with study requirements

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

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

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

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

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AMB-05X<br>Subjects will receive an injection of AMB-05X once every 4 weeks for 24 weeks (for 6 treatments total). Based on ongoing review of the available safety, PK, PD, and efficacy data, the Sponsor may either increase or decrease the dose. | Biological: AMB-05X<br>* A fully human monoclonal immunoglobulin (IgG2) directed against c-fms<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate for Part 1 | Proportion of subjects who achieve an OR (objective response rate [ORR]) by central radiology review per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Part 1 Week 24 | 
| Treatment-emergent adverse events | Frequency and severity of reported treatment-emergent adverse events | Part 1 Week 24 and Part 2 Week 72 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate | Proportion of subjects who achieve an OR (objective response rate [ORR]) by central radiology review per modified Response Evaluation Criteria in Solid Tumors | Part 2 Week 72 | 
| Objective Response Rate (AMB-051-01 subjects) | Proportion of re-treated subjects who achieve an OR (objective response rate [ORR]) by central radiology review per modified Response Evaluation Criteria in Solid Tumors | Part 2 Week 72 | 
| Objective Response Rate per modified RECIST | Proportion of subjects who achieve an overall response (OR) per modified RECIST | Part 1 Week 24 and Part 2 Week 72 | 
| Tumor response based on tumor volume score (TVS) | Proportion of subjects who achieve an overall tumor response (OR) per the tumor volume score | Part 1 Week 24 and Part 2 Week 72 | 
| Duration of Response | Median duration of response per RECIST v1.1, modified RECIST, and TVS | Part 1 Week 24 and Part 2 Week 72 | 
| Time to Response | Time to response (TTR) per RECIST v1.1, modified RECIST, and TVS | Part 1 Week 24 and Part 2 Week 72 | 
| Mean change from Baseline in joint range of motion (ROM) | ROM of the joint will be assessed by qualified assessors. Measurements will be recorded in degrees. At baseline, the plane of movement with the smallest (worst) relative value will be identified; only this plane will be used for evaluating change in ROM subsequently. | Part 1 Week 24 and Part 2 Week 72 | 
| Mean change from Baseline in the Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function score | The PROMIS Physical Function Scale will be used to assess physical function. The scale ranges from 1 ('unable to do' or 'cannot do') to 5 ('without any difficulty' or 'not at all'), where higher scores represent better outcomes. | Part 1 Week 24 and Part 2 Week 72 | 
| Mean change from Baseline in Worst Stiffness Numeric Rating Scale (NRS) score | The Worst Stiffness NRS is a 1-item, self-administered questionnaire assessing the worst stiffness within the last 24 hours. The NRS for this item ranges from 0 (no stiffness) to 10 (stiffness as bad as you can imagine). | Part 1 Week 24 and Part 2 Week 72 | 
| Mean change from Baseline in the Brief Pain Inventory (BPI) score | Brief Pain Inventory (BPI) Short Form is a self-administered questionnaire used to evaluate the severity of a subject's pain and the impact of this pain on the subject's daily functioning. The subject is asked to rate their worst, least, average, and current pain intensity, list current treatments and their perceived effectiveness, and rate the degree that pain interferes with general activity, mood, walking ability, normal work, relations with other persons, sleep, and enjoyment of life on a scale from 0 to 10. | Part 1 Week 24 and Part 2 Week 72 | 
| Decrease of at least 30% in mean Brief Pain Inventory from Baseline | Brief Pain Inventory (BPI) Short Form is a self-administered questionnaire used to evaluate the severity of a subject's pain and the impact of this pain on the subject's daily functioning. The subject is asked to rate their worst, least, average, and current pain intensity, list current treatments and their perceived effectiveness, and rate the degree that pain interferes with general activity, mood, walking ability, normal work, relations with other persons, sleep, and enjoyment of life on a scale from 0 to 10. | Part 1 Week 24 and Part 2 Week 72 | 
| Mean change from Baseline in PROMIS Pain Interference score | The PROMIS Item Bank v1.1 Pain Interference Short Form 8a, provided in Appendix 4, is an 8 question PRO instrument used to evaluate how much a subject's pain interferes with daily functioning (Health Measures, 2022). Subjects rate the degree to which pain interfered with their daily activity over the past 7 days on a scale of 1 to 5 (ranging from 1, Not at all, to 5, Very much). | Part 1 Week 24 and Part 2 Week 72 | 
| Mean change from Baseline in Patient Global Impression of Change (PGIC) in Physical Functioning for capacity to perform everyday tasks | The Patient Global Impression of Change (PGIC), also known as Subject Global Impression. For this study, subjects will rate how much their TGCT has restricted their ability to perform everyday tasks, using the following scales that are based on the PGIC: PGIC Physical Functioning scale (ranging from 1, Not at all, to 5, Extremely. | Part 1 Week 24 and Part 2 Week 72 | 
| Mean change from Baseline in PGIC in TGCT-related stiffness score | The Patient Global Impression of Change (PGIC), also known as Subject Global Impression. For this study, subjects will rate how much their TGCT has restricted their ability to perform everyday tasks, using the PGIC to rate their change in stiffness using the PGIC Stiffness scale (ranging from 1, Very much improved to 7, Very much worse. | Part 1 Week 24 and Part 2 Week 72 | 
| Mean change from Baseline in Worst Pain NRS score | The Worst Pain NRS is an item in the BPI that assesses a subject's worst pain in the last 24 hours. The 11-point NRS for this item ranges from 0 (no pain) to 10 (pain as bad as you can imagine). | Part 1 Week 24 and Part 2 Week 72 | 
| EuroQol 5 Dimension 5 Level (EQ-5D-5L) Health Assessment | EQ-5D-5L is a widely used quality of life instrument that includes questions in each of 5 domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The choices include 5 levels of severity for each domain followed by a general health visual analogue scale (VAS). | Part 1 Week 24 and Part 2 Week 72 | 

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