EMACTUZUMAB for Tenosynovial giant cell tumour

Inclusion criteria

• {"criterion_text":"- 1. Written informed consent.\n- 2. Biopsy-confirmed (standard of care diagnosis history) local or diffuse TGCT where a multidisciplinary tumour board or equivalent* determines: - Surgical resection is predicted to be associated with worsening functional limitations due to surgical damage to the joint and adjacent soft tissues; and/or - Subject presents with an anticipated high risk of early recurrence after surgery; and/or - Surgical treatment is not expected to improve the clinical outcomes of the subject; and/or - Any other significant morbidity that would impede surgery for their TGCT.ie other reasons why surgery for TGCT is not recommended. *The multidisciplinary tumour board or equivalent must comprise at least 2 individuals: the Investigator plus at least one other qualified physician (orthopaedic surgeon or medical oncologist) not involved in this study.\n- 3. Measurable disease: longest diameter ≥20 mm on central read.\n- 4. Age ≥ 12 years and weight ≥ 30kg Note: in Sweden and The Netherlands, subjects must be aged ≥16 years and adolescent subjects aged 16-17 years must fulfil Tanner Stage 5 criteria. In other countries, legislation requirements for adulthood consideration will determine inclusion age limit for study entry.\n- 5. Adequate organ and bone marrow function: haemoglobin (Hb) >10.0 g/dL, neutrophils >1.5 × 109/L and platelets >100 × 109/L.\n- 6. Minimum mean score of 4 on NRS for Worst Pain during 7 days prior to randomisation, based upon a minimum of 4 days of completed diary data. If applicable, subjects should be on a stable analgesic regime for the period of 2 weeks prior to randomisation.\n- 7. Minimum mean score of 4 on NRS for Worst Stiffness during 7 days prior to randomisation, based upon a minimum of 4 days of completed diary data.\n- 8. Women of childbearing potential (WOCBP) must have a negative urine and serum pregnancy test prior to starting treatment. WOCBP must agree to use a highly effective method of contraception throughout the treatment period and for 7 months after discontinuation of treatment. Acceptable methods of contraception are: - Hormonal contraception associated with inhibition of ovulation. Oral contraception and parenteral hormonal contraceptives (patches, injectables and implants) that may be affected by enzyme-inducing drugs should only be used in combination with a barrier method. -Intrauterine device (IUD). - Intrauterine hormone-releasing system (IUS). - Bilateral tubal occlusion. - Vasectomised partner. - Sexual abstinence, in line with the preferred and usual lifestyle of the subject. Periodic abstinence (such as calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. All men with partners of childbearing potential or whose partners are pregnant must use barrier contraception for the duration of dosing and for 5 months post-dosing, unless surgically sterile.\n- 9. For OL Phase ONLY: Adult subjects only a.\tSubjects who were randomised and completed Month 6 of the Double-Blind Phase of the study b.\tSubjects deemed to have progression of disease by either: •\tobjective progressive disease as measured locally by MRI •\tor symptomatic progression by clinical evaluation in the opinion of the Investigator c.\tSubjects will be assessed as having progressed and are treated with emactuzumab after Visit 10 (Month 6) and up to Visit 19 (Month 54) per SoA of the Double-Blind Phase. d.\tSubjects have not been unblinded to treatment prior to Visit 10 (Month 6) e.\tSubjects have not had surgery for TGCT prior to Visit 10 (Month 6) f.\tToxicities to prior treatment have resolved to Grade 1 or less (see exclusion criteria 7) prior to starting an OL treatment course. g.\tAt least 3 months have elapsed between the completion of a treatment course and commencement of an OL treatment course. h.\tFor OL Phase Treatment Course 2, subjects meeting inclusion criterion 9 items b, f, and g will be eligible after Visit 10 ol (Month 6-ol) and up to Visit 18 ol (Month 48 ol) per SoA of the OL Phase Treatment Course 1."}

Exclusion criteria

• {"criterion_text":"- 1. Pregnant, planning to be pregnant or breast feeding.\n- 2. Medical conditions, requiring systemic immunosuppression. Any systemic treatment for these conditions (eg, glucocorticoids) is not allowed within 4 weeks of Screening and during the study. Patients with auto-immune disease, including but not limited to autoimmune thyroid disease, systemic lupus erythematosus, Sjögren’s syndrome, glomerulonephritis, multiple sclerosis, rheumatoid arthritis, vasculitis, idiopathic pulmonary fibrosis (including bronchiolitis obliterans organizing pneumonia), and inflammatory bowel disease, are to be excluded from study participation.\n- 3. Metastatic TGCT.\n- 4. TGCT currently affecting multiple joints.\n- 5. Previous use of systemic therapy (investigational or approved) targeting CSF-1 or CSF-1R, any multi-tyrosine kinase inhibitor (eg nilotinib and imatinib) or investigational systemic therapy within 3 months of Screening, or 5 half-lives, whichever is longer.\n- 6. Any surgery, chemotherapy or, radiotherapy within 3 months of screening or 5 half-lives, which ever is longer\n- 7. Clinically significant toxicity from a previous treatment not resolved to Grade 1or less.\n- 8. Current or chronic history of liver disease. This includes, but is not limited to, hepatitis virus infections, drug- or alcohol-related liver disease, non-alcoholic steatohepatitis, autoimmune hepatitis, haemochromatosis, Wilson’s disease, α-1 antitrypsin deficiency, primary biliary cholangitis, primary sclerosing cholangitis, or any other liver disease which in the opinion of the Investigator is considered clinically significant.\n- 9. Renal function: creatinine clearance <60 mL/min (Cockcroft-Gault formula).\n- 10. Liver function: ALT and / or AST >3.0 × ULN; OR total bilirubin >1.5 × ULN. For Gilbert syndrome ALT and AST as above AND bilirubin ≥3 × ULN.\n- 11. 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), including severe thromboembolic event; incompletely healed clinically significant wounds, including bone fractures; pathological fracture or significant hypercalcaemia.\n- 12. Clinically significant active infection requiring systemic antibiotic treatment. Rescreening may occur any time after 7 days post-completion of treatment.\n- 13. Systemic antiretroviral therapy within 3 months of baseline.\n- 14. Other active cancer that requires concurrent or planned treatment or history of malignancy other than TGCT, unless there is the expectation that the malignancy has been cured, and tumour specific treatment for the malignancy has not been administered within the previous 5 years.\n- 15. Planned surgery during the course of the study with the exception of dental treatment.(See exclusion criterion 11 for wound healing)\n- 16. Inability to comply with the study procedures.\n- 17. For the Double-Blind Phase ONLY: Previous exposure to emactuzumab and/or neutralising antibodies.\n- 18. Known allergy/hypersensitivity to the active ingredients or to the excipients."}

Primary endpoints

• {"endpoint_text":"- ORR according to RECIST v1.1 by 6 months from initiation of therapy based on independent, blinded central review","definition_or_measurement_approach":"Objective response rate (ORR) measured according to RECIST v1.1 at 6 months from treatment initiation based on independent, blinded central review."}

Secondary endpoints

• {"endpoint_text":"- Key secondary efficacy endpoint: ORR according to Tumour Volume Score (TVS) at 6 months from initiation of therapy based\n- Key secondary efficacy endpoint: Change in Patient-Reported Outcomes Measurement Information System -Physical Function Scale (PROMIS-PF) TGCT T-score from baseline to 6 months\n- Key secondary efficacy endpoint: Change in Physician/Healthcare Professional (HCP)-Reported Joint Mobility Score by goniometry from baseline to 6 months\n- Key secondary efficacy endpoint: Change in Worst Stiffness Numerical Rating Scale (NRS) from baseline to 6 months\n- Key secondary efficacy endpoint: Change in Worst Pain NRS from baseline to 6 months\n- Key secondary efficacy endpoint: Change in EuroQoL 5 Dimension, 5 Level questionnaire (EQ-5D-5L) Visual Analogue Scale (VAS) from baseline to 6 months\n- Change in PROMIS-PF TGCT T-score from baseline over time\n- Change in Physician/Healthcare Professional (HCP)-Reported Joint Mobility Score by goniometry from baseline over time\n- Change in Worst Pain (NRS) from baseline over time\n- Change in Worst Stiffness NRS from baseline over time (this was previously #6)\n- Change in EQ-5D-5L VAS from baseline over time\n- Change in EQ-5D-5L 5 dimension scores from baseline over time\n- Change in Short Form 12-Item Survey version 2 (SF-12 v2) from baseline over time\n- Changes in PGI severity from baseline over time\n- PGI-change over time\n- Duration of response (DoR) as measured by RECIST version 1.1 based on independent, blinded central review\n- Disease control rate (DCR) at 6 month as per RECIST v1.1 definition based on independent, blinded central review\n- Time to response (TTR) as measured by RECIST v1.1 based on independent, blinded central review\n- Time to progression (TTP)as measured by RECIST v1.1 based on independent, blinded central review\n- Change in (TVS) from baseline over time\n- Surgical intervention rate, defined as the number of subjects who undergo surgery during the study for TGCT\n- AES\n- Deaths\n- Healthcare utilisation\n- Ability to work\n- Serum concentrations of emactuzumab","definition_or_measurement_approach":"Definitions/measurement approaches where specified in protocol: ORR by TVS at 6 months; PROMIS-PF TGCT T-score changes from baseline to 6 months and over time (patient-reported); HCP-Reported Joint Mobility by goniometry; Worst Stiffness and Worst Pain by Numerical Rating Scale (NRS) from baseline to 6 months and over time; EQ-5D-5L VAS and 5-dimension scores; SF-12 v2 changes; PGI severity and PGI change over time; Duration of response, disease control rate, time to response, time to progression measured per RECIST v1.1 by independent, blinded central review; surgical intervention rate defined as number of subjects undergoing surgery for TGCT during study; AES/Deaths/Healthcare utilisation/Ability to work/Serum concentrations of emactuzumab (PK measurement)."}

Methods

• Country-specific recruitment arrangements and brochures (e.g., recruitment brochures and flipcharts) distributed to clinicians and patients (documents available for PL, AUT, FR, SE, ES, NL, IT, BE).
• Physician/Dr-to-patient letters and physician letters to inform clinicians about the trial (country-specific templates present).
• Website and landing pages (desktop and mobile) / Citeline website content — country-specific landing pages and scripts to direct potential participants to prescreener and study information.
• Social media advertising (visuals provided e.g., 1080x1080 and 1200x628) and keyword/Google ads targeted to likely patients (country-specific social media ad assets exist).
• Pre-screener questionnaires and online prescreen tools (country-specific prescreeners) to identify potentially eligible subjects.
• Patient-facing materials and patient information sheets available for distribution (including flipcharts and brochures) to patients and patient groups.
• Dr-to-Patient SMS / social media messaging templates (country-specific) to reach patients via digital messaging channels.
• Mobile landing pages and mobile prescreening to facilitate remote initial eligibility assessment.

Poland

Earliest CTIS Part Ii Submission Date

24-07-2024

Latest Decision Or Authorization Date

15-05-2025

Processing Time Days

295

Number Of Sites

2

Number Of Participants

4

Austria

Earliest CTIS Part Ii Submission Date

01-07-2024

Latest Decision Or Authorization Date

15-05-2025

Processing Time Days

318

Number Of Sites

2

Number Of Participants

7

France

Earliest CTIS Part Ii Submission Date

29-07-2024

Latest Decision Or Authorization Date

11-05-2026

Processing Time Days

651

Number Of Sites

7

Number Of Participants

31

Sweden

Earliest CTIS Part Ii Submission Date

22-07-2024

Latest Decision Or Authorization Date

08-05-2026

Processing Time Days

655

Number Of Sites

1

Number Of Participants

6

Spain

Earliest CTIS Part Ii Submission Date

01-08-2024

Latest Decision Or Authorization Date

11-05-2026

Processing Time Days

648

Number Of Sites

5

Number Of Participants

20

Netherlands

Earliest CTIS Part Ii Submission Date

09-08-2024

Latest Decision Or Authorization Date

07-05-2026

Processing Time Days

636

Number Of Sites

1

Number Of Participants

11

Italy

Earliest CTIS Part Ii Submission Date

23-05-2024

Latest Decision Or Authorization Date

08-05-2026

Processing Time Days

715

Number Of Sites

8

Number Of Participants

15

Belgium

Earliest CTIS Part Ii Submission Date

24-07-2024

Latest Decision Or Authorization Date

11-05-2026

Processing Time Days

656

Number Of Sites

2

Number Of Participants

7

Primary sponsor

Full Name

Synox Therapeutics Limited

Organisation Type

Pharmaceutical company

Country Of Registered Address

Ireland

Contract research organisations

Name

PPD Development L.P.

Responsibilities

Subject Enrollment- Department within PPD developing patient material and online recruitment strategy, Accelerated Enrollment Solutions and Data Analytics

Name

PPD International Holdings LLC

Responsibilities

Central Lab analysis (hematology, chemistry) for EMEA and handling of samples to be sent to analytics labs (ADA, PK)

Name

Clinipace Inc.

Third parties

• {"country":"United States","full_name":"Catalent Pharma Solutions LLC","duties_or_roles":"IMP shipment / Management","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"ATOM International Limited","duties_or_roles":"Central Physio-Goniometry Training and ​storage of video ion goniometry assessments and storage of Exit Interview audio files","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Chillibean Limited","duties_or_roles":"subcontracted by ATOM - storage of videos on goniometry assessments","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"PPD Development L.P.","duties_or_roles":"Subject Enrollment- Department within PPD developing patient material and online recruitment strategy, Accelerated Enrollment Solutions and Data Analytics","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Bioagilytix Labs LLC","duties_or_roles":"Analyses of ADA, PK, samples from all regions (NA, EU, APAC)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Medidata Solutions Inc.","duties_or_roles":"URL set up and maintainance, RAVE EDC (eCRF)/ Patient Cloud (ePRO and eDiary)/RTSM (IRT) / Medical Imaging Portal (upload AE Dermatology Images for Central Dermatology Review)","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Germany","full_name":"Azenta Germany GmbH","duties_or_roles":"Long term storage of samples for EMEA","organisation_type":"Pharmaceutical company"}
• {"country":"Belgium","full_name":"PPD International Holdings LLC","duties_or_roles":"Central Lab analysis (hematology, chemistry) for EMEA and handling of samples to be sent to analytics labs (ADA, PK)","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Veramed Limited","duties_or_roles":"Statistics and Programming Services","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Sprout Health Solutions Limited","duties_or_roles":"Analysis of transcripts from Audio Recordings for 6M and 12M Subject Qualitative Exit Interviews​ (Subset of subjects in specific countries)​","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Clinipace Inc.","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Scout Clinical","duties_or_roles":"Subject Concierge Services (Travel​ and Expense Management Services​), Investigator Meeting Planner","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"United States","full_name":"Spire Sciences LLC","duties_or_roles":"Central Imaging (MRI)","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Germany","full_name":"Azenta Germany GmbH","duties_or_roles":"Long term storage of samples for EMEA","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Clinipace Inc.","duties_or_roles":"","organisation_type":"Pharmaceutical company"}