A Phase III, Multicentre, Randomised, Double-Blind Study to Assess the Safety and Efficacy of Emactuzumab vs. Placebo in Subjects with Tenosynovial Giant Cell Tumour
- Conditions
- Tenosynovial Giant Cell Tumour
- Interventions
- Drug: Placebo
- Registration Number
- 2023-510422-32-00
- Lead Sponsor
- Synox Therapeutics Limited
- Brief Summary
The primary efficacy objective of this study is to estimate the treatment effect of emactuzumab by objective response rate (ORR) by 6 months from initiation of therapy in the blinded phase compared to placebo
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- Not specified
- Target Recruitment
- 93
Subjects are eligible to be included in the study only if all of the following criteria apply: 1. Written informed consent. 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. 3. Measurable disease: longest diameter ≥20 mm on central read. 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. 5. Adequate organ and bone marrow function: haemoglobin (Hb) >10.0 g/dL, neutrophils >1.5 × 109/L and platelets >100 × 109/L.
- 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. 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. 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. 9. For Open-Label Phase ONLY: Adult subjects only •Subjects who were randomised and completed the 6-month double blind phase of the study •Subjects deemed to have progression of disease by either: objective progressive disease as measured locally by MRI imaging or symptomatic progression by clinical evaluation in the opinion of the investigator •Patients will be assessed as having progressed and are treated with emactuzumab after Visit 10 (Day 181) and up to Visit 13 (Day 541) per Schedule of Assessments. •Patients have not been unblinded to treatment prior to Visit 10 (Day 181) •Patients have not had surgery for TGCT prior to Visit 10 (Day 181) •Toxicities to prior blinded treatment have resolved to grade 1 or less (see exclusion criteria 7) prior to starting open label treatment. •At least 3 months have elapsed between open label and double-blind treatments
Subjects are excluded from the study if any of the following criteria apply: 1. Pregnant, planning to be pregnant or breast feeding. 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. 3. Metastatic TGCT. 4. TGCT currently affecting multiple joints. 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. 6. Any surgery, chemotherapy or, radiotherapy within 3 months of screening or 5 half-lives, which ever is longer 7. Clinically significant toxicity from a previous treatment not resolved to Grade 1or less. 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. 9. Renal function: creatinine clearance <60 mL/min (Cockcroft-Gault formula).
- Liver function: ALT and / or AST >3.0 × ULN; OR total bilirubin >1.5 × ULN. 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. 12. Clinically significant active infection requiring systemic antibiotic treatment. Rescreening may occur any time after 7 days post-completion of treatment. 13. Systemic antiretroviral therapy within 3 months of baseline. 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. 15. Planned surgery during the course of the study with the exception of dental treatment.(See exclusion criterion 11 for wound healing) 16. Inability to comply with the study procedures. 17. For the Double-Blind Phase ONLY: Previous exposure to emactuzumab and/or neutralising antibodies. 18. Known allergy/hypersensitivity to the active ingredients or to the excipients.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- Not specified
- Arm && Interventions
Group Intervention Description Group 1 in Part 1/Part 2: Emactuzumab Emactuzumab Group 1: Subjects receiving emactuzumab administered intravenously (i.v) 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. Eligible Subjects assigned to active drug in Part 1 have the option to receive open-label retreatment in Part 2. Group 2 in Part 1 and Part 2: Placebo Placebo Group 2: Subjects receiving placebo administered intravenously (i.v) 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. In Part 2, Eligible Subjects will have the option to receive open-label emactuzumab, administered by i.v once every 2 weeks (Q2W) for a total of 5 times.
- Primary Outcome Measures
Name Time Method ORR according to RECIST v1.1 by 6 months from initiation of therapy based on independent, blinded central review ORR according to RECIST v1.1 by 6 months from initiation of therapy based on independent, blinded central review
- Secondary Outcome Measures
Name Time Method Key secondary endpoint: Change in Patient-Reported Outcomes Measurement Information System -Physical Function Scale (PROMIS-PF) TGCT from baseline to 6 months Key secondary endpoint: Change in Patient-Reported Outcomes Measurement Information System -Physical Function Scale (PROMIS-PF) TGCT from baseline to 6 months
Change in PROMIS-PF TGCT from baseline over time Change in PROMIS-PF TGCT from baseline over time
Physician/Healthcare Professional (HCP)-Reported Joint Mobility Score by goniometry from baseline over time Physician/Healthcare Professional (HCP)-Reported Joint Mobility Score by goniometry from baseline over time
Change in Worst Pain Numerical Rating Scale (NRS) from baseline over time Change in Worst Pain Numerical Rating Scale (NRS) from baseline over time
Change in Short Form 12-Item Survey version 2 (SF-12 v2) from baseline over time Change in Short Form 12-Item Survey version 2 (SF-12 v2) from baseline over time
Change in Worst Stiffness NRS from baseline over time Change in Worst Stiffness NRS from baseline over time
PGI of change and severity over time PGI of change and severity over time
Change in EuroQoL 5-Dimension, 5-Level questionnaire (EQ-5D-5L) from baseline over time Change in EuroQoL 5-Dimension, 5-Level questionnaire (EQ-5D-5L) from baseline over time
Duration of response (DoR) as measured by RECIST version 1.1 based on independent, blinded central review Duration of response (DoR) as measured by RECIST version 1.1 based on independent, blinded central review
Disease control rate (DCR) as per RECIST v1.1 definition based on independent, blinded central review Disease control rate (DCR) as per RECIST v1.1 definition based on independent, blinded central review
Time to response as measured by RECIST v1.1 based on independent, blinded central review Time to response as measured by RECIST v1.1 based on independent, blinded central review
Time to progression as measured by RECIST v1.1 based on independent, blinded central review Time to progression as measured by RECIST v1.1 based on independent, blinded central review
Change in Tumour volume score (TVS) from baseline over time Change in Tumour volume score (TVS) from baseline over time
Surgical intervention rate, defined as the number of subjects who undergo surgery during the study for TGCT Surgical intervention rate, defined as the number of subjects who undergo surgery during the study for TGCT
AEs AEs
Deaths Deaths
Healthcare utilisation Healthcare utilisation
Ability to work Ability to work
PK parameters PK parameters
Trial Locations
- Locations (47)
NextGen Oncology
🇺🇸Beverly Hills, California, United States
Sarcoma Oncology Research Center, LLC
🇺🇸Los Angeles, California, United States
USC Norris Comprehensive Cancer Center
🇺🇸Los Angeles, California, United States
University of Kansas Cancer Center (Overland Park) - USOR
🇺🇸Overland Park, Kansas, United States
University of Minnesota
🇺🇸Minneapolis, Minnesota, United States
Duke Cancer Center
🇺🇸Durham, North Carolina, United States
The Ohio State University
🇺🇸Columbus, Ohio, United States
OHSU Knight Cancer Institute Hematology Oncology
🇺🇸Portland, Oregon, United States
MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
MedStar Washington Hospital Center
🇺🇸Georgetown, Washington, United States
Scroll for more (37 remaining)NextGen Oncology🇺🇸Beverly Hills, California, United StatesDr Kamalesh SankhalaPrincipal Investigator