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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Synox Therapeutics Limited

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

10 Sep 2024 → ongoing

Decision date (initial)

2024-08-26

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Synox Therapeutics Inc

External identifiers

EU CT number

2023-510422-32-00

ClinicalTrials.gov

NCT05417789

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

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

Secondary objectives 7

1. Secondary efficacy objectives of the study are to estimate: - the effect of emactuzumab on clinical outcome assessments (COAs) for: o Physical functioning o Range of motion (ROM) o Pain o Stiffness o Patient Global Impressions (PGIs) o QoL
2. Secondary efficacy objectives of the study are to estimate further clinical benefit derived from the antitumour activity of emactuzumab in TGCT compared to placebo
3. Secondary efficacy objectives of the study are to estimate Surgical Intervention Rate
4. Secondary efficacy objectives of the study are to estimate Safety and tolerability of emactuzumab versus placebo
5. Secondary efficacy objectives of the study are to assess the health economic impact of treatment with emactuzumab
6. Secondary efficacy objectives of the study are to further characterise the (PK) profile of emactuzumab
7. Durability of response

Conditions and MedDRA coding

Tenosynovial Giant Cell Tumour

Study design 7 periods

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration, Paul-Ehrlich-Institut, Swedish Medical Products Agency

EMA paediatric investigation plan (PIP)

EMEA-003172-PIP01-21

Plan to share IPD

No

IPD plan description

Summary (synopsis) of the CSR

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 2

1. 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.
2. 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. 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 OL Phase ONLY: Adult subjects only a. Subjects who were randomised and completed Month 6 of the Double-Blind Phase of the study b. Subjects deemed to have progression of disease by either: • objective progressive disease as measured locally by MRI • or symptomatic progression by clinical evaluation in the opinion of the Investigator c. Subjects 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. Subjects have not been unblinded to treatment prior to Visit 10 (Month 6) e. Subjects have not had surgery for TGCT prior to Visit 10 (Month 6) f. Toxicities to prior treatment have resolved to Grade 1 or less (see exclusion criteria 7) prior to starting an OL treatment course. g. At least 3 months have elapsed between the completion of a treatment course and commencement of an OL treatment course. h. For 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 2

1. 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).
2. 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. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. ORR according to RECIST v1.1 by 6 months from initiation of therapy based on independent, blinded central review

Secondary endpoints 26

1. Key secondary efficacy endpoint: ORR according to Tumour Volume Score (TVS) at 6 months from initiation of therapy based
2. 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
3. Key secondary efficacy endpoint: Change in Physician/Healthcare Professional (HCP)-Reported Joint Mobility Score by goniometry from baseline to 6 months
4. Key secondary efficacy endpoint: Change in Worst Stiffness Numerical Rating Scale (NRS) from baseline to 6 months
5. Key secondary efficacy endpoint: Change in Worst Pain NRS from baseline to 6 months
6. Key secondary efficacy endpoint: Change in EuroQoL 5 Dimension, 5 Level questionnaire (EQ-5D-5L) Visual Analogue Scale (VAS) from baseline to 6 months
7. Change in PROMIS-PF TGCT T-score from baseline over time
8. Change in Physician/Healthcare Professional (HCP)-Reported Joint Mobility Score by goniometry from baseline over time
9. Change in Worst Pain (NRS) from baseline over time
10. Change in Worst Stiffness NRS from baseline over time (this was previously #6)
11. Change in EQ-5D-5L VAS from baseline over time
12. Change in EQ-5D-5L 5 dimension scores from baseline over time
13. Change in Short Form 12-Item Survey version 2 (SF-12 v2) from baseline over time
14. Changes in PGI severity from baseline over time
15. PGI-change over time
16. Duration of response (DoR) as measured by RECIST version 1.1 based on independent, blinded central review
17. Disease control rate (DCR) at 6 month as per RECIST v1.1 definition based on independent, blinded central review
18. Time to response (TTR) as measured by RECIST v1.1 based on independent, blinded central review
19. Time to progression (TTP)as measured by RECIST v1.1 based on independent, blinded central review
20. Change in (TVS) from baseline over time
21. Surgical intervention rate, defined as the number of subjects who undergo surgery during the study for TGCT
22. AES
23. Deaths
24. Healthcare utilisation
25. Ability to work
26. Serum concentrations of emactuzumab

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Synox Therapeutics Limited

Sponsor organisation

Synox Therapeutics Limited

Address

25 North Wall Quay, North Wall North Wall

City

Dublin 1

Postcode

D01 H104

Country

Ireland

Scientific contact point

Organisation

Synox Therapeutics Limited

Contact name

Rowena Abbey

Public contact point

Organisation

Synox Therapeutics Limited

Contact name

Rowena Abbey

Third parties 13

Locations

8 EU/EEA countries · 28 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 223 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

11 submissions — initial application plus substantial / non-substantial modifications