腱鞘巨細胞瘤

本試驗的目的是評估 TGCT 受試者靜脈輸注 Emactuzumab 相較於安慰劑的安全性和療效。

液劑

Emactuzumab

970

250mg/10ml

主要
‧ 本試驗的主要療效目標是在盲性期基於 ORR 評估 Emactuzumab自治療開始起 6 個月相較於安慰劑的治療效果
評估指標
‧ 基於獨立盲性中央審查，依據
第 1.1 版 RECIST 確定的自治療開始起 6 個月內 ORR

5.1 Inclusion Criteria
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 associated with the surgery that would impede the subject’s participation in the study.
*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.
4. Age >12 years .
Note: in Sweden, 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.
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.
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 must either:
‧ Have responded based on RECIST v1.1 (CR or PR) to initial treatment with emactuzumab during the Double-Blind Phase and then progressed (objective progressive disease on MRI imaging centrally confirmed) within 18 months of initiation of treatment on D 1 (Visit 1) with a minimum 6-month washout period between treatments; or
‧ Have received placebo, completed the 6-month visit on D 181/Visit 10 (3 months treatment and 3 months observation) of the Double-Blind Phase, and have i) progressed according to RECIST v1.1 (objective progressive disease on MRI imaging centrally confirmed) within 18 months of initiation of treatment on D 1 (Visit 1), or ii) have stable disease according to RECIST v1.1 (on MRI imaging centrally confirmed) and clinically relevant deterioration as assessed by the Investigator and confirmed by the Medical Monitor within 18 months of initiation of treatment on D 1 (Visit 1).

5.2 Exclusion Criteria
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, including autoimmune, requiring systemic immunosuppression. Any systemic treatment for these conditions (eg, glucocorticoids) is not allowed within 4 weeks of Screening and during the study. All Lupus Erythematosus are excluded irrespective of treatment.
3. Metastatic TGCT.
4. TGCT currently affecting multiple joints.
5. Previous use of systemic therapy (investigational or approved) targeting CSF 1 or CSF 1R within 3 months of Screening.
6. Nilotinib, imatinib, other chemotherapy, radiotherapy, or investigational therapy within 4 weeks of Screening.
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).
10. 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).
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.
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.