E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Tenosynovial Giant Cell Tumour |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10025564 |
E.1.2 | Term | Malignant giant cell tumor |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To estimate the treatment effect of emactuzumab on objective response rate (ORR) by 6 months from initiation of therapy in the blinded phase compared to placebo. |
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E.2.2 | Secondary objectives of the trial |
-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
-Further antitumour activity of emactuzumab in TGCT compared to placebo.
-Surgical Intervention Rate.
-The Safety Objective of this study is to monitor subject wellbeing and assess treatment tolerability .
-To assess the health economic impact of treatment with emactuzumab.
-To further characterize the pharmacokinetic (PK) profile of emactuzumab. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Written informed consent. 2. Biopsy-confirmed (standard of care diagnosis history) local or diffuse TGCT where surgical resection would be associated with predicted 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 as determined by a multidisciplinary tumour board or equivalent*, or any other morbidity associated with the surgery, and/or surgical treatment is not expected to improve the clinical outcomes of the subject. *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. 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 randomization, 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 randomization, 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 according to protocol description. 9. For Open-Label Phase ONLY: 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 imaging) within 9-18 months of initial treatment on D 1 (Visit 1) with a minimum 6-month washout period between treatments; or -Have received placebo and completed the 6-month visit on D 181/Visit 10 (3 months treatment and 3 months observation) of the Double-Blind Phase and have not completed more than 18 months of the study since initial treatment on D1 (Visit1). |
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E.4 | Principal exclusion criteria |
1. Pregnant or breast feeding. 2. Medical conditions, including auto-immune, 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. Pexidartinib therapy within 3 months of Screening. 6. Nilotinib, imatinib; other chemotherapy, radiotherapy, or investigational therapy within 4 weeks of Screening. 7. Unresolved clinically significant toxicity from a previous treatment or any history of serious liver toxicity. 8. Current or chronic history of liver disease. This includes, but is not limited to, hepatitis virus infections, drug- or alcohol-related liver disease, nonalcoholic 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 >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 treatment or history of malignancy other than TGCT, unless there is the expectation that the malignancy has been cured, and tumor 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 neutralizing antibodies. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy objective of this study is to estimate the treatment effect of emactuzumab on objective response rate (ORR) by 6 months from initiation of therapy in the blinded phase compared to placebo. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
ORR by 6 months from initiation of therapy based on independent, blinded central review. |
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E.5.2 | Secondary end point(s) |
Change in Patient-Reported Outcomes Measurement Information System-Physical Function (PROMIS-PF) TGCT from baseline to 6 months.
Other secondary endpoints: -Change in PROMIS-PF TGCT 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 Short Form 12-Item Survey version 2 (SF-12 v2) from baseline over time. -Change in Worst Stiffness NRS from baseline over time. -PGI of change and severity over time. -Change in EuroQol 5-dimension, 5-level questionnaire (EQ-5D-5L) from baseline over time. -Duration of response (DoR) as measured by Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 based on independent, blinded central review. -Disease control rate (DCR) 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. -Surgical intervention rate, defined as the number of subjects who undergo surgery for TGCT during the study. -AEs. -Deaths. -Any laboratory abnormalities. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 45 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
United States |
Austria |
France |
Poland |
Sweden |
Netherlands |
Spain |
Switzerland |
Germany |
Italy |
Belgium |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the study is defined as the date of the last visit of the last subject in the study. A subject is considered to have completed the study if he/she has completed all periods of the study including the last visit. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |