E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Tenosynovial Giant Cell Tumor |
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E.1.1.1 | Medical condition in easily understood language |
Tenosynovial Giant Cell Tumor is a rare, locally aggressive and destructive neoplasm (newly formed tissue) that arises in the synovium (joint fluid) of joints, bursae, or tendon sheaths |
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E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 23.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10084212 |
E.1.2 | Term | Pigmented villonodular synovitis |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The objectives of this study are to evaluate the safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of intra-articular (IA) AMB-05X in the treatment of tenosynovial giant cell tumor (TGCT), both after an initial 24 weeks of treatment (Part 1) and after extended treatment or observation (Part 2). In particular, Part 2 will evaluate the durability of tumor response in subjects who achieve an objective response (OR) and whether extended treatment with AMB-05X improves clinical outcomes. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion Criteria for Enrollment into Part 1 1. Has never received AMB-05X in another study. 2. Male or female ≥18 years of age. 3. Able to understand and willing to adhere to the requirements of this study. Voluntarily signs the ICF before the conduct of any study-specific procedures. 4. TGCT with only 1 joint involvement that has been diagnosed histologically by a pathologist and documented. If a histological diagnosis has not been made previously, biopsy with histological diagnosis is required before enrollment. a. Individuals with TGCT of the knee joint are eligible. Depending on results in Cohort A and the recommendations of the DMC, individuals with TGCT of the hip and shoulder joint may also be allowed after Cohort A. b. Individuals with TGCT that are amenable or non-amenable to surgery are eligible. 5. Measurable disease of at least 1 cm per RECIST v1.1, assessed from MRI scans by central radiology review. 6. If the subject uses prescription analgesic, subject must be on a stable prescription analgesic regimen during the 2 weeks before Baseline. 7. Agrees to follow contraception guidelines 8. Adequate hematologic, hepatic, and renal function at Screening 9. Symptomatic TGCT defined as at least 1 of the following: a. A BPI worst pain score (Question #3, Appendix 3) of at least 4 before dosing at Baseline. b. A Worst Stiffness NRS score (Appendix 2) of at least 4 before dosing at Baseline.
Inclusion Criteria for Enrollment into Part 2 without Completing Part 1 1. Have measurable disease of at least 1 cm per RECIST v1.1, assessed from MRI scans by central radiology review, assessed from MRI scans by central radiology review, and received treatment in Study AMB-051-01. 2. Able to understand and willing to adhere to the requirements of this study. Voluntarily signs the ICF before the conduct of any study-specific procedures. 3. Agrees to follow contraception guidelines 4. Adequate hematologic, hepatic, and renal function at Screening 5. Symptomatic TGCT defined as at least 1 of the following: a. A BPI worst pain score of at least 4 before dosing at Baseline. b. A Worst Stiffness NRS score of at least 4 before dosing at Baseline. |
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E.4 | Principal exclusion criteria |
1. Use of any investigational drug within 4 weeks or 5 half-lives (whichever is longer) before Study Baseline (other than AMB-05X in a previous study for individuals enrolling directly into Part 2). 2. Use of any of the following: a. Pexidartinib, any other oral tyrosine kinase inhibitor (eg, imatinib or nilotinib), or any biologic treatment targeting CSF1 or CSF1R (except AMB-05X), within 3 months before the Baseline visit b. Current or recent (within 10 days before starting study treatment) full-dose oral anticoagulants (eg, warfarin), daily treatment with high-dose aspirin (>325 mg/day) or clopidogrel (>75 mg/day). 3. History of extensive or reconstructive surgery on the affected joint (eg, involving plates, screws, or metal implants). A history of prior diagnostic or partial synovectomy is not exclusionary if performed at least 3 months before Study Baseline. 4. Current or prior radiotherapy within 3 months before Study Baseline. 5. Current or prior active cancer within 3 years before Study Baseline that requires/required therapy (eg, surgery, chemotherapy, or radiation therapy), except adequately treated basal or squamous cell carcinoma of the skin, melanoma in situ, carcinoma in situ of the cervix or breast, or prostate carcinoma not requiring treatment apart from active surveillance. 6. Known metastatic TGCT or malignant transformation of TGCT. 7. Hepatitis C virus (HCV) or hepatitis B virus (HBV) or known active or chronic infection with human immunodeficiency virus (HIV). 8. Known active Tuberculosis. 9. Significant concomitant arthropathy in the affected joint, serious illness, uncontrolled infection, or a medical or psychiatric history that, in the Investigator's opinion, would likely interfere with the subject’s study participation or the interpretation of the subject’s results. 10. A female who is pregnant or breastfeeding. For females of childbearing potential, a positive pregnancy test at either Screening or Study Baseline will be exclusionary. 11. A screening QT interval corrected using Fridericia’s formula (QTcF) ≥ 470 ms 12. MRI contraindications 13. History of hypersensitivity to any ingredient in the study drug. 14. History of drug or alcohol abuse within 3 months before Study Baseline. 15. Any other severe acute or chronic medical or psychiatric condition or clinically significant laboratory abnormality that may increase the risk associated with study participation/treatment, interfere with interpretation of study results, or, in the Investigator’s opinion, make the subject inappropriate for this study. 16. An individual who is held in detention as the result of a judicial or official decision or who is in a subordinate relationship to the Sponsor or Investigator. 17. An individual who, in the Investigator’s opinion, should not participate in this study for any reason, including instances where the subject’s stability or ability to comply with study requirements is in question 18. Subjects with TGCT that is only extra-articular by MRI. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary outcome measures will be the following: • Proportion of subjects who achieve an OR (objective response rate [ORR]) by central radiology review (which includes both CR and PR) per RECIST v1.1 (Eisenhauer, 2009) at Week 24 for Part 1 • Frequency and severity of reported TEAEs. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Week 24 (part 1) and after extended treatment or observation (part 2). |
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E.5.2 | Secondary end point(s) |
Efficacy Secondary Outcome Measures The following secondary endpoints will be evaluated for Part 1 and Part 2, unless otherwise stated: • Proportion of subjects who achieve an OR (ORR) by central radiology review (which includes both CR and PR) per RECIST v1.1 (for Part 2 only) • Proportion of subjects who were re-treated with AMB-05X (ie, subjects entering the study from Study AMB-051-01) who achieve an OR (ORR) by central radiology review (which includes both CR and PR) per RECIST v1.1 (for Part 2 only) • Proportion of subjects who achieve an OR (which includes both CR and PR) per modified RECIST (Peterfy, 2017) • Proportion of subjects who achieve an OR per TVS, a TGCT-specific method that calculates tumor volume as a percentage of the estimated maximally distended synovial cavity (Tap, 2015) • Median duration of response per RECIST v1.1, modified RECIST, and TVS • Time to response (TTR) per RECIST v1.1, modified RECIST, and TVS • Mean change from Baseline in joint ROM score • Mean change from Baseline in the PROMIS Physical Function score • Mean change from Baseline in Worst Stiffness NRS score • Percentage of subjects who respond with a decrease of at least 30% in mean BPI score from Baseline • Mean change from Baseline in BPI score • Mean change from Baseline in PROMIS Pain Interference score • Mean change from Baseline in Patient Global Impression of Change (PGIC) in Physical Functioning for capacity to perform everyday tasks • Mean change from Baseline in PGIC in TGCT-related stiffness score • Mean change from Baseline in Worst Pain NRS score • Mean change from Baseline in EQ-5D-5L health assessment
Pharmacokinetic and Pharmacodynamic Secondary Outcome Measures - Serum and synovial AMB-05X levels - Serum and synovial ADA levels against AMB-05X - Serum and synovial CSF1 levels |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
After extended treatment or observation (part 2). |
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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 | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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 | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 8 |
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 |
Australia |
Czechia |
France |
Netherlands |
Poland |
United States |
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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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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 | 3 |
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 | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |