E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pigmented villonodular synovitis (PVNS)/Diffuse Type Tenosynovial Giant Cell Tumor (dt-TGCT) |
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E.1.1.1 | Medical condition in easily understood language |
Joint disease involving inflammation and overgrowth of the joint lining |
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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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10047413 |
E.1.2 | Term | Villonodular synovitis |
E.1.2 | System Organ Class | 100000004859 |
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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 |
Phase 1: to determine the recommended dose (RD) of cabiralizumab in patients with pigmented villonodular synovitis (PVNS)/diffuse type tenosynovial giant cell tumor (dt-TGCT) Phase 2: to estimate the objective response rate (ORR = Complete Response+Partial Response) of FPA008 (cabiralizumab) in patients with PVNS/dt-TGCT |
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E.2.2 | Secondary objectives of the trial |
- to characterize the safety and tolerability of cabiralizumab in patients with PVNS/dt-TGCT - to determine the duration of response in responding patients - to assess the pharmacokinetics of cabiralizumab in patients with PVNS/dt-TGCT |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Understand and sign an Institutional Review Board/Independent Ethics Committee-approved informed consent form prior to any study-specific evaluation 2. Age >=18 years 3. Histologically confirmed diagnosis of inoperable PVNS/ dt-TGCT or potentially resectable tumor that would result in unacceptable functional loss or morbidity as determined by a qualified surgeon or multi-disciplinary tumor board (must be determined in the CRF during screening) 4. Measurable PVNS/dt-TGCT by RECIST v1.1 on MRI 5. ECOG performance status <=1 6. Willing and able to comply with all study procedures 7. In sexually-active patients (i.e., females of childbearing potential, who have not undergone menopause as defined by 12 consecutive months of amenorrhea or had a permanent sterilization procedure and males, who have not had a permanent sterilization procedure), willingness to use 2 effective methods of contraception, of which one must be a physical barrier method (condom, diaphragm, or cervical/vault cap) during the study and until 6 months after the last dose of cabiralizumab. Other effective forms of contraception are permanent sterilization (hysterectomy and/or bilateral oophorectomy, or bilateral tubal ligation with surgery, or vasectomy) at least 6 months prior to Screening. Females <55 years of age should have FSH >40. Female patients of childbearing potential must be on stable oral contraceptive therapy or intrauterine or implant device for at least 90 days prior to the study, or abstain from sexual intercourse as a way of living. 8. Patients being retreated with cabiralizumab must have completed 6 cycles of initial treatment at the 1 mg/kg or 2 mg/kg dose levels and the End-of- Treatment Follow-Up Period. Note: Prior to re-treatment, patients will be re-assessed to ensure they meet the same eligibility requirements as untreated patients. 9. Patients must have a minimum average Brief Pain Inventory (BPI) score of two points during screening (based on the average of questions 3-6 of the BPI, assessed for at least 5 of 14 days prior to C1D1; see Appendix 7). 10. Patients must be on a stable analgesic regimen for two weeks prior to first dose. No waivers of these inclusion criteria will be granted. |
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E.4 | Principal exclusion criteria |
Patients enrolling into Phase 1 or Phase 2 will be excluded if any of the following criteria apply: 1. Prior therapy with another anti-CSF1R antibody within three months of first study dose administration (Note: Patients that discontinued prior anti-CSF1R antibody due to a drug-related serious adverse events will not be permitted to enroll) 2. Prior therapy with pexidartinib (PLX3397), imatinib, or nilotinib within four weeks of first study dose administration 3. Liver function tests (including ALT, AST, and total bilirubin), outside of the range of local laboratory normal at Screening 4. Inadequate organ or bone marrow function defined as: hemoglobin < 10 g/dL, absolute neutrophil count <1.5x 10x9/L, platelet count <100x 10x9/L, serum creatinine >1.5x ULN or calculated creatinine clearance <30 mL/min 5. Any surgical procedure of the involved joint within 12 weeks prior to first study dose administration (except baseline synovium biopsy, if performed) 6. Current or history of clinically significant muscle disorders (e.g., myositis), recent unresolved muscle injury, or any condition known to elevate serum CK levels 7. History of congestive heart failure or myocardial infarction <1 year prior to first study dose administration 8. Decreased cardiac function with NYHA > Class 2 9. Uncontrolled or significant heart disorder such as unstable angina 10. Significant abnormalities on ECG at Screening. QTcF >450 msec for males or >470 msec for females at Screening 11. Contraindications to MRI and use of intravenous gadolinium-based contrast agents 12. History of severe allergic, anaphylactic, or other infusion related reaction to a previous biologic agent 13. Treatment with any anticancer therapy or participation in another therapeutic clinical study with investigational drugs ≤ 28 days prior to first dose of cabiralizumab 14. Known history of ADAs to previous biologic agents 15. Known history of sensitivity to any component of the study drug formulation 16. Consumption of non-pasteurized milk on a regular basis, or known significant risk of exposure to opportunistic intracellular infections such as listeria, or other such pathogens. 17. Receipt of any vaccine within 28 days prior to first day of treatment. The effect of cabiralizumab on mounting an immunologic vaccine response is not known. Flu or other vaccinations may be administered while on study but the impact of cabiralizumab on the safety and efficacy of the vaccination is unknown. 18. Current unresolved infection or history of chronic active clinically significant infection (viral [e.g., HBV, HCV], bacterial, fungal, or other), which in the opinion of the Investigator would place the patient at risk from exposure to a CSF1R inhibitor 19. Known positive test for human immunodeficiency virus (HIV) 20. Active TB 21. Positive test for latent TB at Screening (T-spot or Quantiferon test) 22. History of prior malignancy, except: • Curatively treated non-melanoma skin malignancy • Cervical cancer in situ • Solid tumor treated curatively more than 2 years previously without evidence of recurrence 23. Lack of peripheral venous access or any condition that would interfere with drug administration or collection of study samples 24. Any uncontrolled medical condition or psychiatric disorder which in the opinion of the Investigator would pose a risk to patient safety or interfere with study participation or interpretation of individual patient results 25. Inability to perform and/or comply with study and follow-up procedures. 26. Known history of metastatic PVNS/dt-TGCT 27. Creatine kinase (CK) ≥ 1.5x ULN 28. Patients with a Screening anti-nuclear antibody (ANA) titer of 1:160 or higher 29. Active, known, or suspected autoimmune disease. Patients with type I diabetes mellitus, hypothyroidism requiring only hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. No waivers of these exclusion criteria will be granted. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Phase 1: The incidence of Grade 3 and Grade 4 adverse events (AEs) and clinical laboratory abnormalities defined as dose-limiting toxicities (DLTs) Phase 2: The incidence of confirmed objective responses per RECIST v1.1 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
PK parameters The incidence of AEs, clinical laboratory abnormalities, and ECG abnormalities Duration of response per RECIST v1.1 |
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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 | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
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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 | 6 |
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 |
France |
Korea, Republic of |
Netherlands |
Poland |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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 | 3 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |