MCS110 in Patients With Pigmented Villonodular Synovitis (PVNS)

Study Overview
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Brief Summary
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This study, designed as a proof of concept study of MCS110 in pigmented villonodular synovitis, assessed the clinical response to MCS110 treatment in Pigmented Villonodular Synovitis (PVNS) patients, after a single or multiple intravenous doses of MCS110, using magnetic resonance imaging to assess tumor volume, and evaluated the pharmacokinetics/pharmacodynamics, safety and tolerability in this population.

Official Title
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A Phase II Randomized, Double -Blind, Placebo Controlled Study to Assess Safety, Tolerability and Effect on Tumor Size of MCS110 in Patients With Pigmented Villonodular Synovitis (PVNS)

Conditions
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PVNS, GCTS, Pigmented Villonodular Synovitis, Giant Cell Tumor of the Tendon Sheath, GCCTS, Tenosynovial Giant Cell Tumor Localized or Diffused Type

Intervention / Treatment
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* Drug: MCS110
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Males and Females aged ≥ 18 years (≥ 12 years in PART C) with PVNS or GCTTS with, at least, one measurable site of disease on MRI. Patients expected to get surgery (PART A of study only). Vital signs within the ranges: systolic blood pressure 80-150 mmHg , diastolic blood pressure 50-100 mmHg, pulse rate 40-100 bpm, oral body temperature 35.0-37.5°C. Patients with normal level of serum ionized calcium and phosphate. Women of child-bearing potential must use highly effective contraception during the study and for 84 days after the study drug infusion. Exclusion criteria: Patients with major surgery less than 3 months prior to start study drug or who have still side effects of such therapy. Presence of systemic illness precluding definitive surgery or increasing the risk to patients due to potential immunosuppression. Use previously of intra-articular treatment within 4 weeks prior dosing. Patients with dermal change indicative of lymphedema or phlebolymphedema. disease. Patients with elevated troponin T and/or CK levels (> 1.5 x ULN for the laboratory) or with history of myositis, rhabdomyolysis or other myopathic disease. Patients receiving immunosuppressive treatment as well as corticosteroids which cannot be discontinued at least 4 weeks before dosing. Patients engaged in a resistance exercise training program. Patients with pacemakers or any metallic objects as exclusion for MRI Patients with concomitant disease know to get influence on bone metabolism Patients who have history of drug or alcohol abuse within 12 months prior study dosing. Pregnant or nursing (lactating) women. Other protocol-defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MCS110<br>Participants will receive a single dose of 10mg/kg on day 1 administered by regular infusion. | Drug: MCS110<br>* Patients will receive up to 6 doses of MCS110 (3 or 5 or 10mg/kg) administered intravenously once every 4 weeks. Before each dosing, safety will be assessed.<br>* Other names: Intravenous infusion of MCS110.;|
| Placebo Comparator: Placebo<br>Part A: single-dose placebo to match MCS110 (10 mg/kg, 1 h i.v. infusion) Part B: single dose placebo to match MCS110 (10 mg/kg, 1 h i.v. infusion administered i.v. at Day 1, followed by 6 doses of placebo to match MCS110 (10 mg/kg) | Drug: Placebo<br>* Participants will receive a single dose of NaCl on day 1 through intravenous infusion.<br>* Other names: Intravenous infusion of placebo.;|
| Experimental: MCS110 3 mg/kg<br>Part C: MCS110 3 mg/kg (i.v. infusion) | Drug: MCS110<br>* Patients will receive up to 6 doses of MCS110 (3 or 5 or 10mg/kg) administered intravenously once every 4 weeks. Before each dosing, safety will be assessed.<br>* Other names: Intravenous infusion of MCS110.;|
| Experimental: MCS110 5 mg/kg<br>Part C: MCS110 5 mg/kg (i.v. infusion) | Drug: MCS110<br>* Patients will receive up to 6 doses of MCS110 (3 or 5 or 10mg/kg) administered intravenously once every 4 weeks. Before each dosing, safety will be assessed.<br>* Other names: Intravenous infusion of MCS110.;|
| Experimental: MCS110 10 mg/kg<br>Part C: MCS110 10 mg/kg (i.v. infusion) | Drug: MCS110<br>* Patients will receive up to 6 doses of MCS110 (3 or 5 or 10mg/kg) administered intravenously once every 4 weeks. Before each dosing, safety will be assessed.<br>* Other names: Intravenous infusion of MCS110.;|
| Experimental: MCS110 3 mg/kg & MCS110 10mg/kg<br>Part C: MCS110 3 mg/kg (i.v. infusion) & MCS110 10 mg/kg (i.v. infusion) | Drug: MCS110<br>* Patients will receive up to 6 doses of MCS110 (3 or 5 or 10mg/kg) administered intravenously once every 4 weeks. Before each dosing, safety will be assessed.<br>* Other names: Intravenous infusion of MCS110.;|
| Experimental: MCS110 5 mg/kg & MCS110 10mg/kg<br>Part C: MCS110 5 mg/kg (i.v. infusion) & MCS110 10 mg/kg (i.v. infusion) | Drug: MCS110<br>* Patients will receive up to 6 doses of MCS110 (3 or 5 or 10mg/kg) administered intravenously once every 4 weeks. Before each dosing, safety will be assessed.<br>* Other names: Intravenous infusion of MCS110.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Pigmented Villonodular Synovitis (PVNS) Tumor Size | To assess the efficacy of a single i.v. dose of MCS110 in changing the size of PVNS tumors (as compared to baseline) compared to placebo over 4 weeks evaluated by volume of PVNS tumors by 3-dimensional MRI. This analysis includes all data from patients 4 weeks after receiving the first dose of MCS110 (3, 5 or 10 mg/kg) or placebo and assesses the tumor volume changes at week 4 as compared to baseline. As all parts (Part A, B and C) of the study are assessed after a single dose at week 4 the data set is called ABC4. | Week 4 | 
| Percent Change in Pigmented Villonodular Synovitis (PVNS) Tumor Size | To assess the efficacy of a single i.v. dose of MCS110 in percent change of the PVNS tumor volume at week 4 as compared to baseline and compared to placebo evaluated by volume of PVNS tumors by 3-dimensional MRI. This analysis includes all data from patients who received at least a single dose of MCS110 (3, 5 or 10 mg/kg) or placebo and assesses the tumor volume changes at week 4 as compared to baseline. As all parts (Part A, B and C) of the study are assessed after a single dose at week 4 the data set is called ABC4. | Week 4 | 
| Change in Pigmented Villonodular Synovitis (PVNS) or Giant Cell Tumor of the Tendon Sheath (GCTTS) Tumor Size | Assessment of maximum efficacy (multiple i.v.monthly doses (2 to 6) of 3, 5 or 10 mg/kg MCS110 or 3 & 10 mg/kg or 5 & 10 mg/kg in changing PVNS tumor volume (as compared to baseline) up to 8 weeks post last dose evaluated by MRI. Analysis included data starting from 1st dose of MCS110 in all treatment groups of Parts B and C. Part B patients who received placebo as 1st dose, measurement prior to receiving first dose of MCS110, was used as baseline and assessment time-points were adjusted accordingly. For Part C, participants starting treatment with low dose of MCS110 of 3 or 5 mg/kg could switch to 10 mg/kg after 3 monthly doses, if MCS110 was well tolerated and tumor volume reduction was ≤ 45%. Analysis includes data from patients who received at least 2 doses. The following five groups were assessed: Subjects receiving only 3 mg/kg, only 5 mg/kg or 10 mg/kg and those who switched after 3 doses of 3 mg/kg to 10 mg/kg [3/10 mg/kg] or after 3 doses of 5 mg/kg to 10 mg/kg [5/10 mg/kg] | Up to 8 weeks post last dose | 
| Percentage Change in Pigmented Villonodular Synovitis (PVNS) or Giant Cell Tumor of the Tendon Sheath (GCTTS) Tumor Size | To assess the maximum efficacy of multiple monthly i.v. doses (2 to 6) of 3, 5 or 10 mg/kg MCS110 or 3 and 10 mg/kg or 5 and 10 mg/kg by percent change in the PVNS tumor volume (as compared to baseline) up to 8 weeks post last dose evaluated by MRI. Subjects starting treatment with a low dose of MCS110 of 3 or 5 mg/kg could switch to 10 mg/kg after 3 monthly doses, if MCS110 was well tolerated and the tumor volume reduction was ≤ 45%. This analysis includes data from all participants who received at least 2 doses of MCS110 and thus includes only patients from Part B and C of the study, thus the data set is called Part BC. The following five groups were assessed: Subjects receiving only 3 mg/kg, only 5 mg/kg or 10 mg/kg and those who switched after 3 doses of 3 mg/kg to 10 mg/kg [3/10 mg/kg] or after 3 doses of 5 mg/kg to 10 mg/kg [5/10 mg/kg]. | Up to 8 weeks post last dose | 
| Number of Participants With Adverse Events | Overall incidence of Adverse Events | Approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics of MCS110 Area Under the Serum Concentration-time Curve (AUC) | Pharmacokinetic for a single dose of MCS110 for serum concentration -time curve (AUC). | Day 1 (0 - 5 hr), Day 29, Day 85, Day 112, PART B (Day 1: (0 -5 hr), (Day 85: 0 - 5 hr) PART C (Day 1: 0 -5 hr), (Day 85: 0-5 hr) | 
| Pharmacokinetics of MCS110 Maximum Concentration (Cmax) | Pharmacokinetic characterization of a single dose of MCS110 for maximum serum concentration (Cmax) | Day 1 (0 - 5 hr), Day 29, Day 85, Day 112, PART B (Day 1: (0 -5 hr), (Day 85: 0 - 5 hr) PART C (Day 1: 0 -5 hr), (Day 85: 0-5 hr) | 
| Pharmacokinetics of MCS110 Total Maximum Concentration (Tmax) | Pharmacokinetic characterization of a single dose of MCS110 for time to maximum concentration (Tmax) | Day 1 (0 - 5 hr), Day 29, Day 85, Day 112, PART B (Day 1: (0 -5 hr), (Day 85: 0 - 5 hr) PART C (Day 1: 0 -5 hr), (Day 85: 0-5 hr) | 
| Change in Macrophage-colony Stimulating Factor (M-CSF) Plasma Concentrations Over Time | Pharmacokinetic characterization of a single dose of MCS110 for evaluation of macrophage-colony stimulating factor (M-CSF) plasma concentrations over time | Baseline, Day 1, Day 85, Day 169 | 
| Change in Serum C-terminal Type 1 Collagen Peptide Concentrations (CTX-I). | Pharmacodynamic characterization of a single dose of MCS110 by measuring C-terminal telopeptide of Type 1 Collagen peptide (CTX-I), a biomarker of bone resorption. Data measured in participants from three arms: participants from Part A, B and C who received a single dose of 10 mg/kg and had assessment at week 4 (Part ABC4); participants from Part A and B who received placebo ; and participants from Part B and C who received multiple monthly doses of MCS110 (10 mg/kg.) Serum CTX-I data were generated in Part A and Part B. In Part C, samples were collected for serum bone CTX-I analysis. The analysis was not performed, as enough information on compound mode of action was obtained using creatine kinase (CK) and monocytes (hematology) data. Only data from 10mg/kg (single and multiple doses) are available. | Baseline, Week 4, Week 24, Week 104 | 
| Number of Participants With Negative Anti-MCS110 Antibody | To assess the immunogenicity of MCS110 in serum anti-MCS110 antibody concentrations | Baseline, throughout the study up to Day 505 | 
| Assessment of Change From Baseline in Joint Range of Motion for Knee Extension and Flexion | To assess the clinical response of joint range of motion following a single i.v. dose of MCS110 or placebo as compared to baseline 4 weeks post-dose evaluated in participants, who had a knee tumor, which was the majority of participants (75%). The analysis includes all data from patients 4 weeks after receiving the first dose of MCS110 (3, 5 or 10 mg/kg) or placebo. As all parts (Part A, B and C) of the study are assessed after a single dose at week 4 the data set is called ABC4. | Week 4 | 
| Assessment of Change From Baseline in Joint Range of Motion for Knee Extension and Flexion | To assess the clinical response of joint range of motion following multiple dose treatment with MCS110 3, 5, or 10 mg/kg evaluated in participants with knee tumor, which was the majority of participants (75%). The data presented are changes from baseline in degree. Participants, who started treatment with a low dose of MCS110 of 3 or 5 mg/kg could switch to 10 mg/kg after 3 monthly doses, if MCS110 was well tolerated and the tumor volume reduction was ≤ 45%. This analysis includes data from participants with knee tumor who received at least 2 doses of MCS110 and thus includes only patients from Part B and C of the study, thus the data set is called Part BC. The following five groups were assessed: Subjects receiving only 3 mg/kg, only 5 mg/kg or 10 mg/kg and those who switched after 3 doses of 3 mg/kg to 10 mg/kg [3/10 mg/kg] or after 3 doses of 5 mg/kg to 10 mg/kg [5/10 mg/kg]. | Week 24/28, Week 104 | 
| Change From Baseline in Joint Pain Using a Visual Analog Scale (VAS) | Measurement of the participant's pain with a 100 mm visual analog scale (VAS) following treatment with MCS110 3, 5, or 10 mg/kg evaluated. Data presented are changes from baseline in degree. Participants were asked to place a line perpendicular to the VAS line at the point that represented her/his pain intensity. Using a ruler, the score was determined by measuring the distance (mm) on the 10-cm line between the no pain anchor and the participants mark, providing a score from 0-100. Analysis includes data from participants with knee tumor who received at least 2 doses of MCS110 and thus includes only patients from Part B and C of the study, thus the data set is called Part BC. The following five groups were assessed: Subjects receiving only 3 mg/kg, only 5 mg/kg or 10 mg/kg and those who switched after 3 doses of 3 mg/kg to 10 mg/kg [3/10 mg/kg] or after 3 doses of 5 mg/kg to 10 mg/kg [5/10 mg/kg]. | Baseline, Week 4, Week 12, Week 24, Week 28, Week 40, Week 48, Week 104 | 
| Time to Relapse | Time to relapse describes the time frame from baseline when the tumor volume increases again after the treatment with MCS110. To be considered a relapse tumor volume had to increase greater than 50% of the difference between tumor volume at baseline and the lowest tumor volume measured by MRI. In this assessment the Part B and Part C patients were analyzed separately. N/A (not available):Data analysis not performed as sample size was not analyzable as no patient had surgery/relapse. | Up to Week 104 | 
| Time to Surgery | Time to surgery describes the time frame from baseline to the time point when participants had surgical removement of PVNS tumor. This could be either residual tumor after the tumor volume was reduced or surgery due to relapse. In this assessment the Part B and Part C patients were analyzed separately. Not Available (NA): Data analysis not performed as sample size was not analyzable as no patient had surgery. | Up to Week 104 | 
| Average of Health-Related Quality of Life Questionnaire Score for mHAQ | The mHAQ assesses 20 activities in 8 categories related to daily life, which are rated on a 4-point Likert scale. The mHAQ is calculated as the average of the single scores with the following scoring: without difficulty =0; with some difficulty =1; with much difficulty =2; unable to do =3. Total score is between 0 - 3.0. Values <0.3 are considered normal. Data presented include only participants, who received multiple doses of MCS110. | up to 104 weeks | 
| Number of CD14+ Monocytes and Number of CD14 + Monocytes and CD16+ Monocytes | Blood samples were collected for the evaluation of CD14+ monocytes (using FACS) and CD14+ CD16+ monocytes. Based on preliminary analysis, the quality of the samples did not allow meaningful conclusions to be drawn. Thus, in Part B, the monocyte sample collection was discontinued. | Baseline Up to Week 104 | 
| Change From Baseline Per Treatment for Activities of Daily Living (ADL) in the Knee Injury and Osteoarthritis Outcome Score (KOOS) | The KOOS is a patient-reported outcome measurement instrument developed to assess the subject's opinion about their knee and associated problems. The KOOS questionnaire collected data on 5 knee-specific patient-centered outcomes: activities of daily life (ADL), knee related quality of life (QOL), pain and discomfort, sport/recreation, symptoms. The 5 KOOS sub-scales were scored separately on a Likert scale scored from 0 (no problems) to 4 (extreme problems) and scores were transformed to a 0.100 scale with 0 representing extreme knee problems and 100 representing no problems. The 5 dimensions were analyzed independently. Positive changes (i.e. increases in the score) are beneficial. KOOS was assessed in Part B and C only in participants with knee PVNS tumor. | Baseline, Week 4, Week 12, Week 24, Week 48, Week 40, Week 72, Week 104 (end of study) | 
| Change From Baseline Per Treatment for Knee Related Quality of Life in the Knee Injury and Osteoarthritis Outcome Score (KOOS) | The KOOS is a patient-reported outcome measurement instrument developed to assess the subject's opinion about their knee and associated problems. The KOOS questionnaire collected data on 5 knee-specific patient-centered outcomes: activities of daily life (ADL), knee related quality of life, pain and discomfort, sport/recreation, symptoms. The 5 KOOS sub-scales were scored separately on a Likert scale scored from 0 (no problems) to 4 (extreme problems) and scores were transformed to a 0.100 scale with 0 representing extreme knee problems and 100 representing no problems. The 5 dimensions were analyzed independently. Positive changes (i.e. increases in the score) are beneficial. KOOS was assessed in Part B and C only in participants with knee PVNS tumor. | Baseline, Week 4, Week 12, Week 24, Week 48, Week 40, Week 72, Week 104 (end of study) | 
| Change From Baseline Per Treatment for Pain and Discomfort in the Knee Injury and Osteoarthritis Outcome Score (KOOS) | The KOOS is a patient-reported outcome measurement instrument developed to assess the subject's opinion about their knee and associated problems. The KOOS questionnaire collected data on 5 knee-specific patient-centered outcomes: activities of daily life (ADL), knee related quality of life, pain and discomfort, sport/recreation, symptoms. The 5 KOOS sub-scales were scored separately on a Likert scale scored from 0 (no problems) to 4 (extreme problems) and scores were transformed to a 0.100 scale with 0 representing extreme knee problems and 100 representing no problems. The 5 dimensions were analyzed independently. Positive changes (i.e. increases in the score) are beneficial. KOOS was assessed in Part B and C only in participants with knee PVNS tumor. | Baseline, Week 4, Week 12, Week 24, Week 48, Week 40, Week 72, Week 104 (end of study) | 
| Change From Baseline Per Treatment for Sport/Recreation in the Knee Injury and Osteoarthritis Outcome Score (KOOS) | The KOOS is a patient-reported outcome measurement instrument developed to assess the subject's opinion about their knee and associated problems. The KOOS questionnaire collected data on 5 knee-specific patient-centered outcomes: activities of daily life (ADL), knee related quality of life, pain and discomfort, sport/recreation, symptoms. The 5 KOOS sub-scales were scored separately on a Likert scale scored from 0 (no problems) to 4 (extreme problems) and scores were transformed to a 0.100 scale with 0 representing extreme knee problems and 100 representing no problems. The 5 dimensions were analyzed independently. Positive changes (i.e. increases in the score) are beneficial. KOOS was assessed in Part B and C only in participants with knee PVNS tumor. | Baseline, Week 4, Week 12, Week 24, Week 48, Week 40, Week 72, Week 104 (end of study) | 
| Change From Baseline Per Treatment for Symptoms in the Knee Injury and Osteoarthritis Outcome Score (KOOS) | The KOOS is a patient-reported outcome measurement instrument developed to assess the subject's opinion about their knee and associated problems. The KOOS questionnaire collected data on 5 knee-specific patient-centered outcomes: activities of daily life (ADL), knee related quality of life, pain and discomfort, sport/recreation, symptoms. The 5 KOOS sub-scales were scored separately on a Likert scale scored from 0 (no problems) to 4 (extreme problems) and scores were transformed to a 0.100 scale with 0 representing extreme knee problems and 100 representing no problems. The 5 dimensions were analyzed independently. Positive changes (i.e. increases in the score) are beneficial. KOOS was assessed in Part B and C only in participants with knee PVNS tumor. | Baseline, Week 4, Week 12, Week 24, Week 48, Week 40, Week 72, Week 104 (end of study) | 
| Change From Baseline Per Treatment Using EuroQol-5 Dimensional (EQ-5D VAS)Visual Analog Scale Quality of Life Questionnaire | The EQ-5D is a standardized measure of health status. The EQ visual analogue scale (EQ VAS)has a range from 0-100: worst possible to perfect health. Data show the absolute change from baseline of EQ5D VAS and at the different visits for participants, who received multiple doses of MCS110. (PART B and PART C). | Week 4, Week 24, up to 104 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pigmented Villonodular Synovitis, PVNS, Giant cell tumor of the tendon sheath, GCCTS, Tenosynovial giant cell tumor (localized or diffused type), GCTS, MCS110