Musculoskeletal Diseases

All Conditions

Neoplasms

Skin and Connective Tissue Diseases

Wounds and Injuries

Nervous System Diseases

Rare Diseases

Synovitis

Giant Cell Tumors

Giant Cell Tumor of Tendon Sheath

Synovitis, Pigmented Villonodular

Joint Diseases

Neoplasms, Connective Tissue

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Tendinopathy

Muscular Diseases

Pigmented Villonodular Synovitis

Participants will receive a single dose of 10mg/kg on day 1 administered by regular infusion.

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)

Part C: MCS110 3 mg/kg (i.v. infusion) \& MCS110 10 mg/kg (i.v. infusion)

Part C: MCS110 5 mg/kg (i.v. infusion) \& MCS110 10 mg/kg (i.v. infusion)

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.

MCS110

Participants will receive a single dose of NaCl on day 1 through intravenous infusion.

Placebo

Novartis Pharmaceuticals

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.

MCS110 in Patients With Pigmented Villonodular Synovitis (PVNS)

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)

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

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".

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".

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 \[5/10 mg/kg\]

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 \[5/10 mg/kg\].

Pharmacokinetic for a single dose of MCS110 for serum concentration -time curve (AUC).

Pharmacokinetic characterization of a single dose of MCS110 for maximum serum concentration (Cmax)

Pharmacokinetic characterization of a single dose of MCS110 for time to maximum concentration (Tmax)

Pharmacokinetic characterization of a single dose of MCS110 for evaluation of macrophage-colony stimulating factor (M-CSF) plasma concentrations over time

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.

To assess the immunogenicity of MCS110 in serum anti-MCS110 antibody concentrations

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".

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 \[5/10 mg/kg\].

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 \[5/10 mg/kg\].

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.

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.

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.

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.

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.

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.

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).

Participants received a single dose of 10 mg/kg on Day 1 administered by i.v. infusion

MCS110 10 mg/kg (PART A)

Participants received single dose placebo by i.v. infusion to match MCS110 10 mg/kg

Placebo (PART A)

MCS110 10mg/kg (PART B)

Participants received single dose placebo to match first dose of MCS110 10 mg/kg and then continued with monthly administration of MCS110 10 mg/kg. fter this first single dose of placebo participants switched to monthly administration of MCS110 10 mg/kg and were added to the MCS110 10 mg/kg (PART B) group, which then increased from 8 to 11 participants. Participants could have received a 2nd treatment cycle (6 x 10 mg/kg MCS110) if tumor grew again

Placebo/10mg/kg (PART B)

MCS110 3mg/kg (PART C)

MCS110 5mg/kg (PART C)

MCS110 10mg/kg (PART C)

Participants received multiple monthly doses of MCS110 10 mg/kg. This group also included participants who had received placebo as a 1st dose

MCS110 10 mg/kg (PART B)

Participants received multiple monthly doses of MCS110 3 mg/kg. Participants could have received a 2nd treatment cycle (6 x 10 mg/kg MCS110) if tumor grew again

MCS110 3 mg/kg (Part C)

Participants received multiple monthly doses of MCS110 5 mg/kg. Participants could have received a 2nd treatment cycle (6 x 10 mg/kg MCS110) if tumor grew again

MCS110 5 mg/kg (Part C)

Participants received multiple monthly doses of MCS110 10 mg/kg. Participants could have received a 2nd treatment cycle (6 x 10 mg/kg MCS110) if tumor grew again

MCS110 10 mg/kg (Part C)

Participants received 3 doses of 3 mg/kg and if not efficacious (≥45% of tumor volume reduction) could switch to 10 mg/kg. This is a subset of participants who started with a dose of 3 mg/kg. Participants could have received a 2nd treatment cycle (6 x 10 mg/kg MCS110) if tumor grew again.

MCS110 3 mg/kg & MCS110 10mg/kg (Part C)

Participants received 3 doses of 5 mg/kg and if not efficacious (≥45% of tumor volume reduction) could switch to 10 mg/kg. This is a subset of participants who started with a dose of 5 mg/kg. Participants could have received a 2nd treatment cycle (6 x 10 mg/kg MCS110) if tumor grew again.

MCS110 5 mg/kg & MCS110 10mg/kg (PART C)

Total

Age, Continuous

Sex: Female, Male

Caucasian

Black

Other

Race/Ethnicity, Customized

Study Director

Placebo (PART ABC4)

Single dose MCS110 3 mg/kg. This group included also the subjects who later switch to MCS110 10 mg/kg

MCS110 3 mg/kg (PART ABC4)

Single dose MCS110 5 mg/kg. This group included also the subjects who later switch to MCS110 10 mg/kg.

MCS110 5 mg/kg (PART ABC4)

MCS110 10 mg/kg (PART ABC4)

Change in Pigmented Villonodular Synovitis (PVNS) Tumor Size

Percent Change in Pigmented Villonodular Synovitis (PVNS) Tumor Size

Participants received multiple monthly doses of MCS110 3 mg/kg

MCS110 3 mg/kg (PART C)

MCS110 5 mg/kg (PART C)

Participants received multiple monthly doses of MCS110 10 mg/kg. This included patients who started with single dose placebo, then switched to MCS110 10mg/kg after they switched to MCS110 10mg/kg and had their baseline re-calculated.

MCS110 10 mg/kg (PART BC)

Participants received 3 monthly doses of 5 mg/kg and switched to monthly doses of 10 mg/kg (max 3 doses)

MCS110 5 mg/kg & MCS110 10mg/kg (Part C)

Change in Pigmented Villonodular Synovitis (PVNS) or Giant Cell Tumor of the Tendon Sheath (GCTTS) Tumor Size

MCS110 3 mg/kg (PART BC)

Participants received multiple monthly doses of MCS110 5 mg/kg

MCS110 5 mg/kg (PART BC)

Participants received 3 monthly doses of 3 mg/kg and switched to monthly doses of 10 mg/kg (max 3 doses)

MCS110 3 mg/kg & MCS110 10mg/kg (Part BC)

MCS110 5 mg/kg & MCS110 10mg/kg (Part BC)

Percentage Change in Pigmented Villonodular Synovitis (PVNS) or Giant Cell Tumor of the Tendon Sheath (GCTTS) Tumor Size

AEs of mild severity

AEs of moderate severity

AEs of severe severity

Study drug related AEs

Serious AEs

AEs leading to discontinuation

Participants received a single dose of 10mg/kg on day 1 administered by i.v. infusion.

Participants received single dose placebo to match MCS110 10mg/kg (i.v. infusion)

Participants received single dose placebo to match first dose of MCS110 10 mg/kg (i.v. infusion) and then continued with monthly administration of MCS110 10 mg/kg. Subset of MCS110 (Part B)

Placebo (PART B)

Participants received multiple monthly doses of MCS110 10 mg/kg. This group includes also participants who had received before 3 monthly doses of 3 or 5 mg/kg and then switched to MCS110 10 mg/kg

MCS110 10 mg/kg (PART C)

Number of Participants With Adverse Events

Day 1

Day 29

Day 85

Day 112

Participants received single dose placebo to match first dose of MCS110 10 mg/kg (i.v. infusion)and then continued with monthly administration of MCS110 10 mg/kg. Participants could receive a 2nd treatment cycle (6 x 10 mg/kg MCS110) if tumor growth again

Placebo/10 mg kg (PART B)

Participants received multiple monthly doses of MCS110 3 mg/kg. Participants could receive a 2nd treatment cycle (6 x 10 mg/kg MCS110) if tumor growth again

Participants received multiple monthly doses of MCS110 10 mg/kg. Participants could receive a 2nd treatment cycle (6 x 10 mg/kg MCS110) if tumor growth again

MCS110 mg/kg (PART C)

Pharmacokinetics of MCS110 Area Under the Serum Concentration-time Curve (AUC)

Pharmacokinetics of MCS110 Maximum Concentration (Cmax)

Pharmacokinetics of MCS110 Total Maximum Concentration (Tmax)

Baseline

Day 169

Participants received single dose placebo to match MCS110 10 mg/k

Placebo/MCS110 10mg/kg (PART A)

Change in Macrophage-colony Stimulating Factor (M-CSF) Plasma Concentrations Over Time

Week 4

Week 24

Week 104

Participants received a single dose of MCS110 10 mg/kg

PART A: Participants received single dose placebo to match MCS110 10mg/kg (i.v. infusion). PART B: Participants received single dose placebo to match first dose of MCS110 10 mg/kg (i.v. infusion) and then continued with monthly administration of MCS110 10 mg/kg.

Placebo (PARTS A and B)

Change in Serum C-terminal Type 1 Collagen Peptide Concentrations (CTX-I).

Day 127

Day 336

Day 393

Day 505

Participants received a single dose of 10mg/kg on day 1 administered by regular infusion.

Participants received single dose placebo to match MCS110 10 mg/kg

Participants received single dose placebo to match first dose of MCS110 10 mg/kg (i.v. infusion) and then continued with monthly administration of MCS110 10 mg/kg

Participants received multiple monthly doses of MCS110 10 mg/kg

Participants received 3 doses of 5 mg/kg and if not efficacious (≥45% of tumor volume reduction) could switch to 10 mg/kg. This is a subset of patients who started with a dose of 5 mg/kg

Number of Participants With Negative Anti-MCS110 Antibody

Knee Extension

Knee Flexion

Assessment of Change From Baseline in Joint Range of Motion for Knee Extension and Flexion

Week 24/28: Knee extension

Week 24/28:(Knee Flexion)

Week 104:(Knee Extension)

Week 104: (Knee Flexion)

MCS110 3 mg/kg (Part BC)

MCS110 5 mg/kg (Part BC)

MCS110 10 mg/kg (Part BC)

MCS110 3 mg/kg & MCS110 10mg/kg (PART BC)

MCS110 5 mg/kg & MCS110 10mg/kg (PART BC)

Week 12

Week 28

Week 40

Week 48

MCS110 3 mg/kg & MCS110 10 mg/kg (PART BC)

MCS110 5 mg/kg & MCS110 10 mg/kg (PART BC)

Change From Baseline in Joint Pain Using a Visual Analog Scale (VAS)

Participants received multiple monthly doses of MCS110 5 mg/k. Participants could have received a 2nd treatment cycle (6 x 10 mg/kg MCS110) if tumor grew again

Participants received 3 monthly doses of 3 mg/kg and switched to monthly doses of 10 mg/kg (max 3 doses

MCS110 3/10 mg/kg (PART C)

MCS110 5/10 mg/kg (PART C)

Time to Relapse

Time to Surgery

Average of Health-Related Quality of Life Questionnaire Score for mHAQ

Participants received multiple monthly doses of MCS110 10 mg/kg )

Participants received 3 doses of 3 mg/kg and if not efficacious (≥45% of tumor volume reduction) could switch to 10 mg/kg. This is a subset of patients who started with a dose of 3 mg/kg

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
MCS110 in Patients With Pigmented Villonodular Synovitis (PVNS)	NCT01643850	Pigmented Villo... PVNS Giant Cell Tumo... GCCTS Tenosynovial Gi... GCTS	MCS110 Placebo	12 Years -	Novartis
MCS110 in Patients With Pigmented Villonodular Synovitis (PVNS)	NCT01643850	Pigmented Villo... PVNS Giant Cell Tumo... GCCTS Tenosynovial Gi... GCTS	MCS110 Placebo	12 Years -	Novartis
MCS110 in Patients With Pigmented Villonodular Synovitis (PVNS)	NCT01643850	Pigmented Villo... PVNS Giant Cell Tumo... GCCTS Tenosynovial Gi... GCTS	MCS110 Placebo	12 Years -	Novartis

Spots Global Cancer Trial Database for giant cell tumor of the tendon sheath