Giant Cell Tumor of Tendon Sheath, Pigmented Villonodular Synovitis, Tenosynovial Giant Cell Tumor, Tenosynovial Giant Cell Tumor, Diffuse, Tenosynovial Giant Cell Tumor, Localized
Conditions
Keywords
TGCT, PVNS
Brief summary
This is a multicenter Phase 3 clinical study, which aims to evaluate the effectiveness of an investigational drug called vimseltinib for the treatment of tenosynovial giant cell tumor (TGCT) in cases where surgical removal of the tumor is not an option. The study consists of two parts. In Part 1, eligible study participants will be assigned to receive either vimseltinib or matching placebo for 24 weeks. A number of assessments will be carried out during the course of the study, including physical examinations, blood tests, imaging studies, electrocardiograms, and questionnaires. MRI scans will be used to evaluate the response of the tumors to the treatment. Participants assigned to placebo in Part 1 will have the option to receive vimseltinib for Part 2. Part 2 is a long-term treatment phase in which all participants receive open-label vimseltinib.
Interventions
DRUGVimseltinib
Administered orally
DRUGPlacebo
Administered orally
Sponsors
Deciphera Pharmaceuticals, LLC
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients ≥18 years of age 2. TGCT for which surgical resection is not an option (tumor biopsy to confirm diagnosis required if no histology/pathology available at screening) 3. Symptomatic disease as defined as at least moderate pain or at least moderate stiffness (defined as a score of 4 or more, with 10 describing the worst condition) within the screening period and documented in the medical record 4. Participants should complete 14 consecutive days of questionnaires during the screening period and must meet minimum requirements as outlined in study protocol 5. Must have stable analgesic regimen, as judged by the investigator, for at least 2 weeks prior to first dose of study drug 6. Must have measurable disease, as per RECIST Version 1.1, with at least one lesion having a minimum size of 2cm 7. Adequate organ and bone marrow function 8. If a female of childbearing potential, must have a negative pregnancy test prior to enrollment and agree to follow the contraception requirements 9. Must provide signed consent to participate in the study and is willing to comply with study-specific procedures 10. Willing and able to complete the patient-reported outcome (PRO) assessments on an electronic device
Exclusion criteria
1. Previous use of systemic therapy (investigational or approved) targeting colony-stimulating factor 1 (CSF1) or colony-stimulating factor 1 receptor (CSF1R); previous therapy with imatinib and nilotinib is allowed 2. Received therapy for TGCT, including investigational therapy during the screening period. Participated in a non-TGCT investigational drug study within 30 days of screening. 3. Known metastatic TGCT or other active cancer that requires concurrent treatment (exceptions will be considered on a case-by-case basis) 4. QT interval corrected by Fridericia's formula (QTcF) \>450 ms in males or \>470 ms in females or history of long QT syndrome 5. Concurrent treatment with any study-prohibited medications 6. Major surgery within 14 days of the first dose of study drug 7. Any clinically significant comorbidities 8. Active liver or biliary disease including nonalcoholic steatohepatitis (NASH) or cirrhosis 9. Malabsorption syndrome or other illness that could affect oral absorption 10. Known active human immunodeficiency virus (HIV), acute or chronic hepatitis B, acute or chronic hepatitis C, or known active mycobacterium tuberculosis infection 11. If female, the participant is pregnant or breastfeeding 12. Known allergy or hypersensitivity to any component of the study drug 13. Contraindication to MRI
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) at Week 25 Per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 | Baseline to Week 25 (Cycle 7, Day 1) | ORR was assessed by blinded independent radiologic review (IRR) using RECIST Version 1.1. ORR was defined as the percentage of participants who achieved either complete response (CR) or partial response (PR). * CR: Disappearance of all target lesions. Any pathological lymph nodes must be \<10 millimeter (mm) in short axis. Non-nodal targets must be absent. * PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| ORR at Week 25 Per Tumor Volume Score (TVS) | Baseline to Week 25 (Cycle 7, Day 1) | TVS is a semi-quantitative magnetic resonance imaging (MRI) scoring system that describes tumor mass and is based on 10% increments of the estimated volume of the maximally distended synovial cavity or tendon sheath involved. A tumor that is equal in volume to that of a maximally distended synovial cavity or tendon sheath was scored 10; a score of 0 indicated no evidence of tumor. ORR was the percentage of participants who achieved either CR or PR as assessed by blinded IRR using TVS. * CR: Lesion completely gone * PR: ≥50% decrease in volume score relative to Baseline. |
| Change From Baseline in Active Range of Motion (ROM) at Week 25 | Baseline to Week 25 (Cycle 7, Day 1) | Presented here is the change from baseline in active ROM to Week 25. Measurement of the affected and contralateral, non-affected joint was assessed by goniometer and measured in degrees. At baseline, the motion with the smallest relative ROM value (worst) was identified, and this motion was used for evaluating the change in relative ROM subsequently. The affected joint measurement was used to derive a relative ROM based on active measurement relative to reference standard value provided by the American Medical Association. Relative ROM is expressed in percent: 100 x (joint ROM measure)/(reference ROM standard). |
| Change From Baseline in the Patient-reported Outcomes Measurement Information System (PROMIS) Physical Function (PF) Score at Week 25 | Baseline to Week 25 (Cycle 7, Day 1) | All participants were asked 15 questions from the PROMIS-PF item bank. The questions used one of two 5-point verbal rating scales: either 1 = "unable to do", 2 = "with much difficulty", 3 = "with some difficulty", 4 = "with a little difficulty", and 5 = "without any difficulty"; or 1 = "cannot do", 2 = "quite a lot", 3 = "somewhat", 4 = "very little", and 5 = "not at all." Total scores were converted to T-scores that ranged from 0 to 100, with higher scores representing less physical function interference and better health outcomes. |
| Change From Baseline in the Worst Stiffness Numeric Rating Scale (NRS) Score at Week 25 | Baseline to Week 25 (Cycle 7, Day 1) | The Worst Stiffness NRS is a single question that asks the participant to assess their worst stiffness in the last 24 hours. Participants rate their worst stiffness on a scale of 0 to 10, where 0 is "no stiffness" and 10 is "worst imaginable." Lower scores represented better level of stiffness. |
| Change From Baseline in EuroQoL Visual Analogue Scale (EQ-VAS) at Week 25 | Baseline to Week 25 (Cycle 7, Day 1) | The EQ-VAS is a standardized tool for measuring overall health. EQ-VAS recorded the participant's self-rated health on a vertical VAS scale ranging from a minimum of 0 (worst imaginable health state) to a maximum of 100 (best imaginable health state). Higher scores indicated better health state. |
| Percentage of Participants With Response at Week 25 Based on Brief Pain Inventory (BPI) Worst Pain NRS Score and Narcotic Analgesic Use | Baseline to Week 25 (Cycle 7, Day 1) | Participants reported responses to the BPI Worst Pain NRS. The BPI Worst Pain NRS ranged from 0 to 10, where 0 is "no pain" and 10 is "pain as bad as you can imagine." A responder was defined as a participant who: (i) experienced a decrease of at least 30% in the mean BPI Worst Pain NRS item and (ii) did not experience a 30% or greater increase in narcotic analgesic use. |
Countries
Australia, Canada, France, Germany, Hong Kong, Italy, Netherlands, Norway, Poland, Spain, Switzerland, United Kingdom, United States
Participant flow
Pre-assignment details
Presented here is data from the Week 25 primary endpoint analysis. The study is ongoing.
Participants by arm
| Arm | Count |
|---|---|
| Part 1/Part 2: Vimseltinib/Vimseltinib Participants received blinded treatment of vimseltinib 30 mg BIW for 24 weeks in Part 1 and open-label vimseltinib 30 mg BIW in Part 2 until EoT. | 83 |
| Part 1/Part 2: Placebo/Vimseltinib Participants received blinded treatment of matching placebo BIW for 24 weeks in Part 1 and open-label vimseltinib 30 mg BIW in Part 2 until end of EoT. | 40 |
| Total | 123 |
Baseline characteristics
| Characteristic | Part 1/Part 2: Placebo/Vimseltinib | Total | Part 1/Part 2: Vimseltinib/Vimseltinib |
|---|---|---|---|
| Age, Continuous | 42.5 years STANDARD_DEVIATION 13.67 | 43.4 years STANDARD_DEVIATION 13.8 | 43.8 years STANDARD_DEVIATION 13.92 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 4 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants | 85 Participants | 62 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 16 Participants | 34 Participants | 18 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 5 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 4 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 15 Participants | 34 Participants | 19 Participants |
| Race (NIH/OMB) White | 21 Participants | 80 Participants | 59 Participants |
| Sex: Female, Male Female | 27 Participants | 73 Participants | 46 Participants |
| Sex: Female, Male Male | 13 Participants | 50 Participants | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 118 | 0 / 39 |
| other Total, other adverse events | 113 / 118 | 32 / 39 |
| serious Total, serious adverse events | 17 / 118 | 1 / 39 |
Outcome results
Primary
Objective Response Rate (ORR) at Week 25 Per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1
ORR was assessed by blinded independent radiologic review (IRR) using RECIST Version 1.1. ORR was defined as the percentage of participants who achieved either complete response (CR) or partial response (PR). * CR: Disappearance of all target lesions. Any pathological lymph nodes must be \<10 millimeter (mm) in short axis. Non-nodal targets must be absent. * PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: Baseline to Week 25 (Cycle 7, Day 1)
Population: The ITT Set consisted of participants who were randomized to a study treatment regimen.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vimseltinib | Objective Response Rate (ORR) at Week 25 Per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 | 39.8 percentage of participants with CR or PR |
| Placebo | Objective Response Rate (ORR) at Week 25 Per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 | 0 percentage of participants with CR or PR |
p-value: <0.000195% CI: [28.4, 49.6]Cochran-Mantel-Haenszel
Secondary
Change From Baseline in Active Range of Motion (ROM) at Week 25
Presented here is the change from baseline in active ROM to Week 25. Measurement of the affected and contralateral, non-affected joint was assessed by goniometer and measured in degrees. At baseline, the motion with the smallest relative ROM value (worst) was identified, and this motion was used for evaluating the change in relative ROM subsequently. The affected joint measurement was used to derive a relative ROM based on active measurement relative to reference standard value provided by the American Medical Association. Relative ROM is expressed in percent: 100 x (joint ROM measure)/(reference ROM standard).
Time frame: Baseline to Week 25 (Cycle 7, Day 1)
Population: The ITT Set consisted of participants who were randomized to a study treatment regimen. Here, Overall Number of Participants Analyzed is the number of participants evaluable for this outcome measure at the specified time point.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Vimseltinib | Change From Baseline in Active Range of Motion (ROM) at Week 25 | 18.4 Change in percent | Standard Error 6.46 |
| Placebo | Change From Baseline in Active Range of Motion (ROM) at Week 25 | 3.8 Change in percent | Standard Error 7.19 |
p-value: 0.007795% CI: [4, 25.3]Mixed model repeated measures
Secondary
Change From Baseline in EuroQoL Visual Analogue Scale (EQ-VAS) at Week 25
The EQ-VAS is a standardized tool for measuring overall health. EQ-VAS recorded the participant's self-rated health on a vertical VAS scale ranging from a minimum of 0 (worst imaginable health state) to a maximum of 100 (best imaginable health state). Higher scores indicated better health state.
Time frame: Baseline to Week 25 (Cycle 7, Day 1)
Population: The ITT Set consisted of participants who were randomized to a study treatment regimen. Here, Overall Number of Participants Analyzed is the number of participants evaluable for this outcome measure at the specified time point.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Vimseltinib | Change From Baseline in EuroQoL Visual Analogue Scale (EQ-VAS) at Week 25 | 13.5 score on a scale | Standard Error 2.35 |
| Placebo | Change From Baseline in EuroQoL Visual Analogue Scale (EQ-VAS) at Week 25 | 6.1 score on a scale | Standard Error 2.85 |
p-value: 0.015595% CI: [1.4, 13.4]Mixed model repeated measures
Secondary
Change From Baseline in the Patient-reported Outcomes Measurement Information System (PROMIS) Physical Function (PF) Score at Week 25
All participants were asked 15 questions from the PROMIS-PF item bank. The questions used one of two 5-point verbal rating scales: either 1 = unable to do, 2 = with much difficulty, 3 = with some difficulty, 4 = with a little difficulty, and 5 = without any difficulty; or 1 = cannot do, 2 = quite a lot, 3 = somewhat, 4 = very little, and 5 = not at all. Total scores were converted to T-scores that ranged from 0 to 100, with higher scores representing less physical function interference and better health outcomes.
Time frame: Baseline to Week 25 (Cycle 7, Day 1)
Population: The ITT Set consisted of participants who were randomized to a study treatment regimen. Here, Overall Number of Participants Analyzed is the number of participants evaluable for this outcome measure at the specified time point.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Vimseltinib | Change From Baseline in the Patient-reported Outcomes Measurement Information System (PROMIS) Physical Function (PF) Score at Week 25 | 4.6 score on a scale | Standard Error 0.96 |
| Placebo | Change From Baseline in the Patient-reported Outcomes Measurement Information System (PROMIS) Physical Function (PF) Score at Week 25 | 1.3 score on a scale | Standard Error 0.88 |
p-value: 0.000795% CI: [1.4, 5.2]Mixed model repeated measures
Secondary
Change From Baseline in the Worst Stiffness Numeric Rating Scale (NRS) Score at Week 25
The Worst Stiffness NRS is a single question that asks the participant to assess their worst stiffness in the last 24 hours. Participants rate their worst stiffness on a scale of 0 to 10, where 0 is no stiffness and 10 is worst imaginable. Lower scores represented better level of stiffness.
Time frame: Baseline to Week 25 (Cycle 7, Day 1)
Population: The ITT Set consisted of participants who were randomized to a study treatment regimen. Here, Overall Number of Participants Analyzed is the number of participants evaluable for this outcome measure at the specified time point.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Vimseltinib | Change From Baseline in the Worst Stiffness Numeric Rating Scale (NRS) Score at Week 25 | -2.1 score on a scale | Standard Error 0.24 |
| Placebo | Change From Baseline in the Worst Stiffness Numeric Rating Scale (NRS) Score at Week 25 | -0.3 score on a scale | Standard Error 0.28 |
p-value: <0.000195% CI: [-2.5, -1.1]Mixed model repeated measures
Secondary
ORR at Week 25 Per Tumor Volume Score (TVS)
TVS is a semi-quantitative magnetic resonance imaging (MRI) scoring system that describes tumor mass and is based on 10% increments of the estimated volume of the maximally distended synovial cavity or tendon sheath involved. A tumor that is equal in volume to that of a maximally distended synovial cavity or tendon sheath was scored 10; a score of 0 indicated no evidence of tumor. ORR was the percentage of participants who achieved either CR or PR as assessed by blinded IRR using TVS. * CR: Lesion completely gone * PR: ≥50% decrease in volume score relative to Baseline.
Time frame: Baseline to Week 25 (Cycle 7, Day 1)
Population: The ITT Set consisted of participants who were randomized to a study treatment regimen.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vimseltinib | ORR at Week 25 Per Tumor Volume Score (TVS) | 67.5 percentage of participants |
| Placebo | ORR at Week 25 Per Tumor Volume Score (TVS) | 0 percentage of participants |
p-value: <0.000195% CI: [57, 77.3]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Response at Week 25 Based on Brief Pain Inventory (BPI) Worst Pain NRS Score and Narcotic Analgesic Use
Participants reported responses to the BPI Worst Pain NRS. The BPI Worst Pain NRS ranged from 0 to 10, where 0 is no pain and 10 is pain as bad as you can imagine. A responder was defined as a participant who: (i) experienced a decrease of at least 30% in the mean BPI Worst Pain NRS item and (ii) did not experience a 30% or greater increase in narcotic analgesic use.
Time frame: Baseline to Week 25 (Cycle 7, Day 1)
Population: The ITT Set consisted of participants who were randomized to a study treatment regimen.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vimseltinib | Percentage of Participants With Response at Week 25 Based on Brief Pain Inventory (BPI) Worst Pain NRS Score and Narcotic Analgesic Use | 48.2 percentage of participants |
| Placebo | Percentage of Participants With Response at Week 25 Based on Brief Pain Inventory (BPI) Worst Pain NRS Score and Narcotic Analgesic Use | 22.5 percentage of participants |
p-value: 0.005695% CI: [9.5, 42.8]Cochran-Mantel-Haenszel