Pigmented Villonodular Synovitis, Tenosynovial Giant Cell Tumor
Conditions
Keywords
Diffuse Type Tenosynovial Giant Cell Tumor (dt-TGCT)
Brief summary
This is a phase 1/2 single arm, open-label, safety, tolerability, and PK study of cabiralizumab in PVNS/dt-TGCT patients.
Detailed description
A Phase 1/2 study was an open-label, dose escalation and dose expansion study designed to evaluate the pharmacokinetics, pharmacodynamics, safety and preliminary efficacy of cabiralizumab, a CSF1-R monoclonal antibody, inpatients with unresectable diffuse tenosynovial giant cell tumors (TGCT).
Interventions
BIOLOGICALFPA008
FPA008 will be administered by IV infusion over approximately 30 minutes every 2 or 4 weeks
Sponsors
Five Prime Therapeutics, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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 documented in the CRF during screening) * Measurable PVNS/dt-TGCT by RECIST 1.1 on MRI * ECOG performance status \<1
Exclusion criteria
* Prior therapy with an anti-CSF1R antibody * Prior therapy with PLX3397 unless discontinued for intolerance (i.e., non-progression on prior kinase inhibitor) * Liver function tests (including ALT, AST, and total bilirubin), outside of the range of local laboratory normal at Screening * Inadequate organ or bone marrow function * History of congestive heart failure or myocardial infarction \<1 year prior to first study dose administration * Significant abnormalities on ECG at Screening * Contraindications to MRI and use of intravenous gadolinium-based contrast agents * Creatine Kinase ≥ 1.5x the upper limit of normal * Positive test for latent TB at Screening (Quantiferon test) * Active known or suspected autoimmune disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Incidence of Grade 3 and Grade 4 Adverse Events (AEs) and Defined as Dose-limiting Toxicities (DLTs) in Phase 1 | 52 weeks | Number of participants with grade 3 and grade 4 adverse events (AE) defined as dose limiting toxicities (DLTs) in Phase 1 |
| The Incidence of Investigator-assessed, Confirmed Objective Responses (ORR) Per RECIST 1.1 (Phase 2) | 52 weeks | Number of confirmed objective responses (ORR) as assessed by the investigator per RECIST 1.1 (Phase 2) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Minimum Serum Concentration (Cmin). | 52 weeks | Composite PK parameters of cabiralizumab: minimum serum concentration (Cmin). |
| Pharmacokinetic Clearance (CL). | 52 weeks | Composite PK parameters of cabiralizumab: clearance (CL) |
| The Incidence of AEs. | 52 weeks | treatment-emergent adverse events (TEAEs) by incidence for the Safety Population. Patients with at lease 1 TEAE. |
| PK Parameters of Cabiralizumab: Area Under Concentration-time Curve (AUC) | 52 weeks | Area under serum concentration-time curve (AUC) for cabiralizumab as a PK parameter |
| The Incidence of ECG Abnormalities. | 52 weeks | The number of patients who had a change in their ECG that were clinically significant |
| Duration of Response Per RECIST 1.1 in Phase 2 | 52 weeks | The length of response per RECIST 1.1 from the time of first response to progression or going off study in Phase 2 |
| The Incidence of Clinical Laboratory Abnormalities. | 52 weeks | The number of patients with a clinical laboratory that is outside the normal range at some time point during the study |
| Maximum Serum Concentration (Cmax). | 52 weeks | Composite PK parameters of cabiralizumab: Maximum observed serum concentration |
Countries
France, Netherlands, Poland, South Korea, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase 1 FPA008 Dose Escalation 1mg/kg Dose Escalation cohort: Dose level 1: 1 mg/kg cabiralizumab every 2 weeks | 3 |
| Phase 1 FPA008 Dose Escalation 2mg/kg Dose Escalation cohort: Dose level 2: 2 mg/kg cabiralizumab every 2 weeks | 3 |
| Phase 1 FPA008 Dose Escalation 4mg/kg Dose Escalation cohort: Dose level 3: 3 mg/kg cabiralizumab every 2 weeks | 3 |
| Phase 2 FPA008 Dose Expansion Cohort 2A Dose Expansion Cohort: patients were treated with 4 mg/kg cabiralizumab every 2 weeks in 28-day cycles for up to 12 doses. | 33 |
| Phase 2 FPA008 Dose Expansion Cohort 2B Dose Expansion Cohort: patients were treated with 4 mg/kg cabiralizumab on Cycle 1 Day 1 and Cycle 1 Day 15 then every 4 weeks thereafter for up to 12 months after Cycle 1, Day 1. | 24 |
| Total | 66 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Death | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 3 | 2 |
| Overall Study | Other | 0 | 0 | 0 | 8 | 9 |
| Overall Study | Study Terminiated by sponsor | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 2 | 5 |
Baseline characteristics
| Characteristic | Phase 2 FPA008 Dose Expansion Cohort 2B | Phase 1 FPA008 Dose Escalation 1mg/kg | Phase 1 FPA008 Dose Escalation 2mg/kg | Total | Phase 1 FPA008 Dose Escalation 4mg/kg | Phase 2 FPA008 Dose Expansion Cohort 2A |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 0 Participants | 1 Participants | 4 Participants | 0 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 22 Participants | 3 Participants | 2 Participants | 62 Participants | 3 Participants | 32 Participants |
| Age, Continuous | 44.1 years STANDARD_DEVIATION 15.32 | 37.7 years STANDARD_DEVIATION 11.24 | 40.7 years STANDARD_DEVIATION 23.07 | 40.8 years STANDARD_DEVIATION 14.03 | 41.7 years STANDARD_DEVIATION 7.51 | 38 years STANDARD_DEVIATION 12.77 |
| Race/Ethnicity, Customized American Indian/alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 0 Participants | 1 Participants | 7 Participants | 0 Participants | 5 Participants |
| Race/Ethnicity, Customized Black | 2 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian/Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 8 Participants | 0 Participants | 0 Participants | 27 Participants | 0 Participants | 19 Participants |
| Race/Ethnicity, Customized Unknown | 4 Participants | 0 Participants | 0 Participants | 5 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 9 Participants | 3 Participants | 2 Participants | 25 Participants | 2 Participants | 9 Participants |
| Sex: Female, Male Female | 10 Participants | 3 Participants | 3 Participants | 40 Participants | 1 Participants | 23 Participants |
| Sex: Female, Male Male | 14 Participants | 0 Participants | 0 Participants | 26 Participants | 2 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 | 0 / 3 | 1 / 32 | 0 / 24 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 33 / 33 | 24 / 24 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 | 2 / 3 | 8 / 33 | 6 / 24 |
Outcome results
Primary
The Incidence of Grade 3 and Grade 4 Adverse Events (AEs) and Defined as Dose-limiting Toxicities (DLTs) in Phase 1
Number of participants with grade 3 and grade 4 adverse events (AE) defined as dose limiting toxicities (DLTs) in Phase 1
Time frame: 52 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1 FPA008 Dose Escalation 1mg/kg | The Incidence of Grade 3 and Grade 4 Adverse Events (AEs) and Defined as Dose-limiting Toxicities (DLTs) in Phase 1 | 0 Participants |
| Phase 1 FPA008 Dose Escalation 2mg/kg | The Incidence of Grade 3 and Grade 4 Adverse Events (AEs) and Defined as Dose-limiting Toxicities (DLTs) in Phase 1 | 0 Participants |
| Phase 1 FPA008 Dose Escalation 4mg/kg | The Incidence of Grade 3 and Grade 4 Adverse Events (AEs) and Defined as Dose-limiting Toxicities (DLTs) in Phase 1 | 0 Participants |
Primary
The Incidence of Investigator-assessed, Confirmed Objective Responses (ORR) Per RECIST 1.1 (Phase 2)
Number of confirmed objective responses (ORR) as assessed by the investigator per RECIST 1.1 (Phase 2)
Time frame: 52 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1 FPA008 Dose Escalation 1mg/kg | The Incidence of Investigator-assessed, Confirmed Objective Responses (ORR) Per RECIST 1.1 (Phase 2) | 8 Participants |
| Phase 1 FPA008 Dose Escalation 2mg/kg | The Incidence of Investigator-assessed, Confirmed Objective Responses (ORR) Per RECIST 1.1 (Phase 2) | 8 Participants |
Secondary
Duration of Response Per RECIST 1.1 in Phase 2
The length of response per RECIST 1.1 from the time of first response to progression or going off study in Phase 2
Time frame: 52 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 FPA008 Dose Escalation 1mg/kg | Duration of Response Per RECIST 1.1 in Phase 2 | 4.4 months |
| Phase 1 FPA008 Dose Escalation 2mg/kg | Duration of Response Per RECIST 1.1 in Phase 2 | NA months |
Secondary
Maximum Serum Concentration (Cmax).
Composite PK parameters of cabiralizumab: Maximum observed serum concentration
Time frame: 52 weeks
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 FPA008 Dose Escalation 1mg/kg | Maximum Serum Concentration (Cmax). | 22.5 ug/mL | Geometric Coefficient of Variation 14.3 |
| Phase 1 FPA008 Dose Escalation 2mg/kg | Maximum Serum Concentration (Cmax). | 52.1 ug/mL | Geometric Coefficient of Variation 22 |
| Phase 1 FPA008 Dose Escalation 4mg/kg | Maximum Serum Concentration (Cmax). | 91.2 ug/mL | Geometric Coefficient of Variation 15 |
| Phase 2 FPA008 Dose Expansion Cohort 2A | Maximum Serum Concentration (Cmax). | 91.8 ug/mL | Geometric Coefficient of Variation 24.8 |
| Phase 2 FPA008 Dose Expansion Cohort 2B | Maximum Serum Concentration (Cmax). | 87 ug/mL | Geometric Coefficient of Variation 12.6 |
Secondary
Minimum Serum Concentration (Cmin).
Composite PK parameters of cabiralizumab: minimum serum concentration (Cmin).
Time frame: 52 weeks
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 FPA008 Dose Escalation 1mg/kg | Minimum Serum Concentration (Cmin). | 2.18 ug/mL | Geometric Coefficient of Variation 117 |
| Phase 1 FPA008 Dose Escalation 2mg/kg | Minimum Serum Concentration (Cmin). | 7.26 ug/mL | Geometric Coefficient of Variation 41.8 |
| Phase 1 FPA008 Dose Escalation 4mg/kg | Minimum Serum Concentration (Cmin). | 21.2 ug/mL | Geometric Coefficient of Variation 59.2 |
| Phase 2 FPA008 Dose Expansion Cohort 2A | Minimum Serum Concentration (Cmin). | 23.9 ug/mL | Geometric Coefficient of Variation 38.3 |
| Phase 2 FPA008 Dose Expansion Cohort 2B | Minimum Serum Concentration (Cmin). | 22.6 ug/mL | Geometric Coefficient of Variation 28.2 |
Secondary
Pharmacokinetic Clearance (CL).
Composite PK parameters of cabiralizumab: clearance (CL)
Time frame: 52 weeks
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 FPA008 Dose Escalation 1mg/kg | Pharmacokinetic Clearance (CL). | .663 L/d | Geometric Coefficient of Variation 16.6 |
| Phase 1 FPA008 Dose Escalation 2mg/kg | Pharmacokinetic Clearance (CL). | .416 L/d | Geometric Coefficient of Variation 24.5 |
| Phase 1 FPA008 Dose Escalation 4mg/kg | Pharmacokinetic Clearance (CL). | .694 L/d | Geometric Coefficient of Variation 0 |
| Phase 2 FPA008 Dose Expansion Cohort 2A | Pharmacokinetic Clearance (CL). | .307 L/d | Geometric Coefficient of Variation 44.9 |
| Phase 2 FPA008 Dose Expansion Cohort 2B | Pharmacokinetic Clearance (CL). | .525 L/d | Geometric Coefficient of Variation 8.42 |
Secondary
PK Parameters of Cabiralizumab: Area Under Concentration-time Curve (AUC)
Area under serum concentration-time curve (AUC) for cabiralizumab as a PK parameter
Time frame: 52 weeks
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 FPA008 Dose Escalation 1mg/kg | PK Parameters of Cabiralizumab: Area Under Concentration-time Curve (AUC) | 102 ug x day/mL | Geometric Coefficient of Variation 10.2 |
| Phase 1 FPA008 Dose Escalation 2mg/kg | PK Parameters of Cabiralizumab: Area Under Concentration-time Curve (AUC) | 283 ug x day/mL | Geometric Coefficient of Variation 26.3 |
| Phase 1 FPA008 Dose Escalation 4mg/kg | PK Parameters of Cabiralizumab: Area Under Concentration-time Curve (AUC) | 593 ug x day/mL | Geometric Coefficient of Variation 31.3 |
| Phase 2 FPA008 Dose Expansion Cohort 2A | PK Parameters of Cabiralizumab: Area Under Concentration-time Curve (AUC) | 660 ug x day/mL | Geometric Coefficient of Variation 17.7 |
| Phase 2 FPA008 Dose Expansion Cohort 2B | PK Parameters of Cabiralizumab: Area Under Concentration-time Curve (AUC) | 593 ug x day/mL | Geometric Coefficient of Variation 12.6 |
Secondary
The Incidence of AEs.
treatment-emergent adverse events (TEAEs) by incidence for the Safety Population. Patients with at lease 1 TEAE.
Time frame: 52 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1 FPA008 Dose Escalation 1mg/kg | The Incidence of AEs. | 3 Participants |
| Phase 1 FPA008 Dose Escalation 2mg/kg | The Incidence of AEs. | 3 Participants |
| Phase 1 FPA008 Dose Escalation 4mg/kg | The Incidence of AEs. | 3 Participants |
| Phase 2 FPA008 Dose Expansion Cohort 2A | The Incidence of AEs. | 33 Participants |
| Phase 2 FPA008 Dose Expansion Cohort 2B | The Incidence of AEs. | 24 Participants |
Secondary
The Incidence of Clinical Laboratory Abnormalities.
The number of patients with a clinical laboratory that is outside the normal range at some time point during the study
Time frame: 52 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 FPA008 Dose Escalation 1mg/kg | The Incidence of Clinical Laboratory Abnormalities. | 3 participants |
| Phase 1 FPA008 Dose Escalation 2mg/kg | The Incidence of Clinical Laboratory Abnormalities. | 2 participants |
| Phase 1 FPA008 Dose Escalation 4mg/kg | The Incidence of Clinical Laboratory Abnormalities. | 3 participants |
| Phase 2 FPA008 Dose Expansion Cohort 2A | The Incidence of Clinical Laboratory Abnormalities. | 33 participants |
| Phase 2 FPA008 Dose Expansion Cohort 2B | The Incidence of Clinical Laboratory Abnormalities. | 24 participants |
Secondary
The Incidence of ECG Abnormalities.
The number of patients who had a change in their ECG that were clinically significant
Time frame: 52 weeks
Population: The changes in the ECG parameters were not clinically significant in any dosing cohort in the study
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1 FPA008 Dose Escalation 1mg/kg | The Incidence of ECG Abnormalities. | 0 Participants |
| Phase 1 FPA008 Dose Escalation 2mg/kg | The Incidence of ECG Abnormalities. | 0 Participants |
| Phase 1 FPA008 Dose Escalation 4mg/kg | The Incidence of ECG Abnormalities. | 0 Participants |
| Phase 2 FPA008 Dose Expansion Cohort 2A | The Incidence of ECG Abnormalities. | 0 Participants |
| Phase 2 FPA008 Dose Expansion Cohort 2B | The Incidence of ECG Abnormalities. | 0 Participants |