Solid Tumor
Conditions
Keywords
PVNS
Brief summary
PLX3397 is a selective inhibitor of Fms, Kit, and oncogenic Flt3 activity. The primary objective of this study is to evaluate the safety and pharmacokinetics of orally administered PLX3397 in patients with advanced, incurable, solid tumors in which these target kinases are linked to disease pathophysiology. The secondary objective is to measure the pharmacodynamic activity of PLX3397 via blood, plasma and urine biomarkers of Fms activity.
Interventions
DRUGPLX3397
Capsules administered once or twice daily, continuous dosing
Sponsors
Plexxikon
Daiichi Sankyo
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age 18 and older * Solid tumors refractory to standard therapy * For the Extension cohorts, patients must have measurable disease by RECIST criteria and meet the following disease-specific criteria: * For advanced or recurrent mucoepidermal carcinoma (MEC) of the salivary gland, patients must not be candidates for curative surgery or radiotherapy. * For pigmented villo-nodular synovitis (PVNS), patients must have a histologically confirmed diagnosis of inoperable progressive or relapsing PVNS, or resectable tumor requesting mutilating surgery, as well as demonstrated progressive disease in the last 12 months. * For gastrointestinal stromal tumors (GIST), patients must have failed previous therapy with imatinib and sunitinib. Patients with known PDGFR mutations are excluded, but mutation testing is not required for study entry. * For anaplastic thyroid cancer (ATC), patients must have histologically or cytologically diagnosed advanced ATC. * For metastatic solid tumors with documented malignant pleural and/or peritoneal effusions, patients must not be receiving specific therapy for the effusion or have an indwelling drain. * Eastern Cooperative Oncology Group performance status 0 or 1 * Life expectancy \>= 3 months * Adequate hepatic, renal, and bone marrow function
Exclusion criteria
* Specific anti-cancer therapy within 3 weeks of study start * Uncontrolled intercurrent illness * Refractory nausea or vomiting, or malabsorption * Mean corrected QT interval (QTc) \>= 450 msec (for males) or QTc \>= 470 msec (for females)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | Every 2 months beginning Cycle 3, Day 1 until disease progression (up to approximately 30 months postdose) | Best overall tumor response (complete response \[CR\], partial response \[PR\], stable disease \[SD\], progressive disease \[PD\]) is reported, including participants who were not evaluable (NE). RECIST v1.1 for target lesions are assessed by magnetic resonance imaging, computed tomography, or positron emission tomography-computed tomography and are summarized as: CR, Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 mm; PR, At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; PD, at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (includes the baseline sum). In addition, the sum must also demonstrate an absolute increase of at least 5 mm; SD, Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. |
| Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension (Efficacy Evaluable Population) | Every 2 months beginning Cycle 3, Day 1 until disease progression (up to approximately 30 months postdose) | Best overall tumor response (complete response \[CR\], partial response \[PR\], stable disease \[SD\], progressive disease \[PD\]) is reported, including participants who were not evaluable (NE). RECIST v1.1 for target lesions are assessed by magnetic resonance imaging, computed tomography, or positron emission tomography-computed tomography and are summarized as: CR, Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 mm; PR, At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; PD, at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (includes the baseline sum). In addition, the sum must also demonstrate an absolute increase of at least 5 mm; SD, Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. |
| Duration of Response (Efficacy Evaluable Population) - Dose Extension | From initial response until disease progression or death, up to approximately 30 months postdose | Duration of Response (DOR) is defined as the number of days from the date of initial response (CR or PR confirmed at least 28 days later) to the date of first documented disease progression/relapse or death, whichever occurs first. If no disease progression or death is documented prior to study termination, analysis cutoff, or the start of confounding anticancer therapy, DOR is censored as of the date of their last imaging exam of target or non-target lesions prior to post-surgery and/or off-treatment scans. |
| Progression-free Survival (Efficacy Evaluable Population) - Dose Extension | From Cycle 1 Day 1 to disease progression or death | Progression-Free Survival (PFS) is defined as the number of days from the first day of treatment to the first documented disease progression or date of death, whichever occurs first. If no disease progression or death is documented prior to study termination, analysis cutoff, or the start of confounding anticancer therapy, PFS is censored at the date of last evaluable tumor assessment. |
| Best Overall Tumor Response (PVNS Cohort) Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension | Every 2 months beginning Cycle 3, Day 1 until disease progression | Best overall tumor response (complete response \[CR\], partial response \[PR\], stable disease \[SD\], progressive disease \[PD\]) is reported, including participants who were not evaluable (NE). RECIST v1.1 for target lesions are assessed by magnetic resonance imaging, computed tomography, or positron emission tomography-computed tomography and are summarized as: CR, Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 mm; PR, At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; PD, at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (includes the baseline sum). In addition, the sum must also demonstrate an absolute increase of at least 5 mm; SD, Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. |
| Summary Statistics for Selected PLX3397 Pharmacokinetics Parameter Cmax, Study Day Cycle 1 Day 15, Stratified by Cohort - Dose Escalation | Cycle 1, Day 15 | Cycle 1 Day 15 pharmacokinetic (PK) timepoints taken are: For once daily (QD) dosing, obtained predose (morning) and 0.5, 1, 2, 4, and 8 hours postdose. For twice a day (BID) dosing predose (morning) and 1, 2, 4, and 7 hours postdose. The second dose will then be administered, and PK obtained 1 hour post the second dose (8 hours post the first dose). For BID dosing, no run-in is planned. |
| Summary Statistics for Selected PLX3397 Pharmacokinetics Parameter Tmax, Study Day Cycle 1 Day 15, Stratified by Cohort - Dose Escalation | Cycle 1, Day 15 | Cycle 1 Day 15 PK timepoints taken are: For QD dosing, obtained predose (morning) and 0.5, 1, 2, 4, and 8 hours postdose. For BID dosing predose (morning) and 1, 2, 4, and 7 hours postdose. The second dose will then be administered, and PK obtained 1 hour post the second dose (8 hours post the first dose). For BID dosing, no run-in is planned. |
| Summary Statistics for Selected PLX3397 Pharmacokinetics Parameter Area Under the Curve (AUC0-24), Study Day Cycle 1 Day 15, Stratified by Cohort - Dose Escalation | Cycle 1, Day 15 (QD dosing: predose [morning] and 0.5, 1, 2, 4, and 8 hours postdose; BID dosing: predose [morning] and 1, 2, 4, and 7 hours postdose) | Cycle 1 Day 15 PK timepoints taken are: For QD dosing, obtained predose (morning) and 0.5, 1, 2, 4, and 8 hours postdose. For BID dosing, predose (morning) and 1, 2, 4, and 7 hours postdose. The second dose will then be administered, and PK obtained 1 hour post the second dose (8 hours post the first dose). For BID dosing, no run-in is planned. |
| Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension | Baseline, Cycle 1 Day 15, Cycle 2, Cycle 3, Cycle 12, Cycle 24, Cycle 36, and Cycle 46 (each cycle was 28 days) | The NRS for PVNS Symptoms instrument is a 5-item self-administered questionnaire to assess the worst of each of the symptoms pain, swelling, stiffness, instability and limited motion in the last 24 hours. A 0 to 10 NRS is provided for each symptom. For pain, 0 indicates no pain and 10 indicates pain as bad as you can imagine. For the other 4 symptoms, 0 indicates no (symptom) and 10 indicates (symptom) worst imaginable, e.g., swelling - worst imaginable. Higher scores indicated worse outcome. |
Countries
United States
Participant flow
Recruitment details
The dose escalation phase administered ascending daily oral doses of PLX3397 to patients with solid tumors and evaluated PK and toxicity. Once the recommended phase 2 dose was reached, 6 extension cohorts were enrolled, consisting of a variety of tumor types.
Pre-assignment details
At least 3 participants and up to 6 participants were to be enrolled in each dose level using 100% dose increments for each level in the absence of Grade 2 or greater drug-attributable toxicity. Dose escalation was only permitted if adequate safety and tolerability were observed at the previous lower dose for 28 days for the first 3 participants.
Participants by arm
| Arm | Count |
|---|---|
| Dose Escalation Cohort 1: 200 mg QD Participants with advanced, incurable, solid tumors who received PLX3397 200 mg QD. | 3 |
| Dose Escalation Cohort 2: 300 mg QD Participants with advanced, incurable, solid tumors who received PLX3397 300 mg QD. | 6 |
| Dose Escalation Cohort 3: 400 mg QD Participants with advanced, incurable, solid tumors who received PLX3397 400 mg QD. | 6 |
| Dose Escalation Cohort 4: 600 mg QD Participants with advanced, incurable, solid tumors who received PLX3397 600 mg QD. | 6 |
| Dose Escalation Cohort 5: 900 mg/Day Participants with advanced, incurable, solid tumors who received PLX3397 900 mg/day. | 7 |
| Dose Escalation Cohort 6: 1200 mg/Day Participants with advanced, incurable, solid tumors who received PLX3397 1200 mg/day. | 6 |
| Dose Escalation Cohort 7: 1000 mg/Day Participants with advanced, incurable, solid tumors who received PLX3397 1000 mg/day. | 7 |
| Dose Extension: MEC Cohort Participants with advanced mucoepidermoid carcinoma (MEC) who received PLX3397. | 4 |
| Dose Extension: PVNS Cohort Participants with advanced pigmented villonodular synovitis (PVNS) who received PLX3397. | 39 |
| Dose Extension: GIST Cohort Participants with advanced gastrointestinal stromal tumor (GIS) who received PLX3397. | 11 |
| Dose Extension: ATC Cohort Participants with anaplastic thyroid carcinoma (ATC) who received PLX3397. | 9 |
| Dose Extension: Malignant Effusion Cohort Participants with advanced solid tumors with malignant effusion who received PLX3397. | 8 |
| Dose Extension: Other Solid Tumor Type Cohort Participants with other solid tumor types who received PLX3397. | 20 |
| Total | 132 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 1 | 0 | 2 | 1 | 1 | 13 | 1 | 1 | 0 | 2 |
| Overall Study | Disease progression | 3 | 4 | 5 | 4 | 4 | 4 | 5 | 1 | 4 | 7 | 6 | 3 | 8 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 3 | 0 | 0 | 1 | 0 |
| Overall Study | Non-compliance | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 5 | 0 | 0 | 0 | 1 |
| Overall Study | Other | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 1 | 2 | 3 |
| Overall Study | Patient completed 12-week follow-up and continued on commercially approved drug | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Patient decision | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 7 | 1 | 1 | 2 | 3 |
| Overall Study | Patient maintained complete response status throughout drug holiday | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Patient withdrew | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Physician Decision | 0 | 2 | 1 | 1 | 1 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 3 |
| Overall Study | Protocol Violation | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Study termination by Sponsor | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Surgical resection | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Transitioned to Phase 4 study | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Dose Escalation Cohort 1: 200 mg QD | Dose Escalation Cohort 2: 300 mg QD | Dose Escalation Cohort 3: 400 mg QD | Dose Escalation Cohort 4: 600 mg QD | Dose Escalation Cohort 5: 900 mg/Day | Dose Escalation Cohort 6: 1200 mg/Day | Dose Escalation Cohort 7: 1000 mg/Day | Dose Extension: MEC Cohort | Dose Extension: PVNS Cohort | Dose Extension: GIST Cohort | Dose Extension: ATC Cohort | Dose Extension: Malignant Effusion Cohort | Dose Extension: Other Solid Tumor Type Cohort |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 39 Participants | 1 Participants | 4 Participants | 4 Participants | 3 Participants | 2 Participants | 3 Participants | 2 Participants | 0 Participants | 2 Participants | 3 Participants | 6 Participants | 4 Participants | 5 Participants |
| Age, Categorical Between 18 and 65 years | 93 Participants | 2 Participants | 2 Participants | 2 Participants | 3 Participants | 5 Participants | 3 Participants | 5 Participants | 4 Participants | 37 Participants | 8 Participants | 3 Participants | 4 Participants | 15 Participants |
| Age, Continuous | 58.3 years STANDARD_DEVIATION 14.9 | 62.7 years STANDARD_DEVIATION 10.1 | 65.7 years STANDARD_DEVIATION 2.3 | 63.5 years STANDARD_DEVIATION 8.6 | 61.5 years STANDARD_DEVIATION 19.1 | 52.3 years STANDARD_DEVIATION 15 | 56.3 years STANDARD_DEVIATION 17.1 | 50.4 years STANDARD_DEVIATION 19.8 | 47.3 years STANDARD_DEVIATION 18.4 | 45.1 years STANDARD_DEVIATION 14 | 57.6 years STANDARD_DEVIATION 12.1 | 65.9 years STANDARD_DEVIATION 14.7 | 58.1 years STANDARD_DEVIATION 13.3 | 52.0 years STANDARD_DEVIATION 15.1 |
| Race/Ethnicity, Customized Asian | 5 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 3 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black of African American | 4 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Multiple races | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 121 Participants | 3 Participants | 6 Participants | 6 Participants | 6 Participants | 7 Participants | 5 Participants | 7 Participants | 4 Participants | 33 Participants | 10 Participants | 8 Participants | 8 Participants | 18 Participants |
| Region of Enrollment United States | 41 participants | 3 participants | 6 participants | 6 participants | 6 participants | 7 participants | 6 participants | 7 participants | 4 participants | 39 participants | 11 participants | 9 participants | 8 participants | 20 participants |
| Sex: Female, Male Female | 68 Participants | 2 Participants | 4 Participants | 3 Participants | 3 Participants | 4 Participants | 3 Participants | 6 Participants | 1 Participants | 22 Participants | 6 Participants | 4 Participants | 5 Participants | 5 Participants |
| Sex: Female, Male Male | 64 Participants | 1 Participants | 2 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 1 Participants | 3 Participants | 17 Participants | 5 Participants | 5 Participants | 3 Participants | 15 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 | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 1 / 6 | 1 / 6 | 0 / 6 | 0 / 7 | 1 / 6 | 0 / 7 | 1 / 4 | 0 / 39 | 3 / 11 | 1 / 9 | 1 / 8 | 1 / 20 |
| other Total, other adverse events | 3 / 3 | 6 / 6 | 6 / 6 | 6 / 6 | 6 / 7 | 6 / 6 | 7 / 7 | 4 / 4 | 39 / 39 | 11 / 11 | 8 / 9 | 8 / 8 | 20 / 20 |
| serious Total, serious adverse events | 0 / 3 | 1 / 6 | 0 / 6 | 0 / 6 | 1 / 7 | 1 / 6 | 3 / 7 | 2 / 4 | 5 / 39 | 4 / 11 | 1 / 9 | 2 / 8 | 3 / 20 |
Outcome results
Primary
Best Overall Tumor Response (PVNS Cohort) Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension
Best overall tumor response (complete response \[CR\], partial response \[PR\], stable disease \[SD\], progressive disease \[PD\]) is reported, including participants who were not evaluable (NE). RECIST v1.1 for target lesions are assessed by magnetic resonance imaging, computed tomography, or positron emission tomography-computed tomography and are summarized as: CR, Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 mm; PR, At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; PD, at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (includes the baseline sum). In addition, the sum must also demonstrate an absolute increase of at least 5 mm; SD, Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Time frame: Every 2 months beginning Cycle 3, Day 1 until disease progression
Population: Best overall tumor response was assessed in the Efficacy Evaluable Population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Escalation Cohort 1: 200 mg QD | Best Overall Tumor Response (PVNS Cohort) Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension | CR | 2 Participants |
| Dose Escalation Cohort 1: 200 mg QD | Best Overall Tumor Response (PVNS Cohort) Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension | PR | 22 Participants |
| Dose Escalation Cohort 1: 200 mg QD | Best Overall Tumor Response (PVNS Cohort) Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension | SD | 8 Participants |
| Dose Escalation Cohort 1: 200 mg QD | Best Overall Tumor Response (PVNS Cohort) Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension | PD | 1 Participants |
| Dose Escalation Cohort 1: 200 mg QD | Best Overall Tumor Response (PVNS Cohort) Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension | NE | 4 Participants |
| Dose Escalation Cohort 1: 200 mg QD | Best Overall Tumor Response (PVNS Cohort) Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension | Overall response rate (CR or PR) | 24 Participants |
Primary
Duration of Response (Efficacy Evaluable Population) - Dose Extension
Duration of Response (DOR) is defined as the number of days from the date of initial response (CR or PR confirmed at least 28 days later) to the date of first documented disease progression/relapse or death, whichever occurs first. If no disease progression or death is documented prior to study termination, analysis cutoff, or the start of confounding anticancer therapy, DOR is censored as of the date of their last imaging exam of target or non-target lesions prior to post-surgery and/or off-treatment scans.
Time frame: From initial response until disease progression or death, up to approximately 30 months postdose
Population: Duration of response was assessed among participants with response of CR or PR in the Efficacy Evaluable Population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation Cohort 2: 300 mg QD | Duration of Response (Efficacy Evaluable Population) - Dose Extension | NA days |
| Dose Escalation Cohort 6: 1200 mg/Day (600mg BID) | Duration of Response (Efficacy Evaluable Population) - Dose Extension | 115 days |
Primary
Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension
The NRS for PVNS Symptoms instrument is a 5-item self-administered questionnaire to assess the worst of each of the symptoms pain, swelling, stiffness, instability and limited motion in the last 24 hours. A 0 to 10 NRS is provided for each symptom. For pain, 0 indicates no pain and 10 indicates pain as bad as you can imagine. For the other 4 symptoms, 0 indicates no (symptom) and 10 indicates (symptom) worst imaginable, e.g., swelling - worst imaginable. Higher scores indicated worse outcome.
Time frame: Baseline, Cycle 1 Day 15, Cycle 2, Cycle 3, Cycle 12, Cycle 24, Cycle 36, and Cycle 46 (each cycle was 28 days)
Population: NRS for PVNS symptoms were assessed in patients with available data in the Efficacy Evaluable Population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Cohort 1: 200 mg QD | Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension | Pain; Baseline | 5.2 units on a scale | Standard Deviation 2.1 |
| Dose Escalation Cohort 1: 200 mg QD | Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension | Pain; Cycle 1 Day 15 | 3.5 units on a scale | Standard Deviation 2.9 |
| Dose Escalation Cohort 1: 200 mg QD | Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension | Pain; Cycle 2 | 3.6 units on a scale | Standard Deviation 2.6 |
| Dose Escalation Cohort 1: 200 mg QD | Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension | Pain; Cycle 3 | 2.3 units on a scale | Standard Deviation 1.9 |
| Dose Escalation Cohort 1: 200 mg QD | Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension | Pain; Cycle 12 | 1.3 units on a scale | Standard Deviation 1.8 |
| Dose Escalation Cohort 1: 200 mg QD | Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension | Pain; Cycle 24 | 1.5 units on a scale | Standard Deviation 1.4 |
| Dose Escalation Cohort 1: 200 mg QD | Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension | Pain; Cycle 36 | 2.0 units on a scale | Standard Deviation 2.8 |
| Dose Escalation Cohort 1: 200 mg QD | Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension | Pain; Cycle 46 | 1.8 units on a scale | Standard Deviation 2 |
| Dose Escalation Cohort 1: 200 mg QD | Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension | Swelling; Baseline | 4.7 units on a scale | Standard Deviation 2.9 |
| Dose Escalation Cohort 1: 200 mg QD | Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension | Swelling; Cycle 1 Day 15 | 3.1 units on a scale | Standard Deviation 2.5 |
| Dose Escalation Cohort 1: 200 mg QD | Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension | Swelling; Cycle 2 | 2.6 units on a scale | Standard Deviation 2.3 |
| Dose Escalation Cohort 1: 200 mg QD | Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension | Swelling; Cycle 3 | 1.5 units on a scale | Standard Deviation 1.4 |
| Dose Escalation Cohort 1: 200 mg QD | Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension | Swelling; Cycle 12 | 0.8 units on a scale | Standard Deviation 1.2 |
| Dose Escalation Cohort 1: 200 mg QD | Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension | Swelling; Cycle 24 | 0.8 units on a scale | Standard Deviation 0.8 |
| Dose Escalation Cohort 1: 200 mg QD | Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension | Swelling; Cycle 36 | 1.2 units on a scale | Standard Deviation 1.8 |
| Dose Escalation Cohort 1: 200 mg QD | Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension | Swelling; Cycle 46 | 1.1 units on a scale | Standard Deviation 1.2 |
| Dose Escalation Cohort 1: 200 mg QD | Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension | Stiffness; Baseline | 4.7 units on a scale | Standard Deviation 2.9 |
| Dose Escalation Cohort 1: 200 mg QD | Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension | Stiffness; Cycle 1 Day 15 | 3.6 units on a scale | Standard Deviation 2.9 |
| Dose Escalation Cohort 1: 200 mg QD | Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension | Stiffness; Cycle 2 | 3.1 units on a scale | Standard Deviation 2.7 |
| Dose Escalation Cohort 1: 200 mg QD | Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension | Stiffness; Cycle 3 | 2.2 units on a scale | Standard Deviation 1.9 |
| Dose Escalation Cohort 1: 200 mg QD | Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension | Stiffness; Cycle 12 | 1.5 units on a scale | Standard Deviation 1.9 |
| Dose Escalation Cohort 1: 200 mg QD | Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension | Stiffness; Cycle 24 | 1.2 units on a scale | Standard Deviation 1.1 |
| Dose Escalation Cohort 1: 200 mg QD | Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension | Stiffness; Cycle 36 | 1.6 units on a scale | Standard Deviation 2.1 |
| Dose Escalation Cohort 1: 200 mg QD | Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension | Stiffness; Cycle 46 | 1.6 units on a scale | Standard Deviation 1.6 |
| Dose Escalation Cohort 1: 200 mg QD | Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension | Instability; Baseline | 2.9 units on a scale | Standard Deviation 2.6 |
| Dose Escalation Cohort 1: 200 mg QD | Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension | Instability; Cycle 1 Day 15 | 2.1 units on a scale | Standard Deviation 2.6 |
| Dose Escalation Cohort 1: 200 mg QD | Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension | Instability; Cycle 2 | 2.1 units on a scale | Standard Deviation 2.5 |
| Dose Escalation Cohort 1: 200 mg QD | Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension | Instability; Cycle 3 | 1.2 units on a scale | Standard Deviation 1.4 |
| Dose Escalation Cohort 1: 200 mg QD | Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension | Instability; Cycle 12 | 0.8 units on a scale | Standard Deviation 1 |
| Dose Escalation Cohort 1: 200 mg QD | Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension | Instability; Cycle 24 | 0.4 units on a scale | Standard Deviation 0.7 |
| Dose Escalation Cohort 1: 200 mg QD | Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension | Instability; Cycle 36 | 0.4 units on a scale | Standard Deviation 0.7 |
| Dose Escalation Cohort 1: 200 mg QD | Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension | Instability; Cycle 46 | 0.4 units on a scale | Standard Deviation 0.7 |
| Dose Escalation Cohort 1: 200 mg QD | Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension | Limited motion; Baseline | 4.8 units on a scale | Standard Deviation 2.8 |
| Dose Escalation Cohort 1: 200 mg QD | Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension | Limited motion; Cycle 1 Day 15 | 3.2 units on a scale | Standard Deviation 2.7 |
| Dose Escalation Cohort 1: 200 mg QD | Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension | Limited motion; Cycle 2 | 3.0 units on a scale | Standard Deviation 2.4 |
| Dose Escalation Cohort 1: 200 mg QD | Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension | Limited motion; Cycle 3 | 1.9 units on a scale | Standard Deviation 1.7 |
| Dose Escalation Cohort 1: 200 mg QD | Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension | Limited motion; Cycle 12 | 1.4 units on a scale | Standard Deviation 1.7 |
| Dose Escalation Cohort 1: 200 mg QD | Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension | Limited motion; Cycle 24 | 1.0 units on a scale | Standard Deviation 1 |
| Dose Escalation Cohort 1: 200 mg QD | Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension | Limited motion; Cycle 36 | 1.7 units on a scale | Standard Deviation 2.3 |
| Dose Escalation Cohort 1: 200 mg QD | Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension | Limited Motion; Cycle 46 | 1.8 units on a scale | Standard Deviation 1.7 |
Primary
Progression-free Survival (Efficacy Evaluable Population) - Dose Extension
Progression-Free Survival (PFS) is defined as the number of days from the first day of treatment to the first documented disease progression or date of death, whichever occurs first. If no disease progression or death is documented prior to study termination, analysis cutoff, or the start of confounding anticancer therapy, PFS is censored at the date of last evaluable tumor assessment.
Time frame: From Cycle 1 Day 1 to disease progression or death
Population: Progression-free survival was assessed in the Efficacy Evaluable Population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation Cohort 1: 200 mg QD | Progression-free Survival (Efficacy Evaluable Population) - Dose Extension | NA days |
| Dose Escalation Cohort 2: 300 mg QD | Progression-free Survival (Efficacy Evaluable Population) - Dose Extension | NA days |
| Dose Escalation Cohort 3: 400 mg QD | Progression-free Survival (Efficacy Evaluable Population) - Dose Extension | 54 days |
| Dose Escalation Cohort 4: 600 mg QD | Progression-free Survival (Efficacy Evaluable Population) - Dose Extension | 50 days |
| Dose Escalation Cohort 5: 900 mg/Day (500mg AM, 400mg PM) | Progression-free Survival (Efficacy Evaluable Population) - Dose Extension | 78 days |
| Dose Escalation Cohort 6: 1200 mg/Day (600mg BID) | Progression-free Survival (Efficacy Evaluable Population) - Dose Extension | 161 days |
Primary
Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population)
Best overall tumor response (complete response \[CR\], partial response \[PR\], stable disease \[SD\], progressive disease \[PD\]) is reported, including participants who were not evaluable (NE). RECIST v1.1 for target lesions are assessed by magnetic resonance imaging, computed tomography, or positron emission tomography-computed tomography and are summarized as: CR, Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 mm; PR, At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; PD, at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (includes the baseline sum). In addition, the sum must also demonstrate an absolute increase of at least 5 mm; SD, Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Time frame: Every 2 months beginning Cycle 3, Day 1 until disease progression (up to approximately 30 months postdose)
Population: Best overall tumor response was assessed in the Efficacy Evaluable Population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Escalation Cohort 1: 200 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | NE | 0 Participants |
| Dose Escalation Cohort 1: 200 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | PR | 0 Participants |
| Dose Escalation Cohort 1: 200 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | PD | 3 Participants |
| Dose Escalation Cohort 1: 200 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | Censored participants | 0 Participants |
| Dose Escalation Cohort 1: 200 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | CR | 0 Participants |
| Dose Escalation Cohort 1: 200 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | SD | 0 Participants |
| Dose Escalation Cohort 2: 300 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | PR | 0 Participants |
| Dose Escalation Cohort 2: 300 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | PD | 4 Participants |
| Dose Escalation Cohort 2: 300 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | CR | 0 Participants |
| Dose Escalation Cohort 2: 300 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | Censored participants | 1 Participants |
| Dose Escalation Cohort 2: 300 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | NE | 0 Participants |
| Dose Escalation Cohort 2: 300 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | SD | 1 Participants |
| Dose Escalation Cohort 3: 400 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | Censored participants | 2 Participants |
| Dose Escalation Cohort 3: 400 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | CR | 0 Participants |
| Dose Escalation Cohort 3: 400 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | PD | 3 Participants |
| Dose Escalation Cohort 3: 400 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | SD | 0 Participants |
| Dose Escalation Cohort 3: 400 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | NE | 2 Participants |
| Dose Escalation Cohort 3: 400 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | PR | 0 Participants |
| Dose Escalation Cohort 4: 600 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | Censored participants | 0 Participants |
| Dose Escalation Cohort 4: 600 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | PR | 0 Participants |
| Dose Escalation Cohort 4: 600 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | SD | 2 Participants |
| Dose Escalation Cohort 4: 600 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | CR | 0 Participants |
| Dose Escalation Cohort 4: 600 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | NE | 0 Participants |
| Dose Escalation Cohort 4: 600 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | PD | 3 Participants |
| Dose Escalation Cohort 5: 900 mg/Day (500mg AM, 400mg PM) | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | Censored participants | 3 Participants |
| Dose Escalation Cohort 5: 900 mg/Day (500mg AM, 400mg PM) | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | CR | 0 Participants |
| Dose Escalation Cohort 5: 900 mg/Day (500mg AM, 400mg PM) | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | PR | 0 Participants |
| Dose Escalation Cohort 5: 900 mg/Day (500mg AM, 400mg PM) | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | SD | 3 Participants |
| Dose Escalation Cohort 5: 900 mg/Day (500mg AM, 400mg PM) | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | PD | 2 Participants |
| Dose Escalation Cohort 5: 900 mg/Day (500mg AM, 400mg PM) | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | NE | 1 Participants |
| Dose Escalation Cohort 6: 1200 mg/Day (600mg BID) | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | SD | 1 Participants |
| Dose Escalation Cohort 6: 1200 mg/Day (600mg BID) | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | PD | 4 Participants |
| Dose Escalation Cohort 6: 1200 mg/Day (600mg BID) | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | PR | 0 Participants |
| Dose Escalation Cohort 6: 1200 mg/Day (600mg BID) | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | Censored participants | 0 Participants |
| Dose Escalation Cohort 6: 1200 mg/Day (600mg BID) | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | NE | 0 Participants |
| Dose Escalation Cohort 6: 1200 mg/Day (600mg BID) | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | CR | 0 Participants |
| Dose Escalation Cohort 7: 1000 mg/Day (500mg BID) | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | SD | 1 Participants |
| Dose Escalation Cohort 7: 1000 mg/Day (500mg BID) | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | Censored participants | 3 Participants |
| Dose Escalation Cohort 7: 1000 mg/Day (500mg BID) | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | CR | 0 Participants |
| Dose Escalation Cohort 7: 1000 mg/Day (500mg BID) | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | PD | 3 Participants |
| Dose Escalation Cohort 7: 1000 mg/Day (500mg BID) | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | NE | 1 Participants |
| Dose Escalation Cohort 7: 1000 mg/Day (500mg BID) | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | PR | 1 Participants |
| All Participants | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | PR | 1 Participants |
| All Participants | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | CR | 0 Participants |
| All Participants | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | Censored participants | 9 Participants |
| All Participants | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | SD | 8 Participants |
| All Participants | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | NE | 4 Participants |
| All Participants | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) | PD | 22 Participants |
Primary
Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension (Efficacy Evaluable Population)
Best overall tumor response (complete response \[CR\], partial response \[PR\], stable disease \[SD\], progressive disease \[PD\]) is reported, including participants who were not evaluable (NE). RECIST v1.1 for target lesions are assessed by magnetic resonance imaging, computed tomography, or positron emission tomography-computed tomography and are summarized as: CR, Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 mm; PR, At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; PD, at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (includes the baseline sum). In addition, the sum must also demonstrate an absolute increase of at least 5 mm; SD, Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Time frame: Every 2 months beginning Cycle 3, Day 1 until disease progression (up to approximately 30 months postdose)
Population: Best overall tumor response was assessed in the Efficacy Evaluable Population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Escalation Cohort 1: 200 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension (Efficacy Evaluable Population) | CR | 0 Participants |
| Dose Escalation Cohort 1: 200 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension (Efficacy Evaluable Population) | PR | 0 Participants |
| Dose Escalation Cohort 1: 200 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension (Efficacy Evaluable Population) | SD | 1 Participants |
| Dose Escalation Cohort 1: 200 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension (Efficacy Evaluable Population) | PD | 1 Participants |
| Dose Escalation Cohort 1: 200 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension (Efficacy Evaluable Population) | NE | 0 Participants |
| Dose Escalation Cohort 1: 200 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension (Efficacy Evaluable Population) | Overall response rate (CR or PR) | 0 Participants |
| Dose Escalation Cohort 2: 300 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension (Efficacy Evaluable Population) | PR | 22 Participants |
| Dose Escalation Cohort 2: 300 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension (Efficacy Evaluable Population) | PD | 1 Participants |
| Dose Escalation Cohort 2: 300 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension (Efficacy Evaluable Population) | Overall response rate (CR or PR) | 24 Participants |
| Dose Escalation Cohort 2: 300 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension (Efficacy Evaluable Population) | CR | 2 Participants |
| Dose Escalation Cohort 2: 300 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension (Efficacy Evaluable Population) | SD | 8 Participants |
| Dose Escalation Cohort 2: 300 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension (Efficacy Evaluable Population) | NE | 4 Participants |
| Dose Escalation Cohort 3: 400 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension (Efficacy Evaluable Population) | Overall response rate (CR or PR) | 0 Participants |
| Dose Escalation Cohort 3: 400 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension (Efficacy Evaluable Population) | NE | 0 Participants |
| Dose Escalation Cohort 3: 400 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension (Efficacy Evaluable Population) | PD | 5 Participants |
| Dose Escalation Cohort 3: 400 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension (Efficacy Evaluable Population) | SD | 4 Participants |
| Dose Escalation Cohort 3: 400 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension (Efficacy Evaluable Population) | CR | 0 Participants |
| Dose Escalation Cohort 3: 400 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension (Efficacy Evaluable Population) | PR | 0 Participants |
| Dose Escalation Cohort 4: 600 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension (Efficacy Evaluable Population) | PD | 6 Participants |
| Dose Escalation Cohort 4: 600 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension (Efficacy Evaluable Population) | PR | 0 Participants |
| Dose Escalation Cohort 4: 600 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension (Efficacy Evaluable Population) | SD | 0 Participants |
| Dose Escalation Cohort 4: 600 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension (Efficacy Evaluable Population) | Overall response rate (CR or PR) | 0 Participants |
| Dose Escalation Cohort 4: 600 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension (Efficacy Evaluable Population) | NE | 0 Participants |
| Dose Escalation Cohort 4: 600 mg QD | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension (Efficacy Evaluable Population) | CR | 0 Participants |
| Dose Escalation Cohort 5: 900 mg/Day (500mg AM, 400mg PM) | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension (Efficacy Evaluable Population) | CR | 0 Participants |
| Dose Escalation Cohort 5: 900 mg/Day (500mg AM, 400mg PM) | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension (Efficacy Evaluable Population) | NE | 1 Participants |
| Dose Escalation Cohort 5: 900 mg/Day (500mg AM, 400mg PM) | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension (Efficacy Evaluable Population) | PR | 0 Participants |
| Dose Escalation Cohort 5: 900 mg/Day (500mg AM, 400mg PM) | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension (Efficacy Evaluable Population) | SD | 3 Participants |
| Dose Escalation Cohort 5: 900 mg/Day (500mg AM, 400mg PM) | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension (Efficacy Evaluable Population) | PD | 2 Participants |
| Dose Escalation Cohort 5: 900 mg/Day (500mg AM, 400mg PM) | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension (Efficacy Evaluable Population) | Overall response rate (CR or PR) | 0 Participants |
| Dose Escalation Cohort 6: 1200 mg/Day (600mg BID) | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension (Efficacy Evaluable Population) | PD | 6 Participants |
| Dose Escalation Cohort 6: 1200 mg/Day (600mg BID) | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension (Efficacy Evaluable Population) | SD | 7 Participants |
| Dose Escalation Cohort 6: 1200 mg/Day (600mg BID) | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension (Efficacy Evaluable Population) | NE | 0 Participants |
| Dose Escalation Cohort 6: 1200 mg/Day (600mg BID) | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension (Efficacy Evaluable Population) | Overall response rate (CR or PR) | 1 Participants |
| Dose Escalation Cohort 6: 1200 mg/Day (600mg BID) | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension (Efficacy Evaluable Population) | PR | 1 Participants |
| Dose Escalation Cohort 6: 1200 mg/Day (600mg BID) | Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension (Efficacy Evaluable Population) | CR | 0 Participants |
Primary
Summary Statistics for Selected PLX3397 Pharmacokinetics Parameter Area Under the Curve (AUC0-24), Study Day Cycle 1 Day 15, Stratified by Cohort - Dose Escalation
Cycle 1 Day 15 PK timepoints taken are: For QD dosing, obtained predose (morning) and 0.5, 1, 2, 4, and 8 hours postdose. For BID dosing, predose (morning) and 1, 2, 4, and 7 hours postdose. The second dose will then be administered, and PK obtained 1 hour post the second dose (8 hours post the first dose). For BID dosing, no run-in is planned.
Time frame: Cycle 1, Day 15 (QD dosing: predose [morning] and 0.5, 1, 2, 4, and 8 hours postdose; BID dosing: predose [morning] and 1, 2, 4, and 7 hours postdose)
Population: Pharmacokinetic parameters were assessed in the Pharmacokinetic Analysis Set.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation Cohort 1: 200 mg QD | Summary Statistics for Selected PLX3397 Pharmacokinetics Parameter Area Under the Curve (AUC0-24), Study Day Cycle 1 Day 15, Stratified by Cohort - Dose Escalation | 26200 ng*hr/mL |
| Dose Escalation Cohort 2: 300 mg QD | Summary Statistics for Selected PLX3397 Pharmacokinetics Parameter Area Under the Curve (AUC0-24), Study Day Cycle 1 Day 15, Stratified by Cohort - Dose Escalation | 50400 ng*hr/mL |
| Dose Escalation Cohort 3: 400 mg QD | Summary Statistics for Selected PLX3397 Pharmacokinetics Parameter Area Under the Curve (AUC0-24), Study Day Cycle 1 Day 15, Stratified by Cohort - Dose Escalation | 40500 ng*hr/mL |
| Dose Escalation Cohort 4: 600 mg QD | Summary Statistics for Selected PLX3397 Pharmacokinetics Parameter Area Under the Curve (AUC0-24), Study Day Cycle 1 Day 15, Stratified by Cohort - Dose Escalation | 81000 ng*hr/mL |
| Dose Escalation Cohort 5: 900 mg/Day (500mg AM, 400mg PM) | Summary Statistics for Selected PLX3397 Pharmacokinetics Parameter Area Under the Curve (AUC0-24), Study Day Cycle 1 Day 15, Stratified by Cohort - Dose Escalation | 107000 ng*hr/mL |
| Dose Escalation Cohort 6: 1200 mg/Day (600mg BID) | Summary Statistics for Selected PLX3397 Pharmacokinetics Parameter Area Under the Curve (AUC0-24), Study Day Cycle 1 Day 15, Stratified by Cohort - Dose Escalation | 173000 ng*hr/mL |
| Dose Escalation Cohort 7: 1000 mg/Day (500mg BID) | Summary Statistics for Selected PLX3397 Pharmacokinetics Parameter Area Under the Curve (AUC0-24), Study Day Cycle 1 Day 15, Stratified by Cohort - Dose Escalation | 115000 ng*hr/mL |
Primary
Summary Statistics for Selected PLX3397 Pharmacokinetics Parameter Cmax, Study Day Cycle 1 Day 15, Stratified by Cohort - Dose Escalation
Cycle 1 Day 15 pharmacokinetic (PK) timepoints taken are: For once daily (QD) dosing, obtained predose (morning) and 0.5, 1, 2, 4, and 8 hours postdose. For twice a day (BID) dosing predose (morning) and 1, 2, 4, and 7 hours postdose. The second dose will then be administered, and PK obtained 1 hour post the second dose (8 hours post the first dose). For BID dosing, no run-in is planned.
Time frame: Cycle 1, Day 15
Population: Pharmacokinetic parameters were assessed in the Pharmacokinetic Analysis Set.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation Cohort 1: 200 mg QD | Summary Statistics for Selected PLX3397 Pharmacokinetics Parameter Cmax, Study Day Cycle 1 Day 15, Stratified by Cohort - Dose Escalation | 1730 ng/mL |
| Dose Escalation Cohort 2: 300 mg QD | Summary Statistics for Selected PLX3397 Pharmacokinetics Parameter Cmax, Study Day Cycle 1 Day 15, Stratified by Cohort - Dose Escalation | 3630 ng/mL |
| Dose Escalation Cohort 3: 400 mg QD | Summary Statistics for Selected PLX3397 Pharmacokinetics Parameter Cmax, Study Day Cycle 1 Day 15, Stratified by Cohort - Dose Escalation | 3160 ng/mL |
| Dose Escalation Cohort 4: 600 mg QD | Summary Statistics for Selected PLX3397 Pharmacokinetics Parameter Cmax, Study Day Cycle 1 Day 15, Stratified by Cohort - Dose Escalation | 6570 ng/mL |
| Dose Escalation Cohort 5: 900 mg/Day (500mg AM, 400mg PM) | Summary Statistics for Selected PLX3397 Pharmacokinetics Parameter Cmax, Study Day Cycle 1 Day 15, Stratified by Cohort - Dose Escalation | 6290 ng/mL |
| Dose Escalation Cohort 6: 1200 mg/Day (600mg BID) | Summary Statistics for Selected PLX3397 Pharmacokinetics Parameter Cmax, Study Day Cycle 1 Day 15, Stratified by Cohort - Dose Escalation | 10600 ng/mL |
| Dose Escalation Cohort 7: 1000 mg/Day (500mg BID) | Summary Statistics for Selected PLX3397 Pharmacokinetics Parameter Cmax, Study Day Cycle 1 Day 15, Stratified by Cohort - Dose Escalation | 6320 ng/mL |
Primary
Summary Statistics for Selected PLX3397 Pharmacokinetics Parameter Tmax, Study Day Cycle 1 Day 15, Stratified by Cohort - Dose Escalation
Cycle 1 Day 15 PK timepoints taken are: For QD dosing, obtained predose (morning) and 0.5, 1, 2, 4, and 8 hours postdose. For BID dosing predose (morning) and 1, 2, 4, and 7 hours postdose. The second dose will then be administered, and PK obtained 1 hour post the second dose (8 hours post the first dose). For BID dosing, no run-in is planned.
Time frame: Cycle 1, Day 15
Population: Pharmacokinetic parameters were assessed in the Pharmacokinetic Analysis Set.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation Cohort 1: 200 mg QD | Summary Statistics for Selected PLX3397 Pharmacokinetics Parameter Tmax, Study Day Cycle 1 Day 15, Stratified by Cohort - Dose Escalation | 2.00 hour |
| Dose Escalation Cohort 2: 300 mg QD | Summary Statistics for Selected PLX3397 Pharmacokinetics Parameter Tmax, Study Day Cycle 1 Day 15, Stratified by Cohort - Dose Escalation | 1.97 hour |
| Dose Escalation Cohort 3: 400 mg QD | Summary Statistics for Selected PLX3397 Pharmacokinetics Parameter Tmax, Study Day Cycle 1 Day 15, Stratified by Cohort - Dose Escalation | 0.98 hour |
| Dose Escalation Cohort 4: 600 mg QD | Summary Statistics for Selected PLX3397 Pharmacokinetics Parameter Tmax, Study Day Cycle 1 Day 15, Stratified by Cohort - Dose Escalation | 1.04 hour |
| Dose Escalation Cohort 5: 900 mg/Day (500mg AM, 400mg PM) | Summary Statistics for Selected PLX3397 Pharmacokinetics Parameter Tmax, Study Day Cycle 1 Day 15, Stratified by Cohort - Dose Escalation | 2.00 hour |
| Dose Escalation Cohort 6: 1200 mg/Day (600mg BID) | Summary Statistics for Selected PLX3397 Pharmacokinetics Parameter Tmax, Study Day Cycle 1 Day 15, Stratified by Cohort - Dose Escalation | 1.05 hour |
| Dose Escalation Cohort 7: 1000 mg/Day (500mg BID) | Summary Statistics for Selected PLX3397 Pharmacokinetics Parameter Tmax, Study Day Cycle 1 Day 15, Stratified by Cohort - Dose Escalation | 2.03 hour |