Safety Study of PLX108-01 in Patients With Solid Tumors

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 1 Study to Assess Safety, Pharmacokinetics, and Pharmacodynamics of PLX3397 in Patients With Advanced, Incurable, Solid Tumors in Which the Target Kinases Are Linked to Disease Pathophysiology

Conditions
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Solid Tumor

Intervention / Treatment
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* Drug: PLX3397


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PLX3397<br> | Drug: PLX3397<br>* Capsules administered once or twice daily, continuous dosing<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Every 2 months beginning Cycle 3, Day 1 until disease progression (up to approximately 30 months postdose) | 
| 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. | Every 2 months beginning Cycle 3, Day 1 until disease progression (up to approximately 30 months postdose) | 
| 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. | From initial response until disease progression or death, up to approximately 30 months postdose | 
| 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. | From Cycle 1 Day 1 to disease progression or death | 
| 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. | Every 2 months beginning Cycle 3, Day 1 until disease progression | 
| 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. | Cycle 1, Day 15 | 
| 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. | Cycle 1, Day 15 | 
| 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. | 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) | 
| 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. | Baseline, Cycle 1 Day 15, Cycle 2, Cycle 3, Cycle 12, Cycle 24, Cycle 36, and Cycle 46 (each cycle was 28 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PVNS