Study of Pexidartinib in Asian Subjects With Advanced Solid Tumors

Study Overview
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Brief Summary
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This is a Phase I, non-randomized, open-label, multiple dose study of pexidartinib in Asian subjects with advanced solid tumors. The study will be conducted in a dose escalation to assess the safety and tolerability, pharmacokinetics (PK) and pharmacodynamics (PD), and preliminary antitumor activity of pexidartinib.

Official Title
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A Phase 1 Study of Single Agent Pexidartinib in Asian Subjects With Advanced Solid Tumors

Conditions
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Advanced Solid Tumors

Intervention / Treatment
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* Drug: Pexidartinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age should be ≥ 20 years Subjects must have a pathologically documented solid tumor that has relapsed from, or is refractory to standard treatment, or for which no standard treatment is available All associated toxicity from previous cancer therapy must have been resolved (to ≤ Grade 1) prior to administration of pexidartinib Eastern Cooperative Oncology Group (ECOG) score of 0 or 1 Adequate hematologic, hepatic, and renal function tests Adequate treatment washout period before registration defined as: Major surgery: ≥ 4 weeks (2 weeks for less invasive surgery, such as colostomy) Radiation therapy (eg, whole brain radiotherapy): ≥ 4 weeks (if palliative stereotactic radiation therapy, ≥ 2 weeks) Chemotherapy or immunotherapy (including targeted therapy with antibody or small molecule, retinoid therapy, and hormonal therapy): 4 weeks or 5 half-lives of the agent, whichever is shorter (if the regimen has contained nitrosoureas or mitomycin C, ≥ 6 weeks) Other investigational drug therapy: ≥ 4 weeks Exclusion Criteria: Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant small bowel resection that would have precluded adequate absorption Previous use of pexidartinib or any biologic treatment targeting colony stimulating factor-1 (CSF-1) or the receptor for colony-stimulating factor-1 (CSF1R); previous use of oral tyrosine kinase inhibitors, eg, imatinib or nilotinib, is allowed Clinically active primary central nervous system tumors or brain metastasis, defined as untreated and symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms Active or chronic infection with hepatitis C or known positive hepatitis B surface. antigen, or known active or chronic infection with human immunodeficiency virus A screening Fridericia-corrected time between the start of the Q wave and the end of the T wave in the heart's electrical cycle (QTcF) ≥ 450 ms (in men) or ≥ 470 ms (in women). A medical history or complications of clinically significant lung disease (eg, interstitial pneumonia, pneumonitis, pulmonary fibrosis, and severe radiation pneumonitis) A history of symptomatic congestive heart failure (CHF) [New York Heart Association (NYHA) Classes II to IV] or serious cardiac arrhythmia requiring treatment A history of myocardial infarction or unstable angina within 6 months before enrollment An uncontrolled infection requiring intravenous injection of antibiotics, antivirals, or antifungals

Ages Eligible for Study
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Minimum Age: 20 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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pexidartinib<br>Pexidartinib capsules administered twice daily in the morning and evening. Each cycle of treatment is 28 days in duration. The cycle of treatment is continued until disease progression, unacceptable toxicity, or consent withdrawal. | Drug: Pexidartinib<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Based on RECIST V1.1 Following Oral Doses of Pexidartinib (Efficacy Analysis Set) | For the assessment of tumor response, participants were classified into the best of the following tumor response categories by RECIST v1.1: complete response (CR), disappearance of all target lesions and normalization of tumor marker level; partial response (PR), at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; stable disease (SD); neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study; progressive disease (PD), at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study and the sum must also demonstrate an absolute increase of at least 5 mm; or not evaluable (NE) for analysis. Objective response rate was defined as CR or PR and disease control rate was defined as CR, PR, or SD. | Day 1 through Day 28 after last dose (within 18 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response or Duration of Stable Disease Following Oral Doses of Pexidartinib (Efficacy Analysis Set) | Based on RECIST v1.1, complete response (CR), disappearance of all target lesions and normalization of tumor marker level; partial response (PR), at least a 30% decrease in sum of diameters of target lesions, with reference to baseline sum diameters; stable disease (SD); neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), with reference to smallest sum diameters; PD, at least a 20% increase in the sum of diameters of target lesions, with reference to smallest sum on study and sum must also demonstrate an absolute increase of at least 5 mm; Duration of response for responders (CR or PR) is defined as the time interval between the date of the earliest qualifying response and the date of PD or death for any cause, whichever occurs earlier. Duration of SD is defined as the time interval, in the absence of either CR or PR that will be calculated between the date of the first administration of the study drug and the date of PD. | Day 1 through Day 28 after last dose (within 18 months) | 
| A Summary of Pexidartinib Pharmacokinetic Parameter (Cmax) by Cohort and Day Following Oral Doses of Pexidartinib | Maximum concentration (Cmax) of pexidartinib was assessed using standard non-compartmental methods. | Cycle 1, Day 1 and Day 15 at predose, 0.5h, 1h, 2h, 4h, and 8h postdose (each cycle was 28 days) | 
| A Summary of Pexidartinib Pharmacokinetic Parameter (AUC[0-8h]) by Cohort and Day Following Oral Doses of Pexidartinib | Area under the curve from 0 to 8 hours (AUC[0-8h]) was assessed using standard non-compartmental methods. | Cycle 1, Day 1 and Day 15 at predose, 0.5h, 1h, 2h, 4h, and 8h postdose (each cycle was 28 days) | 
| A Summary of Pexidartinib Pharmacokinetic Parameter (Tmax) by Cohort and Day Following Oral Doses of Pexidartinib | Time at maximum pexidartinib concentration (Tmax) was assessed using standard non-compartmental methods. | Cycle 1, Day 1 and Day 15 at predose, 0.5h, 1h, 2h, 4h, and 8h postdose (each cycle was 28 days) | 
| A Summary of Pexidartinib Pharmacokinetic Parameter (R[AUC]) by Cohort Following Oral Doses of Pexidartinib | Accumulation ratio of area under the curve (R[AUC]) was assessed using standard non-compartmental methods. | Cycle 1, Day 15 at predose, 0.5h, 1h, 2h, 4h, and 8h postdose (each cycle was 28 days) | 
| A Summary of Pexidartinib Pharmacokinetic Parameter (R[Cmax]) by Cohort Following Oral Doses of Pexidartinib | Accumulation ratio of maximum concentration of pexidartinib (R[Cmax]) was assessed using standard non-compartmental methods. | Cycle 1, Day 15 at predose, 0.5h, 1h, 2h, 4h, and 8h postdose (each cycle was 28 days) | 
| A Summary of Plasma ZAAD-1006a Pharmacokinetic Parameter (AUC[0-8h]) Following Oral Doses of Pexidartinib | Area under the curve from 0 to 8 hours (AUC[0-8h]) was assessed using standard non-compartmental methods. | Cycle 1, Day 1 and Day 15 at predose, 0.5h, 1h, 2h, 4h, and 8h postdose (each cycle was 28 days) | 
| A Summary of Plasma ZAAD-1006a Pharmacokinetic Parameter (Cmax) Following Oral Doses of Pexidartinib | Maximum concentration (Cmax) of pexidartinib was assessed using standard non-compartmental methods. | Cycle 1, Day 1 and Day 15 at predose, 0.5h, 1h, 2h, 4h, and 8h postdose (each cycle was 28 days) | 
| A Summary of Plasma ZAAD-1006a Pharmacokinetic Parameter (Tmax) Following Oral Doses of Pexidartinib | Time at maximum pexidartinib concentration (Tmax) was assessed using standard non-compartmental methods. | Cycle 1, Day 1 and Day 15 at predose, 0.5h, 1h, 2h, 4h, and 8h postdose (each cycle was 28 days) | 
| A Summary of Plasma ZAAD-1006a Pharmacokinetic Parameter (MR AUC[0-8h]) Following Oral Doses of Pexidartinib | Metabolite to parent drug ratio of area under the curve from 0-8 h (MR AUC[0-8h]) was assessed using standard non-compartmental methods. | Cycle 1, Day 1 and Day 15 at predose, 0.5h, 1h, 2h, 4h, and 8h postdose (each cycle was 28 days) | 
| A Summary of Plasma ZAAD-1006a Pharmacokinetic Parameter (MR Cmax) Following Oral Doses of Pexidartinib | Metabolite to parent drug ratio of maximum pexidartinib concentration (MR Cmax) was assessed using standard non-compartmental methods. | Cycle 1, Day 1 and Day 15 at predose, 0.5h, 1h, 2h, 4h, and 8h postdose (each cycle was 28 days) | 
| Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. All TEAEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Event (NCI-CTCAE) Version 4.0. | Baseline through study completion, up to 18 months | 
| Number and Percentage of Participants With Treatment-related TEAEs by Preferred Term (Safety Analysis Set) | An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. All TEAEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Event (NCI-CTCAE) Version 4.0. | Baseline through study completion, up to 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced solid tumors, Asian subjects, Developmental Phase I