Advanced Solid Tumors
Conditions
Keywords
Advanced solid tumors, Asian subjects, Developmental Phase I
Brief summary
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.
Interventions
DRUGPexidartinib
Sponsors
Daiichi Sankyo Co., Ltd.
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
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: 1. Major surgery: ≥ 4 weeks (2 weeks for less invasive surgery, such as colostomy) 2. Radiation therapy (eg, whole brain radiotherapy): ≥ 4 weeks (if palliative stereotactic radiation therapy, ≥ 2 weeks) 3. 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) 4. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Based on RECIST V1.1 Following Oral Doses of Pexidartinib (Efficacy Analysis Set) | Day 1 through Day 28 after last dose (within 18 months) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| A Summary of Pexidartinib Pharmacokinetic Parameter (Cmax) by Cohort and Day Following Oral Doses of Pexidartinib | Cycle 1, Day 1 and Day 15 at predose, 0.5h, 1h, 2h, 4h, and 8h postdose (each cycle was 28 days) | Maximum concentration (Cmax) of pexidartinib was assessed using standard non-compartmental methods. |
| A Summary of Pexidartinib Pharmacokinetic Parameter (AUC[0-8h]) by Cohort and Day Following Oral Doses of Pexidartinib | Cycle 1, Day 1 and Day 15 at predose, 0.5h, 1h, 2h, 4h, and 8h postdose (each cycle was 28 days) | Area under the curve from 0 to 8 hours (AUC\[0-8h\]) was assessed using standard non-compartmental methods. |
| A Summary of Pexidartinib Pharmacokinetic Parameter (Tmax) by Cohort and Day Following Oral Doses of Pexidartinib | Cycle 1, Day 1 and Day 15 at predose, 0.5h, 1h, 2h, 4h, and 8h postdose (each cycle was 28 days) | Time at maximum pexidartinib concentration (Tmax) was assessed using standard non-compartmental methods. |
| A Summary of Pexidartinib Pharmacokinetic Parameter (R[AUC]) by Cohort Following Oral Doses of Pexidartinib | Cycle 1, Day 15 at predose, 0.5h, 1h, 2h, 4h, and 8h postdose (each cycle was 28 days) | Accumulation ratio of area under the curve (R\[AUC\]) was assessed using standard non-compartmental methods. |
| A Summary of Pexidartinib Pharmacokinetic Parameter (R[Cmax]) by Cohort Following Oral Doses of Pexidartinib | Cycle 1, Day 15 at predose, 0.5h, 1h, 2h, 4h, and 8h postdose (each cycle was 28 days) | Accumulation ratio of maximum concentration of pexidartinib (R\[Cmax\]) was assessed using standard non-compartmental methods. |
| A Summary of Plasma ZAAD-1006a Pharmacokinetic Parameter (AUC[0-8h]) Following Oral Doses of Pexidartinib | Cycle 1, Day 1 and Day 15 at predose, 0.5h, 1h, 2h, 4h, and 8h postdose (each cycle was 28 days) | Area under the curve from 0 to 8 hours (AUC\[0-8h\]) was assessed using standard non-compartmental methods. |
| Duration of Response or Duration of Stable Disease Following Oral Doses of Pexidartinib (Efficacy Analysis Set) | Day 1 through Day 28 after last dose (within 18 months) | 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. |
| A Summary of Plasma ZAAD-1006a Pharmacokinetic Parameter (Tmax) Following Oral Doses of Pexidartinib | Cycle 1, Day 1 and Day 15 at predose, 0.5h, 1h, 2h, 4h, and 8h postdose (each cycle was 28 days) | Time at maximum pexidartinib concentration (Tmax) was assessed using standard non-compartmental methods. |
| A Summary of Plasma ZAAD-1006a Pharmacokinetic Parameter (MR AUC[0-8h]) Following Oral Doses of Pexidartinib | Cycle 1, Day 1 and Day 15 at predose, 0.5h, 1h, 2h, 4h, and 8h postdose (each cycle was 28 days) | 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. |
| A Summary of Plasma ZAAD-1006a Pharmacokinetic Parameter (MR Cmax) Following Oral Doses of Pexidartinib | Cycle 1, Day 1 and Day 15 at predose, 0.5h, 1h, 2h, 4h, and 8h postdose (each cycle was 28 days) | Metabolite to parent drug ratio of maximum pexidartinib concentration (MR Cmax) was assessed using standard non-compartmental methods. |
| Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Baseline through study completion, up to 18 months | 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. |
| Number and Percentage of Participants With Treatment-related TEAEs by Preferred Term (Safety Analysis Set) | Baseline through study completion, up to 18 months | 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. |
| A Summary of Plasma ZAAD-1006a Pharmacokinetic Parameter (Cmax) Following Oral Doses of Pexidartinib | Cycle 1, Day 1 and Day 15 at predose, 0.5h, 1h, 2h, 4h, and 8h postdose (each cycle was 28 days) | Maximum concentration (Cmax) of pexidartinib was assessed using standard non-compartmental methods. |
Countries
Taiwan
Participant flow
Recruitment details
A total of 12 participants who met all inclusion and no exclusion criteria were enrolled in the study; 11 participants were treated.
Pre-assignment details
The study was conducted in a dose-escalation 3 + 3 design and was comprised of 2 dose levels (Cohort 1 \[600 mg/day\] and Cohort 2 \[1000 mg/day\]). Selection of the pexidartinib dose of 1000 mg/day as the highest dose and the split-dose administration schedule was based on data from a Phase 1 study on patients with solid tumors (Study PLX108-01).
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 - 600 mg/Day Participants who received pexidartinib 600 mg/day (200 mg in the morning and 400 mg in the evening). | 3 |
| Cohort 2 - 1000 mg/Day Participants who received pexidartinib 1000 mg/day (400 mg in the morning and 600 mg in the evening) for the first 2 weeks. Thereafter, the dose was reduced to 800 mg/day (400 mg in the morning and 400 mg in the evening). | 8 |
| Total | 11 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Clinical progression | 0 | 1 |
| Overall Study | Disease progression | 1 | 5 |
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Cohort 2 - 1000 mg/Day | Total | Cohort 1 - 600 mg/Day |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 5 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 6 Participants | 1 Participants |
| Age, Continuous | 62.4 years STANDARD_DEVIATION 12.2 | 60.4 years STANDARD_DEVIATION 16.5 | 55.0 years STANDARD_DEVIATION 27.9 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 8 Participants | 11 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Taiwan | 8 participants | 11 participants | 3 participants |
| Sex: Female, Male Female | 4 Participants | 5 Participants | 1 Participants |
| Sex: Female, Male Male | 4 Participants | 6 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 1 / 8 |
| other Total, other adverse events | 3 / 3 | 8 / 8 |
| serious Total, serious adverse events | 2 / 3 | 1 / 8 |
Outcome results
Primary
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.
Time frame: Day 1 through Day 28 after last dose (within 18 months)
Population: Best overall response was assessed in the Efficacy Analysis Set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 - 600 mg/Day | Overall Response Based on RECIST V1.1 Following Oral Doses of Pexidartinib (Efficacy Analysis Set) | Stable disease (SD) | 1 Number of participants |
| Cohort 1 - 600 mg/Day | Overall Response Based on RECIST V1.1 Following Oral Doses of Pexidartinib (Efficacy Analysis Set) | Not evaluable (NE) | 0 Number of participants |
| Cohort 1 - 600 mg/Day | Overall Response Based on RECIST V1.1 Following Oral Doses of Pexidartinib (Efficacy Analysis Set) | Partial response (PR) | 1 Number of participants |
| Cohort 1 - 600 mg/Day | Overall Response Based on RECIST V1.1 Following Oral Doses of Pexidartinib (Efficacy Analysis Set) | Objective response rate (CR or PR) | 1 Number of participants |
| Cohort 1 - 600 mg/Day | Overall Response Based on RECIST V1.1 Following Oral Doses of Pexidartinib (Efficacy Analysis Set) | Progressive disease (PD) | 1 Number of participants |
| Cohort 1 - 600 mg/Day | Overall Response Based on RECIST V1.1 Following Oral Doses of Pexidartinib (Efficacy Analysis Set) | Disease control rate (CR or PR or SD) | 2 Number of participants |
| Cohort 1 - 600 mg/Day | Overall Response Based on RECIST V1.1 Following Oral Doses of Pexidartinib (Efficacy Analysis Set) | Complete response (CR) | 0 Number of participants |
| Cohort 2 - 1000 mg/Day | Overall Response Based on RECIST V1.1 Following Oral Doses of Pexidartinib (Efficacy Analysis Set) | Disease control rate (CR or PR or SD) | 3 Number of participants |
| Cohort 2 - 1000 mg/Day | Overall Response Based on RECIST V1.1 Following Oral Doses of Pexidartinib (Efficacy Analysis Set) | Complete response (CR) | 0 Number of participants |
| Cohort 2 - 1000 mg/Day | Overall Response Based on RECIST V1.1 Following Oral Doses of Pexidartinib (Efficacy Analysis Set) | Partial response (PR) | 0 Number of participants |
| Cohort 2 - 1000 mg/Day | Overall Response Based on RECIST V1.1 Following Oral Doses of Pexidartinib (Efficacy Analysis Set) | Stable disease (SD) | 3 Number of participants |
| Cohort 2 - 1000 mg/Day | Overall Response Based on RECIST V1.1 Following Oral Doses of Pexidartinib (Efficacy Analysis Set) | Progressive disease (PD) | 2 Number of participants |
| Cohort 2 - 1000 mg/Day | Overall Response Based on RECIST V1.1 Following Oral Doses of Pexidartinib (Efficacy Analysis Set) | Not evaluable (NE) | 0 Number of participants |
| Cohort 2 - 1000 mg/Day | Overall Response Based on RECIST V1.1 Following Oral Doses of Pexidartinib (Efficacy Analysis Set) | Objective response rate (CR or PR) | 0 Number of participants |
Secondary
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.
Time frame: Cycle 1, Day 1 and Day 15 at predose, 0.5h, 1h, 2h, 4h, and 8h postdose (each cycle was 28 days)
Population: Pharmacokinetic parameters were assessed in the Pharmacokinetic Analysis Set.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 - 600 mg/Day | A Summary of Pexidartinib Pharmacokinetic Parameter (AUC[0-8h]) by Cohort and Day Following Oral Doses of Pexidartinib | Day 1 | 13300 ng*h/mL | Standard Deviation 4720 |
| Cohort 1 - 600 mg/Day | A Summary of Pexidartinib Pharmacokinetic Parameter (AUC[0-8h]) by Cohort and Day Following Oral Doses of Pexidartinib | Day 15 | 50900 ng*h/mL | Standard Deviation 18300 |
| Cohort 2 - 1000 mg/Day | A Summary of Pexidartinib Pharmacokinetic Parameter (AUC[0-8h]) by Cohort and Day Following Oral Doses of Pexidartinib | Day 1 | 16500 ng*h/mL | Standard Deviation 4760 |
| Cohort 2 - 1000 mg/Day | A Summary of Pexidartinib Pharmacokinetic Parameter (AUC[0-8h]) by Cohort and Day Following Oral Doses of Pexidartinib | Day 15 | 64600 ng*h/mL | Standard Deviation 15900 |
Secondary
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.
Time frame: Cycle 1, Day 1 and Day 15 at predose, 0.5h, 1h, 2h, 4h, and 8h postdose (each cycle was 28 days)
Population: Pharmacokinetic parameters were assessed in the Pharmacokinetic Analysis Set.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 - 600 mg/Day | A Summary of Pexidartinib Pharmacokinetic Parameter (Cmax) by Cohort and Day Following Oral Doses of Pexidartinib | Day 1 | 3210 ng/mL | Standard Deviation 1320 |
| Cohort 1 - 600 mg/Day | A Summary of Pexidartinib Pharmacokinetic Parameter (Cmax) by Cohort and Day Following Oral Doses of Pexidartinib | Day 15 | 8490 ng/mL | Standard Deviation 1430 |
| Cohort 2 - 1000 mg/Day | A Summary of Pexidartinib Pharmacokinetic Parameter (Cmax) by Cohort and Day Following Oral Doses of Pexidartinib | Day 1 | 3650 ng/mL | Standard Deviation 1170 |
| Cohort 2 - 1000 mg/Day | A Summary of Pexidartinib Pharmacokinetic Parameter (Cmax) by Cohort and Day Following Oral Doses of Pexidartinib | Day 15 | 10800 ng/mL | Standard Deviation 2860 |
Secondary
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.
Time frame: Cycle 1, Day 15 at predose, 0.5h, 1h, 2h, 4h, and 8h postdose (each cycle was 28 days)
Population: Pharmacokinetic parameters were assessed in the Pharmacokinetic Analysis Set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 - 600 mg/Day | A Summary of Pexidartinib Pharmacokinetic Parameter (R[AUC]) by Cohort Following Oral Doses of Pexidartinib | 4.29 accumulation ratio of AUC | Standard Deviation 2.29 |
| Cohort 2 - 1000 mg/Day | A Summary of Pexidartinib Pharmacokinetic Parameter (R[AUC]) by Cohort Following Oral Doses of Pexidartinib | 4.58 accumulation ratio of AUC | Standard Deviation 2.23 |
Secondary
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.
Time frame: Cycle 1, Day 15 at predose, 0.5h, 1h, 2h, 4h, and 8h postdose (each cycle was 28 days)
Population: Pharmacokinetic parameters were assessed in the Pharmacokinetic Analysis Set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 - 600 mg/Day | A Summary of Pexidartinib Pharmacokinetic Parameter (R[Cmax]) by Cohort Following Oral Doses of Pexidartinib | 2.94 accumulation ratio of Cmax | Standard Deviation 1.19 |
| Cohort 2 - 1000 mg/Day | A Summary of Pexidartinib Pharmacokinetic Parameter (R[Cmax]) by Cohort Following Oral Doses of Pexidartinib | 4.58 accumulation ratio of Cmax | Standard Deviation 2.23 |
Secondary
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.
Time frame: Cycle 1, Day 1 and Day 15 at predose, 0.5h, 1h, 2h, 4h, and 8h postdose (each cycle was 28 days)
Population: Pharmacokinetic parameters were assessed in the Pharmacokinetic Analysis Set.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 - 600 mg/Day | A Summary of Pexidartinib Pharmacokinetic Parameter (Tmax) by Cohort and Day Following Oral Doses of Pexidartinib | Day 1 | 3.95 hours | Standard Deviation 3.51 |
| Cohort 1 - 600 mg/Day | A Summary of Pexidartinib Pharmacokinetic Parameter (Tmax) by Cohort and Day Following Oral Doses of Pexidartinib | Day 15 | 1.00 hours | Standard Deviation 1 |
| Cohort 2 - 1000 mg/Day | A Summary of Pexidartinib Pharmacokinetic Parameter (Tmax) by Cohort and Day Following Oral Doses of Pexidartinib | Day 1 | 2.48 hours | Standard Deviation 1.18 |
| Cohort 2 - 1000 mg/Day | A Summary of Pexidartinib Pharmacokinetic Parameter (Tmax) by Cohort and Day Following Oral Doses of Pexidartinib | Day 15 | 1.26 hours | Standard Deviation 0.94 |
Secondary
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.
Time frame: Cycle 1, Day 1 and Day 15 at predose, 0.5h, 1h, 2h, 4h, and 8h postdose (each cycle was 28 days)
Population: Pharmacokinetic parameters were assessed in the Pharmacokinetic Analysis Set.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 - 600 mg/Day | A Summary of Plasma ZAAD-1006a Pharmacokinetic Parameter (AUC[0-8h]) Following Oral Doses of Pexidartinib | Day 1 | 14800 ng*h/mL | Standard Deviation 8010 |
| Cohort 1 - 600 mg/Day | A Summary of Plasma ZAAD-1006a Pharmacokinetic Parameter (AUC[0-8h]) Following Oral Doses of Pexidartinib | Day 15 | 91600 ng*h/mL | Standard Deviation 37500 |
| Cohort 2 - 1000 mg/Day | A Summary of Plasma ZAAD-1006a Pharmacokinetic Parameter (AUC[0-8h]) Following Oral Doses of Pexidartinib | Day 1 | 15600 ng*h/mL | Standard Deviation 9130 |
| Cohort 2 - 1000 mg/Day | A Summary of Plasma ZAAD-1006a Pharmacokinetic Parameter (AUC[0-8h]) Following Oral Doses of Pexidartinib | Day 15 | 120000 ng*h/mL | Standard Deviation 61100 |
Secondary
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.
Time frame: Cycle 1, Day 1 and Day 15 at predose, 0.5h, 1h, 2h, 4h, and 8h postdose (each cycle was 28 days)
Population: Pharmacokinetic parameters were assessed in the Pharmacokinetic Analysis Set.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 - 600 mg/Day | A Summary of Plasma ZAAD-1006a Pharmacokinetic Parameter (Cmax) Following Oral Doses of Pexidartinib | Day 1 | 2930 ng/mL | Standard Deviation 935 |
| Cohort 1 - 600 mg/Day | A Summary of Plasma ZAAD-1006a Pharmacokinetic Parameter (Cmax) Following Oral Doses of Pexidartinib | Day 15 | 13200 ng/mL | Standard Deviation 5120 |
| Cohort 2 - 1000 mg/Day | A Summary of Plasma ZAAD-1006a Pharmacokinetic Parameter (Cmax) Following Oral Doses of Pexidartinib | Day 1 | 3200 ng/mL | Standard Deviation 1630 |
| Cohort 2 - 1000 mg/Day | A Summary of Plasma ZAAD-1006a Pharmacokinetic Parameter (Cmax) Following Oral Doses of Pexidartinib | Day 15 | 17800 ng/mL | Standard Deviation 9630 |
Secondary
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.
Time frame: Cycle 1, Day 1 and Day 15 at predose, 0.5h, 1h, 2h, 4h, and 8h postdose (each cycle was 28 days)
Population: Pharmacokinetic parameters were assessed in the Pharmacokinetic Analysis Set.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 - 600 mg/Day | A Summary of Plasma ZAAD-1006a Pharmacokinetic Parameter (MR AUC[0-8h]) Following Oral Doses of Pexidartinib | Day 1 | 0.801 metabolite to parent drug ratio | Standard Deviation 0.454 |
| Cohort 1 - 600 mg/Day | A Summary of Plasma ZAAD-1006a Pharmacokinetic Parameter (MR AUC[0-8h]) Following Oral Doses of Pexidartinib | Day 15 | 1.27 metabolite to parent drug ratio | Standard Deviation 0.416 |
| Cohort 2 - 1000 mg/Day | A Summary of Plasma ZAAD-1006a Pharmacokinetic Parameter (MR AUC[0-8h]) Following Oral Doses of Pexidartinib | Day 1 | 0.658 metabolite to parent drug ratio | Standard Deviation 0.298 |
| Cohort 2 - 1000 mg/Day | A Summary of Plasma ZAAD-1006a Pharmacokinetic Parameter (MR AUC[0-8h]) Following Oral Doses of Pexidartinib | Day 15 | 1.33 metabolite to parent drug ratio | Standard Deviation 0.711 |
Secondary
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.
Time frame: Cycle 1, Day 1 and Day 15 at predose, 0.5h, 1h, 2h, 4h, and 8h postdose (each cycle was 28 days)
Population: Pharmacokinetic parameters were assessed in the Pharmacokinetic Analysis Set.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 - 600 mg/Day | A Summary of Plasma ZAAD-1006a Pharmacokinetic Parameter (MR Cmax) Following Oral Doses of Pexidartinib | Day 1 | 0.669 metabolite to parent drug ratio | Standard Deviation 0.189 |
| Cohort 1 - 600 mg/Day | A Summary of Plasma ZAAD-1006a Pharmacokinetic Parameter (MR Cmax) Following Oral Doses of Pexidartinib | Day 15 | 1.10 metabolite to parent drug ratio | Standard Deviation 0.44 |
| Cohort 2 - 1000 mg/Day | A Summary of Plasma ZAAD-1006a Pharmacokinetic Parameter (MR Cmax) Following Oral Doses of Pexidartinib | Day 1 | 0.639 metabolite to parent drug ratio | Standard Deviation 0.314 |
| Cohort 2 - 1000 mg/Day | A Summary of Plasma ZAAD-1006a Pharmacokinetic Parameter (MR Cmax) Following Oral Doses of Pexidartinib | Day 15 | 1.18 metabolite to parent drug ratio | Standard Deviation 0.695 |
Secondary
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.
Time frame: Cycle 1, Day 1 and Day 15 at predose, 0.5h, 1h, 2h, 4h, and 8h postdose (each cycle was 28 days)
Population: Pharmacokinetic parameters were assessed in the Pharmacokinetic Analysis Set.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 - 600 mg/Day | A Summary of Plasma ZAAD-1006a Pharmacokinetic Parameter (Tmax) Following Oral Doses of Pexidartinib | Day 1 | 6.55 hours | Standard Deviation 2.24 |
| Cohort 1 - 600 mg/Day | A Summary of Plasma ZAAD-1006a Pharmacokinetic Parameter (Tmax) Following Oral Doses of Pexidartinib | Day 15 | 1.5 hours | Standard Deviation 2.18 |
| Cohort 2 - 1000 mg/Day | A Summary of Plasma ZAAD-1006a Pharmacokinetic Parameter (Tmax) Following Oral Doses of Pexidartinib | Day 1 | 5.00 hours | Standard Deviation 2.87 |
| Cohort 2 - 1000 mg/Day | A Summary of Plasma ZAAD-1006a Pharmacokinetic Parameter (Tmax) Following Oral Doses of Pexidartinib | Day 15 | 1.43 hours | Standard Deviation 0.87 |
Secondary
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.
Time frame: Day 1 through Day 28 after last dose (within 18 months)
Population: Duration of response or duration of stable disease was assessed in the Efficacy Analysis Set.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 - 600 mg/Day | Duration of Response or Duration of Stable Disease Following Oral Doses of Pexidartinib (Efficacy Analysis Set) | Duration of response (n=1,0) | 7.62 months | Standard Deviation 0 |
| Cohort 1 - 600 mg/Day | Duration of Response or Duration of Stable Disease Following Oral Doses of Pexidartinib (Efficacy Analysis Set) | Duration of stable disease (n=1,3) | 1.87 months | Standard Deviation 0 |
| Cohort 2 - 1000 mg/Day | Duration of Response or Duration of Stable Disease Following Oral Doses of Pexidartinib (Efficacy Analysis Set) | Duration of stable disease (n=1,3) | 4.62 months | Standard Deviation 1.6 |
Secondary
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.
Time frame: Baseline through study completion, up to 18 months
Population: Adverse events were assessed in the Safety Analysis Set.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 - 600 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Constipation | 0 Participants |
| Cohort 1 - 600 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Blood cholesterol increased | 1 Participants |
| Cohort 1 - 600 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Fatigue | 1 Participants |
| Cohort 1 - 600 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Gamma-glutamyltransferase increased | 0 Participants |
| Cohort 1 - 600 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Nausea | 0 Participants |
| Cohort 1 - 600 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Weight increased | 1 Participants |
| Cohort 1 - 600 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Malaise | 1 Participants |
| Cohort 1 - 600 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Dysuria | 0 Participants |
| Cohort 1 - 600 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Chronic gastritis | 0 Participants |
| Cohort 1 - 600 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Proteinuria | 1 Participants |
| Cohort 1 - 600 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Alanine aminotransferase increased | 1 Participants |
| Cohort 1 - 600 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Urinary retention | 0 Participants |
| Cohort 1 - 600 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Stomatitis | 0 Participants |
| Cohort 1 - 600 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Cough | 1 Participants |
| Cohort 1 - 600 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Aspartate aminotransferase increased | 2 Participants |
| Cohort 1 - 600 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Haemoptysis | 0 Participants |
| Cohort 1 - 600 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Diarrhoea | 0 Participants |
| Cohort 1 - 600 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Hair colour changes | 2 Participants |
| Cohort 1 - 600 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Blood alkaline phosphatase increased | 1 Participants |
| Cohort 1 - 600 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Pruritus generalised | 1 Participants |
| Cohort 1 - 600 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Face oedema | 0 Participants |
| Cohort 1 - 600 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Rash generalised | 1 Participants |
| Cohort 1 - 600 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Blood bilirubin increased | 1 Participants |
| Cohort 1 - 600 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Skin hypopigmentation | 0 Participants |
| Cohort 1 - 600 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Any TEAE | 3 Participants |
| Cohort 2 - 1000 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Skin hypopigmentation | 1 Participants |
| Cohort 2 - 1000 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Any TEAE | 8 Participants |
| Cohort 2 - 1000 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Chronic gastritis | 1 Participants |
| Cohort 2 - 1000 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Constipation | 2 Participants |
| Cohort 2 - 1000 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Diarrhoea | 3 Participants |
| Cohort 2 - 1000 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Nausea | 1 Participants |
| Cohort 2 - 1000 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Stomatitis | 1 Participants |
| Cohort 2 - 1000 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Face oedema | 1 Participants |
| Cohort 2 - 1000 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Fatigue | 3 Participants |
| Cohort 2 - 1000 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Malaise | 0 Participants |
| Cohort 2 - 1000 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Alanine aminotransferase increased | 3 Participants |
| Cohort 2 - 1000 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Aspartate aminotransferase increased | 3 Participants |
| Cohort 2 - 1000 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Blood alkaline phosphatase increased | 3 Participants |
| Cohort 2 - 1000 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Blood bilirubin increased | 1 Participants |
| Cohort 2 - 1000 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Blood cholesterol increased | 0 Participants |
| Cohort 2 - 1000 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Gamma-glutamyltransferase increased | 2 Participants |
| Cohort 2 - 1000 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Weight increased | 0 Participants |
| Cohort 2 - 1000 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Dysuria | 1 Participants |
| Cohort 2 - 1000 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Proteinuria | 0 Participants |
| Cohort 2 - 1000 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Urinary retention | 1 Participants |
| Cohort 2 - 1000 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Cough | 2 Participants |
| Cohort 2 - 1000 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Haemoptysis | 1 Participants |
| Cohort 2 - 1000 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Hair colour changes | 2 Participants |
| Cohort 2 - 1000 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Pruritus generalised | 0 Participants |
| Cohort 2 - 1000 mg/Day | Number and Percentage of Participants With Common Treatment-emergent Adverse Events (TEAEs) (≥20%) Classified by Preferred Term (Safety Analysis Set) | Rash generalised | 0 Participants |
Secondary
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.
Time frame: Baseline through study completion, up to 18 months
Population: Adverse events were assessed in the Safety Analysis Set.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 - 600 mg/Day | Number and Percentage of Participants With Treatment-related TEAEs by Preferred Term (Safety Analysis Set) | Rash generalised | 1 Participants |
| Cohort 1 - 600 mg/Day | Number and Percentage of Participants With Treatment-related TEAEs by Preferred Term (Safety Analysis Set) | Any treatment-related TEAE | 3 Participants |
| Cohort 1 - 600 mg/Day | Number and Percentage of Participants With Treatment-related TEAEs by Preferred Term (Safety Analysis Set) | Diarrhoea | 0 Participants |
| Cohort 1 - 600 mg/Day | Number and Percentage of Participants With Treatment-related TEAEs by Preferred Term (Safety Analysis Set) | Face oedema | 0 Participants |
| Cohort 1 - 600 mg/Day | Number and Percentage of Participants With Treatment-related TEAEs by Preferred Term (Safety Analysis Set) | Fatigue | 1 Participants |
| Cohort 1 - 600 mg/Day | Number and Percentage of Participants With Treatment-related TEAEs by Preferred Term (Safety Analysis Set) | Alanine aminotransferase increased | 1 Participants |
| Cohort 1 - 600 mg/Day | Number and Percentage of Participants With Treatment-related TEAEs by Preferred Term (Safety Analysis Set) | Aspartate aminotransferase increased | 2 Participants |
| Cohort 1 - 600 mg/Day | Number and Percentage of Participants With Treatment-related TEAEs by Preferred Term (Safety Analysis Set) | Blood alkaline phosphatase increased | 1 Participants |
| Cohort 1 - 600 mg/Day | Number and Percentage of Participants With Treatment-related TEAEs by Preferred Term (Safety Analysis Set) | Blood bilirubin increased | 1 Participants |
| Cohort 1 - 600 mg/Day | Number and Percentage of Participants With Treatment-related TEAEs by Preferred Term (Safety Analysis Set) | Blood cholesterol increased | 1 Participants |
| Cohort 1 - 600 mg/Day | Number and Percentage of Participants With Treatment-related TEAEs by Preferred Term (Safety Analysis Set) | Gamma-glutamyltransferase increased | 0 Participants |
| Cohort 1 - 600 mg/Day | Number and Percentage of Participants With Treatment-related TEAEs by Preferred Term (Safety Analysis Set) | Proteinuria | 1 Participants |
| Cohort 1 - 600 mg/Day | Number and Percentage of Participants With Treatment-related TEAEs by Preferred Term (Safety Analysis Set) | Hair colour changes | 2 Participants |
| Cohort 1 - 600 mg/Day | Number and Percentage of Participants With Treatment-related TEAEs by Preferred Term (Safety Analysis Set) | Pruritus generalised | 1 Participants |
| Cohort 1 - 600 mg/Day | Number and Percentage of Participants With Treatment-related TEAEs by Preferred Term (Safety Analysis Set) | Skin hypopigmentation | 0 Participants |
| Cohort 2 - 1000 mg/Day | Number and Percentage of Participants With Treatment-related TEAEs by Preferred Term (Safety Analysis Set) | Rash generalised | 0 Participants |
| Cohort 2 - 1000 mg/Day | Number and Percentage of Participants With Treatment-related TEAEs by Preferred Term (Safety Analysis Set) | Blood bilirubin increased | 0 Participants |
| Cohort 2 - 1000 mg/Day | Number and Percentage of Participants With Treatment-related TEAEs by Preferred Term (Safety Analysis Set) | Any treatment-related TEAE | 6 Participants |
| Cohort 2 - 1000 mg/Day | Number and Percentage of Participants With Treatment-related TEAEs by Preferred Term (Safety Analysis Set) | Hair colour changes | 2 Participants |
| Cohort 2 - 1000 mg/Day | Number and Percentage of Participants With Treatment-related TEAEs by Preferred Term (Safety Analysis Set) | Diarrhoea | 3 Participants |
| Cohort 2 - 1000 mg/Day | Number and Percentage of Participants With Treatment-related TEAEs by Preferred Term (Safety Analysis Set) | Blood cholesterol increased | 0 Participants |
| Cohort 2 - 1000 mg/Day | Number and Percentage of Participants With Treatment-related TEAEs by Preferred Term (Safety Analysis Set) | Face oedema | 1 Participants |
| Cohort 2 - 1000 mg/Day | Number and Percentage of Participants With Treatment-related TEAEs by Preferred Term (Safety Analysis Set) | Skin hypopigmentation | 1 Participants |
| Cohort 2 - 1000 mg/Day | Number and Percentage of Participants With Treatment-related TEAEs by Preferred Term (Safety Analysis Set) | Fatigue | 3 Participants |
| Cohort 2 - 1000 mg/Day | Number and Percentage of Participants With Treatment-related TEAEs by Preferred Term (Safety Analysis Set) | Gamma-glutamyltransferase increased | 2 Participants |
| Cohort 2 - 1000 mg/Day | Number and Percentage of Participants With Treatment-related TEAEs by Preferred Term (Safety Analysis Set) | Alanine aminotransferase increased | 3 Participants |
| Cohort 2 - 1000 mg/Day | Number and Percentage of Participants With Treatment-related TEAEs by Preferred Term (Safety Analysis Set) | Pruritus generalised | 0 Participants |
| Cohort 2 - 1000 mg/Day | Number and Percentage of Participants With Treatment-related TEAEs by Preferred Term (Safety Analysis Set) | Aspartate aminotransferase increased | 3 Participants |
| Cohort 2 - 1000 mg/Day | Number and Percentage of Participants With Treatment-related TEAEs by Preferred Term (Safety Analysis Set) | Proteinuria | 0 Participants |
| Cohort 2 - 1000 mg/Day | Number and Percentage of Participants With Treatment-related TEAEs by Preferred Term (Safety Analysis Set) | Blood alkaline phosphatase increased | 3 Participants |