STUDY OF TALAZOPARIB MONOTHERAPY IN CHINESE PARTICIPANTS WITH ADVANCED SOLID TUMORS
- Registration Number
- NCT04635631
- Lead Sponsor
- Pfizer
- Brief Summary
A phase1 study to evaluate the PK (single dose and multiple doses) and safety of talazoparib 1 mg Once Daily in Chinese adult participants with advanced solid tumors. A maximum of approximately 15 participants will be enrolled such that approximately 12 evaluable participants complete the study.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 15
- Histological or cytological diagnosis of locally advanced or metastatic solid tumor that is resistant to standard therapy or for which no standard therapy is available.
- ECOG Performance Status 0 or 1.
- Adequate Bone Marrow, Renal and Liver Function.
- Participants with brain metastases.
- Current or anticipated use of P gp inhibitor and/or inducer within 7 days prior to study intervention from lead-in to end of Cycle 1; concomitant use of potent P gp inhibitor after Cycle 1 until the end of treatment.
- Prior treatment with a PARP inhibitor.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description talazoparib talazoparib 1 mg QD
- Primary Outcome Measures
Name Time Method Maximum Observed Concentration (Cmax) of Talazoparib Following Single Oral Dose Pre-dose and 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours, 48 hours, 96 hours, 168 hours and 216 hours post Day -9 dosing Maximum plasma concentration of talazoparib after the participant received a single oral lead-in dose of talazoparib 1 mg on Study Day -9. Cmax was directly observed from data.
Time to Cmax (Tmax) of Talazoparib Following Single Oral Dose Pre-dose and 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours, 48 hours, 96 hours, 168 hours and 216 hours post Day -9 dosing Time to reach Cmax (maximum plasma concentration) of talazoparib after the participant received a single oral lead-in dose of talazoparib 1 mg on Study Day -9.
Apparent Oral Clearance (CL/F) of Talazoparib Following Single Oral Dose Pre-dose and 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours, 48 hours, 96 hours, 168 hours and 216 hours post Day -9 dosing Apparent oral clearance of talazoparib after the participant received a single oral lead-in dose of talazoparib 1 mg on Study Day -9. Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is a quantitative measure of the rate at which a drug substance is removed from the blood. CL/F is calculated as dose/AUCinf. AUCinf = area under the plasma concentration versus time curve from time zero extrapolated to infinite time.
Area Under Plasma Concentration-Time Profile From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Talazoparib Following Single Oral Dose Pre-dose and 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours, 48 hours, 96 hours, 168 hours and 216 hours post Day -9 dosing Area under the plasma concentration versus time curve from time zero to the time of the last quantifiable concentration of talazoparib after the participant received a single oral lead-in dose of talazoparib 1 mg on Study Day -9.
Cmax of Talazoparib Following Multiple Oral Doses (Steady State) Pre-dose and 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours after dosing on Cycle 1 Day 22. Maximum plasma concentration of talazoparib at steady state after the participant received multiple oral doses of talazoparib 1 mg QD from Cycle 1 Day 1 to Cycle 1 Day 22.
AUCtau of Talazoparib Following Multiple Oral Doses (Steady State) Pre-dose and 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours after dosing on Cycle 1 Day 22. Area under the plasma concentration versus time curve within a dosing interval of tau (=24 hours) at steady state after the participant received multiple oral doses of talazoparib 1 mg QD from Cycle 1 Day 1 to Cycle 1 Day 22.
Apparent Volume of Distribution (Vz/F) of Talazoparib Following Single Oral Dose Pre-dose and 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours, 48 hours, 96 hours, 168 hours and 216 hours post Day -9 dosing Apparent volume of distribution of talazoparib after the participant received a single oral lead-in dose of talazoparib 1 mg on Study Day -9. Vz/F is calculated as Dose/(AUCinf \* kel), where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. AUCinf is area under the plasma concentration versus time curve from time zero extrapolated to infinite time.
Minimum Plasma Concentration (Cmin) of Talazoparib Following Multiple Oral Doses (Steady State) Pre-dose and 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours after dosing on Cycle 1 Day 22. Minimum plasma concentration observed during the dosing interval at steady state after the participant received multiple oral doses of talazoparib 1 mg QD from Cycle 1 Day 1 to Cycle 1 Day 22.
Steady-State Accumulation Ratio (Rss) of Talazoparib Following Multiple Oral Doses (Steady State) Pre-dose and 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours after dosing on Cycle 1 Day 22. Steady-state accumulation ratio after the participant received multiple oral doses of talazoparib 1 mg QD from Cycle 1 Day 1 to Cycle 1 Day 22. Rss is calculated as AUCtau/AUCinf, where AUCtau = Area under the plasma concentration versus time curve within a dosing interval of tau (=24 hours) at steady state after multiple doses, AUCinf = Area under the plasma concentration versus time curve from time zero extrapolated to infinite time after single dose.
Area Under the Plasma Concentration-Time Profile From Time Zero to Time Tau (AUCtau) of Talazoparib Following Single Oral Dose Pre-dose and 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours, 48 hours, 96 hours, 168 hours and 216 hours post Day -9 dosing Area under the plasma concentration versus time curve from time zero to the time tau (=24 hours) of talazoparib after the participant received a single oral lead-in dose of talazoparib 1 mg on Study Day -9.
Terminal Half-Life (t1/2) of Talazoparib Following Single Oral Dose Pre-dose and 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours, 48 hours, 96 hours, 168 hours and 216 hours post Day -9 dosing Terminal half-life of talazoparib after the participant received a single oral lead-in dose of talazoparib 1 mg on Study Day -9. t1/2 is defined as the time for plasma concentration of drug to decrease by one half.
Area Under Plasma Concentration-Time Profile From Time Zero to Infinity (AUCinf) of Talazoparib Following Single Oral Dose Pre-dose and 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours, 48 hours, 96 hours, 168 hours and 216 hours post Day -9 dosing Area under the plasma concentration versus time curve from time zero extrapolated to infinite time of talazoparib after the participant received a single oral lead-in dose of talazoparib 1 mg on Study Day -9.
Tmax of Talazoparib Following Multiple Oral Doses (Steady State) Pre-dose and 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours after dosing on Cycle 1 Day 22. Time for Cmax of talazoparib at steady state after the participant received multiple oral doses of talazoparib 1 mg QD from Cycle 1 Day 1 to Cycle 1 Day 22.
CL/F of Talazoparib Following Multiple Oral Doses (Steady State) Pre-dose and 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours after dosing on Cycle 1 Day 22. Apparent clearance at steady state after the participant received multiple oral doses of talazoparib 1 mg QD from Cycle 1 Day 1 to Cycle 1 Day 22. Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is a quantitative measure of the rate at which a drug substance is removed from the blood. Steady-state CL/F is calculated as dose/AUCtau. AUCtau = area under the plasma concentration versus time curve within a dosing interval of tau (=24 hours) at steady state after multiple doses.
Observed Accumulation Ratio (Rac) of Talazoparib Following Multiple Oral Doses (Steady State) Pre-dose and 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours after dosing on Cycle 1 Day 22. Observed accumulation ratio at steady state after the participant received multiple oral doses of talazoparib 1 mg QD from Cycle 1 Day 1 to Cycle 1 Day 22. Rac is calculated as AUCtau/AUCsd,tau, where AUCtau = Area under the plasma concentration versus time curve within a dosing interval of tau (=24 hours) at steady state after multiple doses, AUCsd,tau = area under the plasma concentration versus time curve from time zero extrapolated to the time tau (=24 hours) after single dose.
- Secondary Outcome Measures
Name Time Method Number of Participants With TEAEs Leading to Dose Interruption of Talazoparib by PT Baseline (the latest non-missing value prior to or on the date of first dose of talazoparib) to at least 28 days after the last dose of talazoparib (maximum of approximately 46 weeks) An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with study treatment. TEAEs=AEs with start date during the on-treatment period (including on the date of first dose). Treatment-related TEAEs were determined by the investigator.
Number of Participants With On-Treatment Maximum QT Interval (Bazett's Correction) (QTcB) and QT Interval (Fridericia's Correction) (QTcF) Data by Category From first dose date up to at least 28 days after last dose or to the start of new anti-cancer drug therapy minus 1 day (whichever was earlier) (maximum of approximately 46 weeks) Standard 12-lead electrocardiograms (ECGs) utilizing limb leads (with a 10 second rhythm strip) were collected using an ECG machine that automatically calculated the heart rate and measured PR, RR, QT intervals, QTc, QTcF and QRS complex. All scheduled ECGs were performed after the participant had rested quietly for at least 10 minutes. On-treatment is defined as the time from first dose date through at least 28 days after last dose/start day of new anti-cancer therapy minus 1 day.
Number of Participants With Serious Adverse Events (SAEs) Baseline (the latest non-missing value prior to or on the date of first dose of talazoparib) to at least 28 days after the last dose of talazoparib (maximum of approximately 46 weeks) An SAE was any untoward medical occurrence at any dose that resulted in death; was life threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent disability/incapacity; was a congenital anomaly/birth defect. Treatment-related SAEs were determined by the investigator.
Number of Participants With TEAEs Leading to Dose Reduction of Talazoparib by PT Baseline (the latest non-missing value prior to or on the date of first dose of talazoparib) to at least 28 days after the last dose of talazoparib (maximum of approximately 46 weeks) An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with study treatment. TEAEs=AEs with start date during the on-treatment period (including on the date of first dose). Treatment-related TEAEs were determined by the investigator.
Number of Participants With Grade 3 or 4 All-Causality TEAEs by Preferred Term (PT) and Maximum CTCAE Grade Baseline (the latest non-missing value prior to or on the date of first dose of talazoparib) to at least 28 days after the last dose of talazoparib (maximum of approximately 46 weeks) An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with study treatment. TEAEs=AEs with start date during the on-treatment period (including on the date of first dose). Grades of AEs were defined by NCI CTCAE version 4.03. Grade 3=severe or medically significant but not immediately life-threatening, hospitalization of prolongation of hospitalization indicated; disabling limiting self-care ADL; Grade 4=events with life-threatening consequences, urgent intervention indicated. Treatment-related TEAEs were determined by the investigator. Grade 3 or 4 TEAEs reported by at least 1 participant are reported here.
Number of Participants With Grade 3 or 4 Treatment-Related TEAEs by PT and Maximum CTCAE Grade Baseline (the latest non-missing value prior to or on the date of first dose of talazoparib) to at least 28 days after the last dose of talazoparib (maximum of approximately 46 weeks) An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with study treatment. TEAEs=AEs with start date during the on-treatment period (including on the date of first dose). Grades of AEs were defined by NCI CTCAE version 4.03. Grade 3=severe or medically significant but not immediately life-threatening, hospitalization of prolongation of hospitalization indicated; disabling limiting self-care ADL; Grade 4=events with life-threatening consequences, urgent intervention indicated. Treatment-related TEAEs were determined by the investigator. Grade 3 or 4 treatment-related TEAEs reported by at least 1 participant are reported here.
Number of Participants With TEAEs Leading to Discontinuation From Talazoparib by PT Baseline (the latest non-missing value prior to or on the date of first dose of talazoparib) to at least 28 days after the last dose of talazoparib (maximum of approximately 46 weeks) An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with study treatment. TEAEs=AEs with start date during the on-treatment period (including on the date of first dose). Treatment-related TEAEs were determined by the investigator.
Number of Participants With On-Treatment Urinalysis Laboratory Abnormalities Shifting From <=Grade 2 at Baseline to Grade 3/4 Post-Baseline by Maximum CTCAE Grade From first dose date up to at least 28 days after last dose or to the start of new anti-cancer drug therapy minus 1 day (whichever was earlier) (maximum of approximately 46 weeks) Urinalysis examined pH,glucose,protein,blood,ketones,nitrites,leukocyte esterase/leukocytes,urobilinogen,urine bilirubin,microscopy. Grades of lab results were defined by NCI CTCAE v4.03. Grade 1(mild)=asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated;Grade 2(moderate)=minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental ADL;Grade 3=severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated; disabling limiting self-care ADL;Grade 4=life-threatening consequences, urgent intervention indicated. On-treatment=time from first dose date through at least 28 days after last dose/start day of new anti-cancer therapy minus 1 day. This OM is based only on lab data. Grade 4 proteinuria cannot be assessed based only on lab data, so is not applicable/not reported.
Number of Participants With On-Treatment Maximum Increase From Baseline in QTcB and QTcF Data by Category From first dose date up to at least 28 days after last dose or to the start of new anti-cancer drug therapy minus 1 day (whichever was earlier) (maximum of approximately 46 weeks) Standard 12-lead electrocardiograms (ECGs) utilizing limb leads (with a 10 second rhythm strip) were collected using an ECG machine that automatically calculated the heart rate and measured PR, RR, QT intervals, QTc, QTcF and QRS complex. All scheduled ECGs were performed after the participant had rested quietly for at least 10 minutes. On-treatment is defined as the time from first dose date through at least 28 days after last dose/start day of new anti-cancer therapy minus 1 day.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Baseline (the latest non-missing value prior to or on the date of first dose of talazoparib) to at least 28 days after the last dose of talazoparib (maximum of approximately 46 weeks) An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with study treatment. TEAEs=AEs with start date during the on-treatment period (including on the date of first dose). Grades of AEs were defined by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) version 4.03. Grade 1(mild)=asymptomatic/mild symptoms, clinical or diagnostic observations only, intervention not indicated; Grade 2(moderate)=minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activity of daily living (ADL); Grade 3=severe or medically significant but not immediately life-threatening, hospitalization of prolongation of hospitalization indicated; disabling limiting self-care ADL; Grade 4=events with life-threatening consequences, urgent intervention indicated; Grade 5= death related to AE. Treatment-related TEAEs were determined by the investigator.
Number of Participants With On-Treatment Hematology Laboratory Abnormalities Shifting From <=Grade 2 at Baseline to Grade 3/4 Post-Baseline by Maximum CTCAE Grade From first dose date up to at least 28 days after last dose or to the start of new anti-cancer drug therapy minus 1 day (whichever was earlier) (maximum of approximately 46 weeks) Hematology lab parameters included hemoglobin, hematocrit, red blood cell (RBC) count, platelet count, white blood cell (WBC) count, neutrophils%, eosinophils%, monocytes%, basophils%, lymphocytes%. Grades of lab abnormalities were defined per NCI CTCAE version 4.03. Grade 1(mild)=asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated;Grade 2(moderate)=minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental ADL;Grade 3=severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated; disabling limiting self-care ADL;Grade 4=life-threatening consequences, urgent intervention indicated. On-treatment is defined as time from first dose date of talazoparib through at least 28 days after last dose or start day of new anti-cancer therapy minus 1 day. Shifts meeting criteria and reported in at least 1 participant are reported in this OM.
Number of Participants With On-Treatment Chemistry Laboratory Abnormalities Shifting From <=Grade 2 at Baseline to Grade 3/4 Post-Baseline by Maximum CTCAE Grade From first dose date up to at least 28 days after last dose or to the start of new anti-cancer drug therapy minus 1 day (whichever was earlier) (maximum of approximately 46 weeks) Chemistry lab parameters included blood urea nitrogen or urea,creatinine,glucose (fasting),calcium,sodium,potassium,magnesium,chloride,aspartate aminotransferase,alanine aminotransferase,total bilirubin,alkaline phosphatase,uric acid,albumin,total protein,creatinine clearance. Grades of lab results were defined per NCI CTCAE v4.03.Grade 1=asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated;Grade 2=minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental ADL;Grade 3=severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated; disabling limiting self-care ADL;Grade 4=life-threatening consequences, urgent intervention indicated.On-treatment=time from first dose date through at least 28 days after last dose/start day of new anti-cancer therapy minus 1 day. Shifts meeting criteria and reported in at least 1 participant are reported.
Number of Participants With On-Treatment Vital Signs Data Meeting Pre-Specified Criteria for Potentially Clinically Significant Results From first dose date up to at least 28 days after last dose or to the start of new anti-cancer drug therapy minus 1 day (whichever was earlier) (maximum of approximately 46 weeks) Vital signs data included systolic and diastolic blood pressure (BP), pulse rate, respiratory rate (RR), temperature and weight. BP and pulse rate were recorded in sitting position. Potentially clinically significant vital signs abnormalities are defined as: systolic BP absolute result \>180 mmHg and increase from baseline ≥40 mmHg, absolute result \<90 mmHg and decrease from baseline \>30 mmHg; diastolic BP absolute result \>110 mmHg and increase from baseline ≥30 mmHg, absolute result \<50 mmHg and decrease from baseline \>20 mmHg, increase from baseline ≥20 mmHg; pulse rate absolute result \>120 beats per minute (bpm) and increase from baseline \>30 bpm, absolute result \<50 bpm and decrease from baseline \> 20 bpm; weight \>10% decrease from baseline. Participants with vital signs data meeting any criteria above are reported in this OM if any. On-treatment is defined as time from first dose date through at least 28 days after last dose/start day of new anti-cancer therapy minus 1 day.
Number of Participants With On-Treatment Concomitant Medications With Frequency >=20% by PT From first dose date up to at least 28 days after last dose/start day of new anti-cancer drug therapy minus 1 day (maximum of approximately 46 weeks) Concomitant medications or nondrug treatments/procedures were defined as medications or nondrug treatments/procedures, other than study intervention, which started prior to first dose date of study treatment and continued on on-treatment period as well as those started during the on-treatment period. On-treatment is defined as the time from first dose date through at least 28 days after last dose/start day of new anti-cancer therapy minus 1 day. On-treatment concomitant medications reported in at least 20% participants are reported for this OM.
Number of Participants With On-Treatment Concomitant Nondrug Treatments/Procedures by PT From first dose date up to at least 28 days after last dose/start day of new anti-cancer drug therapy minus 1 day (maximum of approximately 46 weeks) Concomitant medications or nondrug treatments/procedures were defined as medications or nondrug treatments/procedures, other than study intervention, which started prior to first dose date of study treatment and continued on on-treatment period as well as those started during the on-treatment period. On-treatment is defined as the time from first dose date through at least 28 days after last dose/start day of new anti-cancer therapy minus 1 day.
Number of Participants With On-Treatment Concomitant Medications From first dose date up to at least 28 days after last dose/start day of new anti-cancer drug therapy minus 1 day (maximum of approximately 46 weeks) Concomitant medications or nondrug treatments/procedures were defined as medications or nondrug treatments/procedures, other than study intervention, which started prior to first dose date of study treatment and continued on on-treatment period as well as those started during the on-treatment period. On-treatment is defined as the time from first dose date through at least 28 days after last dose/start day of new anti-cancer therapy minus 1 day.
Percentage of Participants Achieving Objective Response (OR) (Complete Response [CR] or Partial Response [PR]) (Confirmed or Unconfirmed) Cycle 1 Day 1 until disease progression, start of subsequent anti-cancer therapy or death due to any cause (maximum of approximately 45 weeks) Tumor assessments were performed regularly during Cycles 1-12, then per local standard practice after Cycle 12. OR by investigator assessment was defined as a CR or PR according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 recorded from Cycle 1 Day 1 until disease progression, start of subsequent anti-cancer therapy or death due to any cause. CR is defined as complete disappearance of all target lesions with the exception of nodal disease. All target nodes must decrease to normal size (short axis \<10 mm). PR is defined as \>=30% decrease under baseline of the sum of diameters of all target measurable lesions. Short diameter is used in the sum for target nodes, while longest diameter is used in the sum for all other target lesions. An exact 95% confidence interval (CI) was calculated using Clopper-Pearson method. Given the exploratory nature of this endpoint, confirmation of response (CR/PR) was not required per protocol.
Number of Participants With On-Treatment Concomitant Nondrug Treatments/Procedures From first dose date up to at least 28 days after last dose/start day of new anti-cancer drug therapy minus 1 day (maximum of approximately 46 weeks) Concomitant medications or nondrug treatments/procedures were defined as medications or nondrug treatments/procedures, other than study intervention, which started prior to first dose date of study treatment and continued on on-treatment period as well as those started during the on-treatment period. On-treatment is defined as the time from first dose date through at least 28 days after last dose/start day of new anti-cancer therapy minus 1 day.
Duration of Response (DOR) for Participant(s) Achieving CR or PR Cycle 1 Day 1 until disease progression, start of subsequent anti-cancer therapy or death due to any cause (maximum of approximately 45 weeks) Tumor assessments were performed regularly during Cycles 1-12 and per local standard practice after Cycle 12. Per RECIST v1.1, CR=complete disappearance of all target lesions with the exception of nodal disease. All target nodes must decrease to normal size (short axis \<10 mm). PR is defined as \>=30% decrease under baseline of the sum of diameters of all target measurable lesions. Short diameter is used in the sum for target nodes, while longest diameter is used in the sum for all other target lesions. For participants with an OR (CR or PR), DOR = the time from first documentation of CR or PR to date of first documentation of objective progression or death. DOR data were censored on the date of last tumor assessment on study for participants who did not have objective tumor progression and who did not die due to any cause while on study. DOR was only calculated for participant(s) with an objective response. DOR was to be summarized using the Kaplan-Meier method if data permitted.
Trial Locations
- Locations (2)
Jilin Cancer Hospital
🇨🇳Changchun, Jilin, China
Cancer Hospital, Chinese Academy of Medical Sciences
🇨🇳Beijing, China