An Open-Label Pharmacokinetics and Safety Study of Talazoparib (MDV3800)

Study Overview
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Brief Summary
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This is a trial to investigate the pharmacokinetics (PK) and the safety of talazoparib in patients with advanced solid tumors and impaired hepatic function.

Detailed Description
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At the end of the study, patients with no clinically significant toxicities, no contraindications to continue treatment with talazoparib, and no disease progression (underlying cancer progression) may be eligible to continue talazoparib treatment in a separate open-label extension study. The decision to allow the patient to continue dosing with talazoparib in an open-label extension (OLE) study will be based on potential overall benefit-risk and patient meeting eligibility criteria for OLE.

Official Title
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A PHASE I OPEN-LABEL PHARMACOKINETICS AND SAFETY STUDY OF TALAZOPARIB (MDV3800) IN PATIENTS WITH ADVANCED SOLID TUMORS AND NORMAL OR VARYING DEGREES OF HEPATIC IMPAIRMENT

Conditions
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Advanced Solid Tumors

Intervention / Treatment
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* Drug: Talazoparib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed and dated Informed Consent Form (by the patient or a legally acceptable representative as per the local regulations). Female or male at least 18 years of age. Histologically or cytologically confirmed advanced solid tumor with no available standard treatment options in the opinion of the Investigator Eastern Cooperative Oncology Group (ECOG) Performance status ≤ 2. Expected life expectancy of ≥ 3 months. Able to swallow the study drug (no contraindication to oral agents). Hepatic function at screening and enrollment as defined by the NCI organ dysfunction working group (NCI-ODWG) criteria. Adequate other organ function at screening and enrollment. Female patients of childbearing potential must have a negative serum pregnancy test at screening and must agree to use a highly effective form of contraception from the time of the first dose of study drug through 7 months after the last dose of study drug. Male patients must agree to use a condom when having sex with a pregnant woman or with a non-pregnant female partner of childbearing potential, from 21 days before the first dose of study drug through 4 months after last dose of study drug. Female patients must not be breastfeeding at screening nor during the study participation until 7 months after the last dose of the study drug. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures. Exclusion Criteria: Treatment within 14 days or five half lives prior to enrollment whichever is longer with any type of systemic anticancer-therapy or any investigational drug Have not recovered (recovery is defined as CTCAE grade ≤ 1) from the acute toxicities of previous anticancer standard or investigational therapy, except treatment-related alopecia or laboratory abnormalities otherwise meeting eligibility requirements. Major surgery within 28 days prior to enrollment. Serious accompanying cardiac disorder Active known or suspected brain metastasis or active leptomeningeal disease needing treatment Symptomatic or impending spinal cord compression or cauda equine syndrome Has undergone a liver transplant, kidney transplant or nephrectomy. Prior allergic reaction or severe intolerance (meeting the criteria for a serious adverse event, a grade 3 or 4 AE, or permanent treatment discontinuation) to a poly ADP ribose polymerase (PARP) inhibitor. Known myelodysplastic syndrome Seropositive for human immunodeficiency virus (HIV). Any serious or unstable medical condition that interferes with ability to tolerate treatment or assessments associated with the protocol. Gastrointestinal disorder affecting absorption. Known or suspected hypersensitivity to any of the talazoparib capsule components. Any condition or reason that interferes with ability to participate in the study, tolerate treatment or assessments associated with the protocol, causes undue risk, or complicates the interpretation of safety data, in the opinion of the Investigator or Medical Monitor

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A (control, normal hepatic function)<br> | Drug: Talazoparib<br>* Daily oral doses of talazoparib 0.5 mg<br>* Other names: BMN673;|
| Experimental: Group B (mild hepatic dysfunction)<br> | Drug: Talazoparib<br>* Daily oral doses of talazoparib 0.5 mg<br>* Other names: BMN673;|
| Experimental: Group C (moderate hepatic dysfunction)<br> | Drug: Talazoparib<br>* Daily oral doses of talazoparib 0.5 mg<br>* Other names: BMN673;|
| Experimental: Group D (severe hepatic dysfunction)<br> | Drug: Talazoparib<br>* Daily oral doses of talazoparib 0.5 mg<br>* Other names: BMN673;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Free Plasma Concentration Time Curve From Zero to 24 Hours (AUC0-24) of Talazoparib on Day 22 | AUC0-24 of talazoparib was defined as the area under the free plasma concentration time curve from time 0 to 24 hours post-dose. | Pre-dose (24 hours +/- 60 minutes from the previous dose on Day 21 but within 60 minutes prior to next dose), 0.5, 1, 2, 4, 6, anytime from 8 to 12 and 24 hours post-dose on Day 22 | 
| Maximum Observed Plasma Concentration (Cmax) of Talazoparib on Day 22 | Cmax was defined as the maximum observed plasma concentration of talazoparib. | Pre-dose (24 hours +/- 60 minutes from the previous dose on Day 21 but within 60 minutes prior to next dose), 0.5, 1, 2, 4, 6, anytime from 8 to 12 and 24 hours post-dose on Day 22 | 
| Unbound Area Under the Free Plasma Concentration Time Curve From Zero to 24 Hours (AUC0-24u) of Talazoparib on Day 22 | AUC0-24u for unbound talazoparib was defined as the area under the free plasma concentration time curve from time 0 to 24 hours post-dose. AUC0-24u = fu*AUC0-24. fu= Fraction of Unbound (fu) Plasma. | Pre-dose (24 hours +/- 60 minutes from the previous dose on Day 21 but within 60 minutes prior to next dose), 0.5, 1, 2, 4, 6, anytime from 8 to 12 and 24 hours post-dose on Day 22 | 
| Unbound Maximum Observed Plasma Concentration (Cmaxu) of Talazoparib on Day 22 | Cmaxu was defined as the maximum observed plasma concentration for unbound talazoparib. Cmaxu = fu*Cmax. | Pre-dose (24 hours +/- 60 minutes from the previous dose on Day 21 but within 60 minutes prior to next dose), 0.5, 1, 2, 4, 6, anytime from 8 to 12 and 24 hours post-dose on Day 22 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Free Plasma Concentration Time Curve From Zero to 24 Hours (AUC0-24) of Talazoparib on Day 1 | AUC0-24 of talazoparib was defined as the area under the free plasma concentration time curve from time 0 to 24 hours post-dose. | Pre-dose (within 60 minutes prior to dose), 0.5, 1, 2, 4, 6, anytime between 8 to 12 and 24 hours post-dose on Day 1 | 
| Maximum Observed Plasma Concentration (Cmax) of Talazoparib on Day 1 | Cmax was defined as the maximum observed plasma concentration of talazoparib. | Pre-dose (within 60 minutes prior to dose), 0.5, 1, 2, 4, 6, anytime between 8 to 12 and 24 hours post-dose on Day 1 | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of Talazoparib on Day 1 | Tmax was defined as the time to reach maximum observed plasma concentration of talazoparib. | Pre-dose (within 60 minutes prior to dose), 0.5, 1, 2, 4, 6, anytime between 8 to 12 and 24 hours post-dose on Day 1 | 
| Fraction of Unbound (fu) Plasma Talazoparib on Day 1 | Fraction of unbound drug (fu) was defined as the ratio of unbound drug concentration to the total drug concentration and reported as percentage (%). | Pre-dose (within 60 minutes prior to dose), 0.5, 1, 2, 4, 6, anytime between 8 to 12 and 24 hours post-dose on Day 1 | 
| Unbound Area Under the Free Plasma Concentration Time Curve From Zero to 24 Hours (AUC0-24u) of Talazoparib on Day 1 | AUC0-24u for unbound talazoparib was defined as the area under the free plasma concentration time curve from time 0 to 24 hours post-dose. AUC0-24u = fu*AUC0-24. | Pre-dose (within 60 minutes prior to dose), 0.5, 1, 2, 4, 6, anytime between 8 to 12 and 24 hours post-dose on Day 1 | 
| Unbound Maximum Observed Plasma Concentration (Cmaxu) of Talazoparib on Day 1 | Cmaxu was defined as the maximum observed plasma concentration for unbound talazoparib. Cmaxu = fu*Cmax | Pre-dose (within 60 minutes prior to dose), 0.5, 1, 2, 4, 6, anytime between 8 to 12 and 24 hours post-dose on Day 1 | 
| Plasma Trough Concentration (Ctrough) of Talazoparib on Day 8, 15 and 22 | Ctrough was defined as plasma trough (pre-dose) concentration of talazoparib. Acceptance criteria for Ctrough on Day 15 and Day 22: received 10 consecutive days of dosing immediately before PK sampling day; Sample drawn within 24 +/-2 hours of the previous dose, and not more than +10 minute after the drug administration on the PK collection day. Ctrough on Day 8: received 7 consecutive days of dosing immediately before PK sampling day; sample drawn within 24 +/- 2 hours of the previous dose, and not more than +10 minute after the drug administration on the PK collection day. | Pre-dose on Day 8, 15 and 22 | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of Talazoparib on Day 22 | Tmax was defined as the time to reach maximum observed plasma concentration of talazoparib. | Pre-dose (24 hours +/- 60 minutes from the previous dose on Day 21 but within 60 minutes prior to next dose), 0.5, 1, 2, 4, 6, anytime from 8 to 12 and 24 hours post-dose on Day 22 | 
| Fraction of Unbound (fu) Plasma Talazoparib on Day 22 | Fraction of unbound drug (fu) was defined as the ratio of unbound drug concentration to the total drug concentration and reported as percentage (%). | Pre-dose (24 hours +/- 60 minutes from the previous dose on Day 21 but within 60 minutes prior to next dose), 0.5, 1, 2, 4, 6, anytime from 8 to 12 and 24 hours post-dose on Day 22 | 
| Accumulation Ratio (Rac) of Plasma Talazoparib | Accumulation ratio for AUC0-24 was calculated as area under the curve from time zero to 24 hours on Day 22 divided by area under the curve from time zero to 24 hours on Day 1. | Pre-dose (within 60 minutes prior to dose) on Day 1, pre-dose(24 hours +/- 60 minutes from the previous dose on Day 21 but within 60 minutes prior to next dose) on Day 22 and 0.5, 1, 2, 4, 6, anytime between 8 to 12 and 24 hours post-dose on Days 1 and 22 | 
| Apparent Clearance (CL/F) of Plasma Talazoparib on Day 22 | Talazoparib clearance is a measure of the rate at which talazoparib is metabolized or eliminated by normal biological processes. | Pre-dose (24 hours +/- 60 minutes from the previous dose on Day 21 but within 60 minutes prior to next dose), 0.5, 1, 2, 4, 6, anytime from 8 to 12 and 24 hours post-dose on Day 22 | 
| Unbound Apparent Clearance (CLu/F) of PlasmaTalazoparib on Day 22 | Clearance of unbound talazoparib is a measure of the rate at which unbound talazoparib is metabolized or eliminated by normal biological processes. | Pre-dose (24 hours +/- 60 minutes from the previous dose on Day 21 but within 60 minutes prior to next dose), 0.5, 1, 2, 4, 6, anytime from 8 to 12 and 24 hours post-dose on Day 22 | 
| Amount of Talazoparib Excreted Unchanged in Urine From Time Zero to 24 Hours (Ae 0-24) on Day 1 | Ae 0-24 is the amount of talazoparib excreted unchanged in urine from time 0 to 24 hours post dose. | A single void at pre-dose, post-dose at any time between 0 to 12 and any time between 12 to 24 hours on Day 1 | 
| Percentage of Talazoparib Excreted in Urine From Time Zero to 24 Hours (Ae 0-24%) on Day 1 | Ae0-24% was defined as the amount of talazoparib excreted in urine from time 0 to 24 hours expressed as percentage of administered dose. | A single void at pre-dose, post-dose at any time between 0 to 12 and any time between 12 to 24 hours on Day 1 | 
| Amount of Talazoparib Excreted Unchanged in Urine From Time Zero to 24 Hours (Ae 0-24) on Day 22 | Ae 0-24 is the amount of talazoparib excreted unchanged in urine from time 0 to 24 hours post dose. | Urine voided post-dose at any time between 0 to 12 and any time between 12 to 24 hours on Day 22 | 
| Percentage of Talazoparib Excreted in Urine From Time 0 to 24 Hours (Ae 0-24%) on Day 22 | Ae 0-24% was defined as the amount of talazoparib excreted in urine from time 0 to 24 hours expressed as percentage of administered dose. | Urine voided post-dose at any time between 0 to 12 and any time between 12 to 24 hours (hrs) on Day 22 | 
| Renal Clearance (CLr) of Talazoparib on Day 22 | Renal clearance was calculated as cumulative amount of drug excreted in urine during the 24 hours dosing interval (Ae) divided by area under the plasma concentration time-curve from time zero to 24 hours post dose (AUC0-24). | Ae: Post-dose at any time between 0 to 12, 12 to 24 hrs on Day 22; AUC0-24: Pre-dose (24 hrs +/- 60 minutes from previous dose on Day 21 but within 60 minutes prior to next dose), 0.5, 1, 2, 4, 6, any time between 8 to12, 24 hrs post-dose on Day 22 | 
| Number of Participants With Clinically Significant Laboratory Abnormalities | Clinically significant laboratory abnormalities included aspartate transaminase (AST) or alanine aminotransferase (ALT) >=3 times ULN (>5 *ULN if baseline ALT/AST is >3 *ULN) and total bilirubin (TBL) >2 times ULN or INR >1.5, AST or ALT >=3 times ULN with signs and symptoms consistent with hepatitis and/or eosinophilia (>=500 eosinophils/microliter). | Baseline up to 30 days after last dose of study drug (up to 52 days) | 
| Change From Baseline in Vital Sign -Blood Pressure at Day 2, 8, 15, 22 and End of Study | Systolic blood pressure and diastolic blood pressure were evaluated for examination of vital signs. | Baseline, Day 2, 8, 15, 22 and End of Study (Day 52) | 
| Change From Baseline in Vital Sign- Heart Rate at Day 2, 8, 15, 22 and End of Study | Heart rate was measured in beats per minute. | Baseline, Day 2, 8, 15, 22 and End of Study (Day 52) | 
| Change From Baseline in Vital Sign- Respiratory Rate at Day 8, 15, 22 and End of Study | Respiratory rate was measured in terms of breaths per minute. | Baseline, Day 8, 15, 22 and End of Study (Day 52) | 
| Change From Baseline in Vital Sign- Weight at Day 8, 15, 22 and End of Study |  | Baseline, Day 8, 15, 22 and End of Study (Day 52) | 
| Number of Participants Who Met the Pre-specified 12-Lead Electrocardiogram (ECG) Criteria | Pre-specified 12-Lead electrocardiogram (ECG) Criteria: QTCF (Fridericia's correction formula) : >=450 to <480 milliseconds, >=480 to <500 milliseconds, >=500 milliseconds, increase from baseline >=30 - <60, increase from baseline >=60, PR interval: >=300 milliseconds, increase from baseline >=25%; QRS duration: >=140 milliseconds, increase from baseline >=50%; QT interval: >=500 milliseconds; QT Interval: >= 500 milliseconds. | Baseline up to 30 days after last dose of study drug (up to 52 days) | 
| Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status | As per ECOG, participant's performance status was measured as: 0=fully active/able to carry on all pre-disease activities without restriction; 1= restricted in physically strenuous activity but ambulatory and able to carry out work of a light and sedentary nature, e.g., light housework, office work; 2= ambulatory and capable of all self-care, but unable to carry out any work activities, up and about more than 50% of waking hours; 3=capable of only limited self-care, confined to bed/chair >50% of waking hours; 4=completely disabled, cannot carry on any self-care, totally confined to bed/chair. | Screening (2 to 28 days prior to Day 1), Day -1 (1 day prior to Day 1), safety follow up (Visit up to Day 52) |