An Open-Label Pharmacokinetics and Safety Study of Talazoparib

Study Overview
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Brief Summary
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This trial will investigate the pharmacokinetics (PK) and safety of talazoparib in patients with advanced solid tumors and impaired renal 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 after discussion with the Principal Investigator and obtaining Sponsor permission. Sponsor decision to allow the patient to continue dosing with talazoparib in an open-label extension study will be based on potential overall benefit-risk, patient acceptance and other relevant criteria.

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 RENAL 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) obtained prior to initiation of any study-specific procedure and treatment. Female or male of at least 18 years of age. Histologically or cytologically confirmed advanced solid tumor with no available standard approved treatment options in the opinion of the Investigator Eastern Cooperative Oncology Group (ECOG) Performance status (PS) ≤ 2. Expected life expectancy of ≥ 3 months. Able to swallow the study drug (no contra indication to oral agents). Renal function at screening and enrollment as defined by the Modification of Diet in Renal Disease (MDRD) equation. Patient has had no clinically significant change in renal status within 3 months prior to screening, according to Investigator's review of clinical patient records. Patient is not currently on hemodialysis and/or peritoneal dialysis for management of chronic kidney disease or acute failure/conditions. Patient has no unstable renal function, defined as a change in estimated glomerular filtration rate (eGFR) (calculated with the MDRD equation) of > 25% for patients with mild and moderate renal impaired or as a change in eGFR > 30% for patients with severe renal impaired, from screening to enrollment. 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 birth control method from the time of the first dose of study drug through 45 days 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 105 days after last dose of study drug. Female patients must not be breastfeeding at screening nor during the study participation until 45 days after the last dose of 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 with any type of systemic anticancer-therapy or any investigational drug, whichever is longer. 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 undergoing or requiring treatment. Symptomatic or impending spinal cord compression or cauda equina 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 renal function)<br> | Drug: Talazoparib<br>* Daily oral doses of talazoparib 0.5 mg<br>* Other names: BMN673;|
| Experimental: Group B (mild renal impairment)<br> | Drug: Talazoparib<br>* Daily oral doses of talazoparib 0.5 mg<br>* Other names: BMN673;|
| Experimental: Group C (moderate renal impairment)<br> | Drug: Talazoparib<br>* Daily oral doses of talazoparib 0.5 mg<br>* Other names: BMN673;|
| Experimental: Group D (severe renal impairment)<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 |
| --- | --- | --- |
| Multiple Dose: Area Under the Concentration Time Curve From 0 to 24 Hours (AUC0-24) of Talazoparib | AUC0-24 of talazoparib was defined as the area under the concentration time curve from time 0 to 24 hours post-dose. | Predose, 0.5, 1, 2, 4, 6, 8 to 12, and 24 hours post-dose on Day 22 | 
| Multiple Dose: Maximum Observed Plasma Concentration (Cmax) of Talazoparib | Cmax was defined as the maximum observed plasma concentration of talazoparib. | Predose, 0.5, 1, 2, 4, 6, 8 to 12, and 24 hours post-dose on Day 22 | 
| Multiple Dose: Area Under the Curve From Time 0 to 24 Hours for Unbound (AUC0-24u) Talazoparib | AUC0-24u for unbound talazoparib was defined as the area under the concentration time curve from time 0 to 24 hours post-dose. | Predose, 0.5, 1, 2, 4, 6, 8 to 12, and 24 hours post-dose on Day 22 | 
| Multiple Dose: Maximum Observed Plasma Concentration for Unbound (Cmaxu) Talazoparib | Cmaxu was defined as the maximum observed plasma concentration for unbound talazoparib. | Predose, 0.5, 1, 2, 4, 6, 8 to 12, and 24 hours post-dose on Day 22 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Single Dose: Area Under the Concentration Time Curve From 0 to 24 Hours (AUC0-24) of Talazoparib | AUC0-24 of talazoparib was defined as the area under the concentration time curve from time 0 to 24 hours post-dose. | Predose, 0.5, 1, 2, 4, 6, 8 to 12, and 24 hours post-dose on Day 1 | 
| Single Dose: Maximum Observed Plasma Concentration (Cmax) of Talazoparib | Cmax was defined as the maximum observed plasma concentration of talazoparib. | Predose, 0.5, 1, 2, 4, 6, 8 to 12, and 24 hours post-dose on Day 1 | 
| Single Dose: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Talazoparib | Tmax was defined as the time to reach maximum observed plasma concentration of talazoparib. | Predose, 0.5, 1, 2, 4, 6, 8 to 12, and 24 hours post-dose on Day 1 | 
| Single Dose: Fraction of Unbound Drug (Fu) in Plasma in Talazoparib | Fraction of unbound drug (fu) was defined as the ratio of unbound drug concentration to the total drug concentration. | Predose, 0.5, 1, 2, 4, 6, 8 to 12, and 24 hours post-dose on Day 1 | 
| Single Dose: Area Under the Curve From Time 0 to 24 Hour for Unbound (AUC0-24u) Talazoparib | AUC0-24u for unbound talazoparib was defined as the area under the concentration time curve from time 0 to 24 hours for unbound talazoparib. | Predose, 0.5, 1, 2, 4, 6, 8 to 12, and 24 hours post-dose on Day 1 | 
| Single Dose: Maximum Observed Plasma Concentration for Unbound (Cmaxu) Talazoparib | Cmaxu was defined as the maximum observed plasma concentration for unbound talazoparib. | Predose, 0.5, 1, 2, 4, 6, 8 to 12, and 24 hours post-dose on Day 1 | 
| Multiple Dose: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Talazoparib | Tmax was defined as the time to reach maximum observed plasma concentration of talazoparib. | Predose, 0.5, 1, 2, 4, 6, 8 to 12, and 24 hours post-dose on Day 22 | 
| Multiple Dose: Plasma Trough Concentration (Ctrough) of Talazoparib | Ctrough was defined as plasma trough (predose) concentration of talazoparib. | Predose on Day 22 | 
| Multiple Dose: Apparent Oral Clearance (CL/F) of Talazoparib | Drug clearance is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. | Predose, 0.5, 1, 2, 4, 6, 8 to 12, and 24 hours post-dose on Day 22 | 
| Multiple Dose: Accumulation Ratio (Rac) of AUC (0-24) | 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, 0.5, 1, 2, 4, 6, 8 to 12, and 24 hours post-dose on Day 1 and Day 22 | 
| Multiple Dose: Fraction of Unbound Drug (Fu) in Plasma in Talazoparib | Fraction of unbound drug (fu) was defined as the ratio of unbound drug concentration to the total drug concentration. | Predose, 0.5, 1, 2, 4, 6, 8-12, and 24 hours post-dose on Day 22 | 
| Multiple Dose: Unbound Apparent Oral Clearance (CLu/F) of Talazoparib | Clearance of unbound drug is a measure of the rate at which unbound drug is metabolized or eliminated by normal biological processes. | Predose, 0.5, 1, 2, 4, 6, 8-12, and 24 hours post-dose on Day 22 | 
| Single Dose: Amount of Talazoparib Excreted Unchanged in Urine From Time 0 to 24 Hours (Ae 0-24) | Ae 0-24 is the amount of drug excreted unchanged in urine from time 0 to 24 hours postdose. | 0 to 24 hours on Day 1 | 
| Single Dose: Percentage of Dose of Talazoparib Excreted in Urine From Time 0 to 24 Hours (Ae 0-24%) at Day 1 | Ae0-24% was defined as the amount of drug excreted in urine from time 0 to 24 hours expressed as percentage of administered dose. | 0 to 24 hours on Day 1 | 
| Multiple Dose: Amount of Talazoparib Excreted in Urine From Time 0 to 24 Hours (Ae 0-24%) | Ae 0-24 is the amount of drug excreted unchanged in urine from time 0 to 24 hours postdose. | 0 to 24 hours on Day 22 | 
| Multiple Dose: Percentage of Talazoparib Excreted in Urine From Time 0 to 24 Hours (Ae 0-24 %) of Talazoparib at Day 22 | Ae 0-24% was defined as the amount of drug excreted in urine from time 0 to 24 hours, expressed as percentage of administered dose. | 0 to 24 hours on Day 22 | 
| Multiple Dose: Renal Clearance (CLr) of Talazoparib at 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 postdose. | 0 to 24 hours on Day 22 | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | An AE was any untoward medical occurrence in a participant who received investigational product without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; medically important events. Treatment-emergent were events between first dose of investigational product and up to 30 days after the last dose of investigational product (up to 52 days) that were absent before treatment or that worsened relative to pretreatment state. AEs included both SAEs and non-SAEs. | Baseline up to 30 days after last dose of study drug (up to 52 days) | 
| Number of Participants With Abnormalities in Physical Examination | Physical examination included examination of the general appearance, head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. Findings were considered to be abnormal based on investigator's decision. | Baseline up to 30 days after last dose of study drug (up to 52 days) | 
| Change From Baseline in Systolic Blood Pressure (SBP) of Participants |  | Baseline, Day 8, Day 15, Day 22, Safety follow up (Day 52) | 
| Change From Baseline in Diastolic Blood Pressure (DBP) of Participants |  | Baseline, Day 8, Day 15, Day 22, Safety follow up (Day 52) | 
| Change From Baseline in Heart Rate of Participants | Heart rate was measured in terms of beats per minute. | Baseline, Day 8, Day 15, Day 22, Safety follow up (Day 52) | 
| Change From Baseline in Respiratory Rate of Participants | Respiratory rate was measured in terms of breaths per minute. | Baseline, Day 8, Day 15, Day 22, Safety follow up (Day 52) | 
| Change From Baseline in Body Weight of Participants |  | Baseline, Day 8, Day 15, Day 22, Safety follow up (Day 52) | 
| Number of Participants With Electrocardiogram (ECG) Abnormalities | ECG parameters included pulse rate (PR) interval, QRS duration, QT interval and corrected QT interval using Fridericia's formula (QTcF). Abnormality criteria: 1) PR interval: greater than equal to (>=) 25 percent (%) increase when baseline >= 300 msec; 2) QRS duration: >=50% increase when baseline >=140 msec; 3) QT interval: >= 500 msec: 4) QTCF interval: QTc interval using Fridericia's formula (QTcF interval) >= 500 msec when baseline >= 60. IFB stands for increase from baseline. | Baseline up to 30 days after last dose of study drug (up to 52 days) | 
| Number of Participants With Laboratory Abnormalities | Laboratory parameters: erythrocytes, hematocrit, hemoglobin, white blood cells, absolute neutrophil count, lymphocytes, platelets ; albumin, alkaline phosphatase, alanine aminotransferase, aspartate transaminase , bilirubin, bicarbonate, blood urea nitrogen , calcium, chloride, creatinine, gamma -glutamyl transferase, glucose, lactate dehydrogenase, sodium, phosphate, potassium, total protein, uric acid, follicle-stimulating hormone; international normalized ratio / prothrombin time [activated] partial thromboplastin time; Urinalysis (pH, specific gravity, protein, glucose, ketones, bilirubin, blood, leukocyte esterase); Serum pregnancy test; Serology for Human Immunodeficiency Virus (HIV). Number of participants with laboratory test abnormalities as per National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) version 4.03 were reported: Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling. | 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 on 5 point scale: 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: 5: dead. | Baseline, Safety follow up (Day 52) |