A Study to Evaluate the Effect of Itraconazole and Rifampin on the Pharmacokinetics of Talazoparib in Patients With Advanced Solid Tumors

Study Overview
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Brief Summary
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This is a study in patients with advanced solid tumors for the investigation of P-gp inhibition and induction on the PK of talazoparib.

Detailed Description
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Subjects participating in this study with no clinically significant toxicities and no disease progression may be eligible to continue treatment on a separate extension protocol (MDV3800-13).

Official Title
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A PHASE 1 OPEN-LABEL, TWO-ARM,DRUG-DRUG INTERACTION STUDY TO EVALUATE THE EFFECT OF ITRACONAZOLE AND RIFAMPIN ON THE PHARMACOKINETICS OF TALAZOPARIB IN PATIENTS WITH ADVANCED SOLID TUMORS

Conditions
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Advanced Solid Tumors

Intervention / Treatment
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* Drug: Talazoparib
* Drug: Itraconazole
* Drug: Rifampin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Arm A: At least 18 years of age and <65 years of age (at the time point of consent) and willing and able to provide informed consent. Arm B: At least 18 years of age (at the time point of consent) and willing and able to provide informed consent. Histologically confirmed advanced solid tumor (limited to platinum-resistant ovarian carcinoma, cervical adenocarcinoma, small cell lung carcinoma or triple-negative breast cancer) judged by the Investigator to not be appropriate for standard therapy. ECOG performance status ≤ 2 at screening and at time of enrollment. Expected life expectancy of ≥ 3 months. Able to swallow the study drug and comply with study requirements. Female subjects may be enrolled if they are considered not of childbearing potential, or who are post-menopausal, or are of childbearing potential using a highly effective form of contraceptive, and female subjects should not donate eggs from the time point of investigational medicinal product (IMP) administration until at least 45 days thereafter. Males with partners of childbearing potential may be enrolled if they use a condom when having sex with a pregnant woman or with a woman of childbearing potential, and do not donate sperm from the time point of study drug administration until at least 105 days thereafter, and males should not donate sperm from the time point of study drug administration until at least 105 days thereafter. Female subjects must not be breastfeeding at screening and during the study participation until 45 days 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 5 half lives prior to dosing with any type of systemic anticancer therapy or any investigational agent, whichever is longer Major surgery within 8 weeks before screening. Serious accompanying disorder or impaired organ function. Symptomatic or impending spinal cord compression or cauda equina syndrome. Non-healing wound, ulcer, or bone fracture, not including a pathological bone fracture caused by a pre-existent pathological bone lesion. Known myelodysplastic syndrome. Subjects with the following serologies should be excluded: HBsAg+ or anti-HBc+;HCV+; HIV+. Serious or unstable medical condition that interferes with ability to tolerate treatment or assessments associated with the protocol. Gastrointestinal disorder affecting absorption. Known hypersensitivity to any of the talazoparib capsule components. Any condition or reason that interferes with ability to participate in the study, causes undue risk, or complicates the interpretation of safety data, in the opinion of the Investigator or Sponsor (e.g. non-compliance, excessive alcohol consumption, intake of drugs of abuse unless these drugs are medically indicated [e.g. opiates for pain relief].

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>Subjects will receive a 0.5 mg talazoparib and 100 mg itraconazole. | Drug: Talazoparib<br>* Arm A: 0.5 mg oral dose Arm B: 1 mg oral dose<br>Drug: Itraconazole<br>* 100 mg oral dose<br>|
| Experimental: Arm B<br>Subjects will receive 1 mg talazoparib and 600 mg rifampin. | Drug: Talazoparib<br>* Arm A: 0.5 mg oral dose Arm B: 1 mg oral dose<br>Drug: Rifampin<br>* 600 mg oral dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) of Talazoparib: Alone and in Combination With Itraconazole | T1= Time frame for Talazoparib 0.5 mg Alone and T2= time frame for Talazoparib 0.5 mg in Combination With Itraconazole 100 mg BID. | T1=Predose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264 and 336 hours post Talazoparib dose on Day 1; T2=Predose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264 and 336 hours post Talazoparib dose on Day 23 | 
| Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-last) of Talazoparib: Alone and in Combination With Itraconazole | T1= Time frame for Talazoparib 0.5 mg Alone and T2= time frame for Talazoparib 0.5 mg in Combination With Itraconazole 100 mg BID. | T1=Predose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264 and 336 hours post Talazoparib dose on Day 1; T2=Predose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264 and 336 hours post Talazoparib dose on Day 23 | 
| Area Under the Plasma Concentration-Time Profile From Time Zero to Extrapolated Infinity (AUC0-inf) of Talazoparib: Alone and in Combination With Itraconazole | T1= Time frame for Talazoparib 0.5 mg Alone and T2= time frame for Talazoparib 0.5 mg in Combination With Itraconazole 100 mg BID. | T1=Predose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264 and 336 hours post Talazoparib dose on Day 1; T2=Predose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264 and 336 hours post Talazoparib dose on Day 23 | 
| Maximum Observed Plasma Concentration (Cmax) of Talazoparib: Alone and in Combination With Rifampin | T3= Time frame for Talazoparib 1.0 mg Alone and T4= time frame for Talazoparib 1.0 mg in Combination With Rifampin 600 mg QD. | T3=Predose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264 and 336 hours post Talazoparib dose on Day 1; T4=Predose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264 and 336 hours post Talazoparib dose on Day 25 | 
| Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-last) of Talazoparib: Alone and in Combination With Rifampin | T3= Time frame for Talazoparib 1.0 mg Alone and T4= time frame for Talazoparib 1.0 mg in Combination With Rifampin 600 mg QD. | T3=Predose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264 and 336 hours post Talazoparib dose on Day 1; T4=Predose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264 and 336 hours post Talazoparib dose on Day 25 | 
| Area Under the Plasma Concentration-Time Curve From Time Zero to Extrapolated Infinite Time (AUC0-inf) of Talazoparib: Alone and in Combination With Rifampin | T3= Time frame for Talazoparib 1.0 mg Alone and T4= time frame for Talazoparib 1.0 mg in Combination With Rifampin 600 mg QD. | T3=Predose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264 and 336 hours post Talazoparib dose on Day 1; T4=Predose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264 and 336 hours post Talazoparib dose on Day 25 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Attain Maximum Observed Plasma Concentration (Tmax) of Talazoparib: Alone and in Combination With Itraconazole | T1= Time frame for Talazoparib 0.5 mg Alone and T2= time frame for Talazoparib 0.5 mg in Combination With Itraconazole 100 mg BID. | T1=Predose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264 and 336 hours post Talazoparib dose on Day 1; T2=Predose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264 and 336 hours post Talazoparib dose on Day 23 | 
| Terminal Elimination Half-Life (t1/2) of Talazoparib: Alone and in Combination With Itraconazole | Terminal elimination half-life was defined as time measured for the plasma concentration of talazoparib to decrease by one half. T1= Time frame for Talazoparib 0.5 mg Alone and T2= time frame for Talazoparib 0.5 mg in Combination With Itraconazole 100 mg BID. | T1=Predose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264 and 336 hours post Talazoparib dose on Day 1; T2=Predose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264 and 336 hours post Talazoparib dose on Day 23 | 
| Apparent Clearance (CL/F) of Talazoparib: Alone and in Combination With Itraconazole | Clearance of talazoparib was measure of the rate at which it was metabolized or eliminated by normal biological processes. T1= Time frame for Talazoparib 0.5 mg Alone and T2= time frame for Talazoparib 0.5 mg in Combination With Itraconazole 100 mg BID. | T1=Predose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264 and 336 hours post Talazoparib dose on Day 1; T2=Predose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264 and 336 hours post Talazoparib dose on Day 23 | 
| Apparent Volume of Distribution During Terminal Phase (Vz/F) of Talazoparib: Alone and in Combination With Itraconazole | Apparent volume of distribution was defined as the theoretical volume in which the total amount of talazoparib would need to be uniformly distributed to produce its desired plasma concentration. T1= Time frame for Talazoparib 0.5 mg Alone and T2= time frame for Talazoparib 0.5 mg in Combination With Itraconazole 100 mg BID. | T1=Predose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264 and 336 hours post Talazoparib dose on Day 1; T2=Predose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264 and 336 hours post Talazoparib dose on Day 23 | 
| Time to Attain Maximum Observed Plasma Concentration (Tmax) of Talazoparib: Alone and in Combination With Rifampin | T3= Time frame for Talazoparib 1.0 mg Alone and T4= time frame for Talazoparib 1.0 mg in Combination With Rifampin 600 mg QD. | T3=Predose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264 and 336 hours post Talazoparib dose on Day 1; T4=Predose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264 and 336 hours post Talazoparib dose on Day 25 | 
| Terminal Elimination Half-Life (t1/2) of Talazoparib: Alone and in Combination With Rifampin | Terminal elimination half-life was defined as time measured for the plasma concentration of talazoparib to decrease by one half. T3= Time frame for Talazoparib 1.0 mg Alone and T4= time frame for Talazoparib 1.0 mg in Combination With Rifampin 600 mg QD. | T3=Predose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264 and 336 hours post Talazoparib dose on Day 1; T4=Predose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264 and 336 hours post Talazoparib dose on Day 25 | 
| Apparent Volume of Distribution During Terminal Phase (Vz/F) of Talazoparib: Alone and in Combination With Rifampin | Apparent volume of distribution was defined as the theoretical volume in which the total amount of talazoparib would need to be uniformly distributed to produce its desired plasma concentration. T3= Time frame for Talazoparib 1.0 mg Alone and T4= time frame for Talazoparib 1.0 mg in Combination With Rifampin 600 mg QD. | T3=Predose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264 and 336 hours post Talazoparib dose on Day 1; T4=Predose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264 and 336 hours post Talazoparib dose on Day 25 | 
| Apparent Clearance (CL/F) of Talazoparib: Alone and in Combination With Rifampin | Clearance of talazoparib was measure of the rate at which it was metabolized or eliminated by normal biological processes. T3= Time frame for Talazoparib 1.0 mg Alone and T4= time frame for Talazoparib 1.0 mg in Combination With Rifampin 600 mg QD. | T3=Predose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264 and 336 hours post Talazoparib dose on Day 1; T4=Predose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264 and 336 hours post Talazoparib dose on Day 25 | 
| 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 study treatment without regard to possibility of causal relationship. An 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 or incapacity, congenital anomaly. A TEAE was defined as an event that emerged during the treatment period that was absent before treatment, or worsened during the treatment period relative to the pre-treatment state. AEs included both serious and non-serious adverse events. | Baseline up to end of study (up to 61 days) | 
| Number of Participants With Clinical Significance Abnormalities in Laboratory Parameters | Chemistry:(sodium135-146,potassium3.5-5.5,chloride95-109,glucose3.3-5.5,urea2.8-7.2,calcium2.2-2.65,phosphate0.8-1.45,triglyceride0.4-1.7,cholesterol2.6-5.2)millimoles/L, (bilirubin[direct0-3,total2-21],creatinine53- 110)micromole/L, (albumin35-52,protein65-83)g/L,(alkaline phosphatase30-120, aspartate amino[A]transferase[T]4-46, alanine AT4-49, lactic acid dehydrogenase200-460, gammaglutamylT7-50,creatinine kinase24-170)U/L. Hematology: hemoglobin(Hb)120-177, hematocrit0.35-0.49L/L, RBC4-5.9T/L, (platelet150- 400,WBC4-10,basophil<0.10,eosinophil<0.40, neutrophil1.50-7.00,monocyte<1.20,lymphocyte1.0 -3.70)G/L. Urine:(glucose,protein,ketone,Hb:negative/positive), specific gravity1.010-1.030g/cm^3, pH4.8-7.8, pale yellow-deep amber, microscopy[WBC0-5,leukocyte0-5,Hb0-3,cast0-1,bacteria0-500,epithelial0-6])Pcs/area. Coagulation:(activated partial thromboplastine time25-43,prothrombin time13.7-15.6) seconds,international normalized ratio0.89-1.1. Investigator judged clinical significance. | Baseline up to end of study (up to 61 days) | 
| Number of Participants With Clinically Significant Abnormalities in Vital Signs | Vital sign abnormalities: a) systolic blood pressure (SBP): 1) minimum less than (<) 90 millimeter of mercury (mmHg), 2) change from baseline maximum decrease greater than equal to (>=) 30 mmHg, 3) change from baseline maximum increase >=30 mmHg; b) diastolic blood pressure (DBP): 1) minimum <50 mmHg, 2) change from baseline maximum decrease >=20 mmHg, 3) change from baseline maximum increase >=20 mmHg; c) supine pulse rate: 1) minimum <40 beats per minute (bpm), 2) maximum >120 bpm; d) standing pulse rate: 1) minimum <40 bpm and 2) maximum >140 bpm. Clinical significance of vital signs abnormalities was judged by investigator. | Baseline up to end of study (up to 61 days) | 
| Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) | ECG abnormalities: a) QT Interval: new absolute values greater than (>) 450, >480, >500 milliseconds (msec), increase from baseline >30 and >60 msec, b) QT interval using Fridericia's correction (QTcF) Interval: new absolute values >450, >480, >500 msec, increase from baseline >30 and > 60 msec, c) Heart rate: increase from baseline >25 percentage (%) and to a value >100 bpm, decrease from baseline >25% and to a value <50 bpm, d) PR Interval: increase from baseline > 25% and to a value >200 msec, e) QRS duration: increase from baseline > 25% and to a value >100 msec. Clinical significance of ECG abnormalities was judged by investigator. | Baseline up to end of study (up to 61 days) | 
| Number of Participants With Clinically Significant Physical Examination Findings | Physical examination included examination of abdomen, cardiovascular, eyes, ears, nose, throat, general appearance, head, neck, thyroid, lymph nodes, musculoskeletal, neurological, skin / subcutaneous tissue, thorax / lungs, abdomen including spleen size, breasts (female only) and respiratory. Clinical significance of physical examination was judged by investigator. | Baseline up to end of study (up to 61 days) |