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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03077607
Recruitment Status : Completed
First Posted : March 13, 2017
Results First Posted : March 29, 2019
Last Update Posted : March 29, 2019
Sponsor:
Collaborator:
Medivation, Inc.
Information provided by (Responsible Party):
Pfizer

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

Condition or disease Intervention/treatment Phase
Advanced Solid Tumors Drug: Talazoparib Drug: Itraconazole Drug: Rifampin Phase 1

Detailed Description:
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).

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 36 participants
Allocation: Non-Randomized
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : November 7, 2016
Actual Primary Completion Date : December 19, 2017
Actual Study Completion Date : December 19, 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm A
Subjects will receive a 0.5 mg talazoparib and 100 mg itraconazole.
Drug: Talazoparib
Arm A: 0.5 mg oral dose Arm B: 1 mg oral dose

Drug: Itraconazole
100 mg oral dose

Experimental: Arm B
Subjects will receive 1 mg talazoparib and 600 mg rifampin.
Drug: Talazoparib
Arm A: 0.5 mg oral dose Arm B: 1 mg oral dose

Drug: Rifampin
600 mg oral dose




Primary Outcome Measures :
  1. Maximum Observed Plasma Concentration (Cmax) of Talazoparib: Alone and in Combination With Itraconazole [ Time Frame: 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 ]
    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".

  2. Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-last) of Talazoparib: Alone and in Combination With Itraconazole [ Time Frame: 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 ]
    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".

  3. Area Under the Plasma Concentration-Time Profile From Time Zero to Extrapolated Infinity (AUC0-inf) of Talazoparib: Alone and in Combination With Itraconazole [ Time Frame: 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 ]
    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".

  4. Maximum Observed Plasma Concentration (Cmax) of Talazoparib: Alone and in Combination With Rifampin [ Time Frame: 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 ]
    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".

  5. Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-last) of Talazoparib: Alone and in Combination With Rifampin [ Time Frame: 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 ]
    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".

  6. Area Under the Plasma Concentration-Time Curve From Time Zero to Extrapolated Infinite Time (AUC0-inf) of Talazoparib: Alone and in Combination With Rifampin [ Time Frame: 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 ]
    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".


Secondary Outcome Measures :
  1. Time to Attain Maximum Observed Plasma Concentration (Tmax) of Talazoparib: Alone and in Combination With Itraconazole [ Time Frame: 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 ]
    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".

  2. Terminal Elimination Half-Life (t1/2) of Talazoparib: Alone and in Combination With Itraconazole [ Time Frame: 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 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".

  3. Apparent Clearance (CL/F) of Talazoparib: Alone and in Combination With Itraconazole [ Time Frame: 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 ]
    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".

  4. Apparent Volume of Distribution During Terminal Phase (Vz/F) of Talazoparib: Alone and in Combination With Itraconazole [ Time Frame: 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 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".

  5. Time to Attain Maximum Observed Plasma Concentration (Tmax) of Talazoparib: Alone and in Combination With Rifampin [ Time Frame: 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 ]
    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".

  6. Terminal Elimination Half-Life (t1/2) of Talazoparib: Alone and in Combination With Rifampin [ Time Frame: 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 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".

  7. Apparent Volume of Distribution During Terminal Phase (Vz/F) of Talazoparib: Alone and in Combination With Rifampin [ Time Frame: 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 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".

  8. Apparent Clearance (CL/F) of Talazoparib: Alone and in Combination With Rifampin [ Time Frame: 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 ]
    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".

  9. Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Baseline up to end of study (up to 61 days) ]
    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 treatment emergent AE 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.

  10. Number of Participants With Clinical Significance Abnormalities in Laboratory Parameters [ Time Frame: Baseline up to end of study (up to 61 days) ]
    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.

  11. Number of Participants With Clinically Significant Abnormalities in Vital Signs [ Time Frame: Baseline up to end of study (up to 61 days) ]
    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.

  12. Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) [ Time Frame: Baseline up to end of study (up to 61 days) ]
    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.

  13. Number of Participants With Clinically Significant Physical Examination Findings [ Time Frame: Baseline up to end of study (up to 61 days) ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. 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.
  2. 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.
  3. ECOG performance status ≤ 2 at screening and at time of enrollment.
  4. Expected life expectancy of ≥ 3 months.
  5. Able to swallow the study drug and comply with study requirements.
  6. 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.
  7. 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.
  8. Female subjects must not be breastfeeding at screening and during the study participation until 45 days after the last dose of the study drug.
  9. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures.

Exclusion Criteria:

  1. 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
  2. Major surgery within 8 weeks before screening.
  3. Serious accompanying disorder or impaired organ function.
  4. Symptomatic or impending spinal cord compression or cauda equina syndrome.
  5. Non-healing wound, ulcer, or bone fracture, not including a pathological bone fracture caused by a pre-existent pathological bone lesion.
  6. Known myelodysplastic syndrome.
  7. Subjects with the following serologies should be excluded: HBsAg+ or anti-HBc+;HCV+; HIV+.
  8. Serious or unstable medical condition that interferes with ability to tolerate treatment or assessments associated with the protocol.
  9. Gastrointestinal disorder affecting absorption.
  10. Known hypersensitivity to any of the talazoparib capsule components.
  11. 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].

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03077607


Locations
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Hungary
PRA Magyarorszag Kft, Fazis I-es Klinikai Farmakologiai Vizsgalohely
Budapest, Hungary, 1077
Moldova, Republic of
ARENSIA Exploratory Medicine Phase I Unit, PMSI Institute of Oncology
Chisinau, Moldova, Republic of, MD2025
Poland
Szpital LUX MED
Warsaw, Poland, 02-801
Russian Federation
I.M. Sechenov First Moscow State Medical University
Moscow, Russian Federation, 119435
I.M. Sechenov First Moscow State Medical University
Moscow, Russian Federation, 119991
"BioEq" LLC
Saint-Petersburg, Russian Federation, 197342
State budget healthcare institution of Yaroslavl region "Regional clinical oncology hospital"
Yaroslavl, Russian Federation, 150054
Sponsors and Collaborators
Pfizer
Medivation, Inc.
Investigators
Layout table for investigator information
Study Director: Pfizer Pfizer CT.gov Call Center Pfizer
  Study Documents (Full-Text)

Documents provided by Pfizer:
Statistical Analysis Plan  [PDF] January 25, 2018
Study Protocol  [PDF] October 11, 2016


Additional Information:
Layout table for additonal information
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT03077607     History of Changes
Other Study ID Numbers: MDV3800-04
C3441004 ( Other Identifier: Alias Study Number )
2016-001813-26 ( EudraCT Number )
First Posted: March 13, 2017    Key Record Dates
Results First Posted: March 29, 2019
Last Update Posted: March 29, 2019
Last Verified: December 2018

Additional relevant MeSH terms:
Layout table for MeSH terms
Itraconazole
Hydroxyitraconazole
Rifampin
Talazoparib
Antifungal Agents
Anti-Infective Agents
14-alpha Demethylase Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Steroid Synthesis Inhibitors
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Cytochrome P-450 CYP3A Inhibitors
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Leprostatic Agents
Nucleic Acid Synthesis Inhibitors
Cytochrome P-450 CYP2B6 Inducers
Cytochrome P-450 Enzyme Inducers
Cytochrome P-450 CYP2C8 Inducers
Cytochrome P-450 CYP2C19 Inducers
Cytochrome P-450 CYP2C9 Inducers
Cytochrome P-450 CYP3A Inducers
Poly(ADP-ribose) Polymerase Inhibitors
Antineoplastic Agents