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An Open-Label Pharmacokinetics and Safety Study of Talazoparib

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: NCT02997163
Recruitment Status : Completed
First Posted : December 19, 2016
Results First Posted : February 20, 2020
Last Update Posted : January 5, 2021
Sponsor:
Collaborator:
Medivation, Inc.
Information provided by (Responsible Party):
Pfizer

Brief Summary:
This trial will investigate the pharmacokinetics (PK) and safety of talazoparib in patients with advanced solid tumors and impaired renal function.

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

Detailed Description:
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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 34 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : February 21, 2017
Actual Primary Completion Date : January 30, 2019
Actual Study Completion Date : January 30, 2019

Arm Intervention/treatment
Experimental: Group A (control, normal renal function) Drug: Talazoparib
Daily oral doses of talazoparib 0.5 mg
Other Names:
  • MDV3800
  • BMN673

Experimental: Group B (mild renal impairment) Drug: Talazoparib
Daily oral doses of talazoparib 0.5 mg
Other Names:
  • MDV3800
  • BMN673

Experimental: Group C (moderate renal impairment) Drug: Talazoparib
Daily oral doses of talazoparib 0.5 mg
Other Names:
  • MDV3800
  • BMN673

Experimental: Group D (severe renal impairment) Drug: Talazoparib
Daily oral doses of talazoparib 0.5 mg
Other Names:
  • MDV3800
  • BMN673




Primary Outcome Measures :
  1. Multiple Dose: Area Under the Concentration Time Curve From 0 to 24 Hours (AUC0-24) of Talazoparib [ Time Frame: Predose, 0.5, 1, 2, 4, 6, 8 to 12, and 24 hours post-dose on Day 22 ]
    AUC0-24 of talazoparib was defined as the area under the concentration time curve from time 0 to 24 hours post-dose.

  2. Multiple Dose: Maximum Observed Plasma Concentration (Cmax) of Talazoparib [ Time Frame: Predose, 0.5, 1, 2, 4, 6, 8 to 12, and 24 hours post-dose on Day 22 ]
    Cmax was defined as the maximum observed plasma concentration of talazoparib.

  3. Multiple Dose: Area Under the Curve From Time 0 to 24 Hours for Unbound (AUC0-24u) Talazoparib [ Time Frame: Predose, 0.5, 1, 2, 4, 6, 8 to 12, and 24 hours post-dose on Day 22 ]
    AUC0-24u for unbound talazoparib was defined as the area under the concentration time curve from time 0 to 24 hours post-dose.

  4. Multiple Dose: Maximum Observed Plasma Concentration for Unbound (Cmaxu) Talazoparib [ Time Frame: Predose, 0.5, 1, 2, 4, 6, 8 to 12, and 24 hours post-dose on Day 22 ]
    Cmaxu was defined as the maximum observed plasma concentration for unbound talazoparib.


Secondary Outcome Measures :
  1. Single Dose: Area Under the Concentration Time Curve From 0 to 24 Hours (AUC0-24) of Talazoparib [ Time Frame: Predose, 0.5, 1, 2, 4, 6, 8 to 12, and 24 hours post-dose on Day 1 ]
    AUC0-24 of talazoparib was defined as the area under the concentration time curve from time 0 to 24 hours post-dose.

  2. Single Dose: Maximum Observed Plasma Concentration (Cmax) of Talazoparib [ Time Frame: Predose, 0.5, 1, 2, 4, 6, 8 to 12, and 24 hours post-dose on Day 1 ]
    Cmax was defined as the maximum observed plasma concentration of talazoparib.

  3. Single Dose: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Talazoparib [ Time Frame: Predose, 0.5, 1, 2, 4, 6, 8 to 12, and 24 hours post-dose on Day 1 ]
    Tmax was defined as the time to reach maximum observed plasma concentration of talazoparib.

  4. Single Dose: Fraction of Unbound Drug (Fu) in Plasma in Talazoparib [ Time Frame: Predose, 0.5, 1, 2, 4, 6, 8 to 12, and 24 hours post-dose on Day 1 ]
    Fraction of unbound drug (fu) was defined as the ratio of unbound drug concentration to the total drug concentration.

  5. Single Dose: Area Under the Curve From Time 0 to 24 Hour for Unbound (AUC0-24u) Talazoparib [ Time Frame: Predose, 0.5, 1, 2, 4, 6, 8 to 12, and 24 hours post-dose on Day 1 ]
    AUC0-24u for unbound talazoparib was defined as the area under the concentration time curve from time 0 to 24 hours for unbound talazoparib.

  6. Single Dose: Maximum Observed Plasma Concentration for Unbound (Cmaxu) Talazoparib [ Time Frame: Predose, 0.5, 1, 2, 4, 6, 8 to 12, and 24 hours post-dose on Day 1 ]
    Cmaxu was defined as the maximum observed plasma concentration for unbound talazoparib.

  7. Multiple Dose: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Talazoparib [ Time Frame: Predose, 0.5, 1, 2, 4, 6, 8 to 12, and 24 hours post-dose on Day 22 ]
    Tmax was defined as the time to reach maximum observed plasma concentration of talazoparib.

  8. Multiple Dose: Plasma Trough Concentration (Ctrough) of Talazoparib [ Time Frame: Predose on Day 22 ]
    Ctrough was defined as plasma trough (predose) concentration of talazoparib.

  9. Multiple Dose: Apparent Oral Clearance (CL/F) of Talazoparib [ Time Frame: Predose, 0.5, 1, 2, 4, 6, 8 to 12, and 24 hours post-dose on Day 22 ]
    Drug clearance is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.

  10. Multiple Dose: Accumulation Ratio (Rac) of AUC (0-24) [ Time Frame: Pre-dose, 0.5, 1, 2, 4, 6, 8 to 12, and 24 hours post-dose on Day 1 and Day 22 ]
    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.

  11. Multiple Dose: Fraction of Unbound Drug (Fu) in Plasma in Talazoparib [ Time Frame: Predose, 0.5, 1, 2, 4, 6, 8-12, and 24 hours post-dose on Day 22 ]
    Fraction of unbound drug (fu) was defined as the ratio of unbound drug concentration to the total drug concentration.

  12. Multiple Dose: Unbound Apparent Oral Clearance (CLu/F) of Talazoparib [ Time Frame: Predose, 0.5, 1, 2, 4, 6, 8-12, and 24 hours post-dose on Day 22 ]
    Clearance of unbound drug is a measure of the rate at which unbound drug is metabolized or eliminated by normal biological processes.

  13. Single Dose: Amount of Talazoparib Excreted Unchanged in Urine From Time 0 to 24 Hours (Ae 0-24) [ Time Frame: 0 to 24 hours on Day 1 ]
    Ae 0-24 is the amount of drug excreted unchanged in urine from time 0 to 24 hours postdose.

  14. Single Dose: Percentage of Dose of Talazoparib Excreted in Urine From Time 0 to 24 Hours (Ae 0-24%) at Day 1 [ Time Frame: 0 to 24 hours on 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.

  15. Multiple Dose: Amount of Talazoparib Excreted in Urine From Time 0 to 24 Hours (Ae 0-24%) [ Time Frame: 0 to 24 hours on Day 22 ]
    Ae 0-24 is the amount of drug excreted unchanged in urine from time 0 to 24 hours postdose.

  16. Multiple Dose: Percentage of Talazoparib Excreted in Urine From Time 0 to 24 Hours (Ae 0-24 %) of Talazoparib at Day 22 [ Time Frame: 0 to 24 hours on 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.

  17. Multiple Dose: Renal Clearance (CLr) of Talazoparib at Day 22 [ Time Frame: 0 to 24 hours 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 postdose.

  18. Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: Baseline up to 30 days after last dose of study drug (up to 52 days) ]
    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.

  19. Number of Participants With Abnormalities in Physical Examination [ Time Frame: Baseline up to 30 days after last dose of study drug (up to 52 days) ]
    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.

  20. Change From Baseline in Systolic Blood Pressure (SBP) of Participants [ Time Frame: Baseline, Day 8, Day 15, Day 22, Safety follow up (Day 52) ]
  21. Change From Baseline in Diastolic Blood Pressure (DBP) of Participants [ Time Frame: Baseline, Day 8, Day 15, Day 22, Safety follow up (Day 52) ]
  22. Change From Baseline in Heart Rate of Participants [ Time Frame: Baseline, Day 8, Day 15, Day 22, Safety follow up (Day 52) ]
    Heart rate was measured in terms of beats per minute.

  23. Change From Baseline in Respiratory Rate of Participants [ Time Frame: Baseline, Day 8, Day 15, Day 22, Safety follow up (Day 52) ]
    Respiratory rate was measured in terms of breaths per minute.

  24. Change From Baseline in Body Weight of Participants [ Time Frame: Baseline, Day 8, Day 15, Day 22, Safety follow up (Day 52) ]
  25. Number of Participants With Electrocardiogram (ECG) Abnormalities [ Time Frame: Baseline up to 30 days after last dose of study drug (up to 52 days) ]
    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.

  26. Number of Participants With Laboratory Abnormalities [ Time Frame: Baseline up to 30 days after last dose of study drug (up to 52 days) ]
    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.

  27. Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status [ Time Frame: Baseline, Safety follow up (Day 52) ]
    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.



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. 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.
  2. Female or male of at least 18 years of age.
  3. Histologically or cytologically confirmed advanced solid tumor with no available standard approved treatment options in the opinion of the Investigator
  4. Eastern Cooperative Oncology Group (ECOG) Performance status (PS) ≤ 2.
  5. Expected life expectancy of ≥ 3 months.
  6. Able to swallow the study drug (no contra indication to oral agents).
  7. Renal function at screening and enrollment as defined by the Modification of Diet in Renal Disease (MDRD) equation.
  8. 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.
  9. Patient is not currently on hemodialysis and/or peritoneal dialysis for management of chronic kidney disease or acute failure/conditions.
  10. 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.
  11. Adequate other organ function at screening and enrollment.
  12. 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.
  13. 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.
  14. Female patients must not be breastfeeding at screening nor during the study participation until 45 days after the last dose of study drug.
  15. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures.

Exclusion Criteria:

  1. 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.
  2. 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.
  3. Major surgery within 28 days prior to enrollment.
  4. Serious accompanying cardiac disorder.
  5. Active known or suspected brain metastasis or active leptomeningeal disease undergoing or requiring treatment.
  6. Symptomatic or impending spinal cord compression or cauda equina syndrome.
  7. Has undergone a liver transplant, kidney transplant or nephrectomy.
  8. 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.
  9. Known myelodysplastic syndrome.
  10. Seropositive for human immunodeficiency virus (HIV).
  11. Any serious or unstable medical condition that interferes with ability to tolerate treatment or assessments associated with the protocol.
  12. Gastrointestinal disorder affecting absorption.
  13. Known or suspected hypersensitivity to any of the talazoparib capsule components.
  14. 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.

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): NCT02997163


Locations
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United States, Indiana
Fort Wayne Medical Oncology and Hematology, Inc.
Fort Wayne, Indiana, United States, 46804
Fort Wayne Medical Oncology and Hematology, Inc.
Fort Wayne, Indiana, United States, 46845
United States, Michigan
Karmanos Cancer Institute
Detroit, Michigan, United States, 48201
Karmanos Cancer Institute Weisberg Cancer Treatment Center
Farmington Hills, Michigan, United States, 48334
United States, New Jersey
Robert Wood Johnson University Hospital
New Brunswick, New Jersey, United States, 08901
Rutgers Cancer Institute of New Jersey
New Brunswick, New Jersey, United States, 08903
United States, Texas
The University of Texas MD Anderson Cancer Center
Houston, Texas, United States, 77030
Canada, Alberta
Cross Cancer Institute
Edmonton, Alberta, Canada, T6G 1Z2
Canada, Ontario
Juravinski Cancer Centre
Hamilton, Ontario, Canada, L8V 5C2
Canada, Quebec
Jewish General Hospital
Montreal, Quebec, Canada, H3T 1E2
Sponsors and Collaborators
Pfizer
Medivation, Inc.
Investigators
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Study Director: Pfizer CT.gov Call Center Pfizer
  Study Documents (Full-Text)

Documents provided by Pfizer:
Study Protocol  [PDF] August 31, 2018
Statistical Analysis Plan  [PDF] February 28, 2019

Additional Information:
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Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT02997163    
Other Study ID Numbers: MDV3800-01
C3441001 ( Other Identifier: Alias Study Number )
2016-002536-33 ( EudraCT Number )
First Posted: December 19, 2016    Key Record Dates
Results First Posted: February 20, 2020
Last Update Posted: January 5, 2021
Last Verified: December 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Talazoparib
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents