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Safety, Pharmacokinetic (PK), Pharmcodynamic (PD), and Drug-Drug Interaction of PLX3397 in Patients With Rheumatoid Arthritis Who Are Receiving Methotrexate

Primary Purpose

Rheumatoid Arthritis

Status
Withdrawn
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
PLX3397
Sponsored by
Plexxikon
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Rheumatoid Arthritis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Male or female patients ≥ 18 years old with a diagnosis of rheumatoid arthritis by ACR criteria for ≥ 3 months.
  • Prior to Baseline, patients must be on oral or subcutaneous methotrexate (≥ 10 mg/week and ≤ 25 mg/week) for at least 12 weeks (with a stable dose for at least 4 weeks) and folate (≥ 5 mg/week) for at least 6 weeks, and willing to continue on this regimen for the duration of the study.
  • Adequate hematologic, hepatic, and renal function (absolute neutrophil count ≥ 1.5 X 109/L, Hgb > 9 g/dL, platelet count ≥ 100 X 109/L, AST/ALT WNL, albumin ≥ 3 g/dL, calculated CrCl>60 mL/min using Cockcroft-Gault formula).
  • Women of child-bearing potential must have a negative pregnancy test within 7 days prior to initiation of dosing and must agree to use a double barrier method of birth control from the time of the negative pregnancy test up to 30 days after the last dose of study drug. Women of non-childbearing potential may be included if they are either surgically sterile or have been postmenopausal for ≥1 year.
  • Fertile men must agree to use an acceptable method of birth control while on study drug. Acceptable methods of contraception must include either abstinence from the first dose of study drug through 4 weeks after the last dose of study drug, or use of a condom with instructions to the female partner of child-bearing potential to also be protected as above.
  • Willing and able to provide written informed consent prior to any study related procedures and to comply with all study requirements.

Exclusion Criteria:

  • Use of biologic response modifiers within the following periods prior to Day 1 Baseline: 4 weeks for Kineret (anakinra) and Enbrel (etanercept); 12 weeks for Remicade (infliximab), Humira (adalimumab), Simponi (golimumab), Orencia (abatacept), Actemra (tocilizumab), or Cimzia (certolizumab); 12 months for Rituxan.
  • Use of Arava (leflunomide) within 12 weeks prior to Day 1 Baseline or any immunosuppressive agents other then hydroxychloroquine or sulfasalazine within 4 weeks of Day 1 Baseline.
  • Investigational drug use within 4 weeks of Day 1 Baseline.
  • Concomitant use of DMARDs (other than methotrexate), biological response modifiers, or known strong inducers or inhibitors of CYP3A4.
  • Positive HepBsAg or HCV, or presence of clinically significant hepatic or biliary disease.
  • Uncontrolled intercurrent illness.
  • Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude adequate absorption.
  • QTc ≥ 450 msec at Screening.
  • The presence of a medical or psychiatric condition that, in the opinion of the Principal Investigator, makes the patient inappropriate for inclusion in this study.

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Placebo Comparator

Arm Label

PLX3397 25 mg

PLX3397 50 mg

PLX3397 100 mg

PLX3397 200 mg

PLX3397 300 mg

Placebo

Arm Description

Outcomes

Primary Outcome Measures

To assess the drug-drug interaction of PLX3397 and Methotrexate in patients with rheumatoid arthritis
Blood samples will be taken at multiple time points during the 2 week time frame plus a 2 week follow up time frame to study the pharmacokinetics of PLX3397 and Methotrexate in patients.

Secondary Outcome Measures

To assess the safety and tolerability of PLX3397 when taken once daily with concomitant methotrexate administration
Adverse events and safety lab tests (including a hematology panel, blood chemistry panel, coagulation and urinalysis) will be monitored throughout the study time frame.
To assess the pharmacokinetics of PLX3397 when taken once daily for 2 weeks at either a 25, 50, 100, 200 or 300 mg dose.
The pharmacokinetic profile of plasma PLX3397 will be analyzed by measurement of area under the plasma concentration-time curve (AUC0-t, AUC0-inf), peak concentration (Cmax), time to peak concentration (Tmax), half-life (t1/2), and terminal elimination rate constant (Kel).
To assess the pharmacodynamics of PLX3397 when taken once daily for 2 weeks at either a 25, 50, 100, 200 or 300 mg dose.
Measured by looking at the factors in the blood that may include, but are not limited to pro- and anti-inflammatory cytokines and mediators of the inflammatory process that may correlate with the activity of the disease and the response to PLX3397 in combination with methotrexate

Full Information

First Posted
March 15, 2010
Last Updated
March 13, 2015
Sponsor
Plexxikon
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1. Study Identification

Unique Protocol Identification Number
NCT01090570
Brief Title
Safety, Pharmacokinetic (PK), Pharmcodynamic (PD), and Drug-Drug Interaction of PLX3397 in Patients With Rheumatoid Arthritis Who Are Receiving Methotrexate
Study Type
Interventional

2. Study Status

Record Verification Date
March 2015
Overall Recruitment Status
Withdrawn
Study Start Date
May 2010 (undefined)
Primary Completion Date
December 2010 (Anticipated)
Study Completion Date
undefined (undefined)

3. Sponsor/Collaborators

Name of the Sponsor
Plexxikon

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
PLX3397 is a selective inhibitor of Fms and Kit activity. The objective of this study is to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and drug-drug interaction (DDI) of orally administered PLX3397 during 2 weeks of dosing in patients with rheumatoid arthritis (RA) who are on maintenance methotrexate. This study is planned to provide data to inform dose selection for a subsequent 12 week dose ranging study in RA.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Rheumatoid Arthritis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
0 (Actual)

8. Arms, Groups, and Interventions

Arm Title
PLX3397 25 mg
Arm Type
Experimental
Arm Title
PLX3397 50 mg
Arm Type
Experimental
Arm Title
PLX3397 100 mg
Arm Type
Experimental
Arm Title
PLX3397 200 mg
Arm Type
Experimental
Arm Title
PLX3397 300 mg
Arm Type
Experimental
Arm Title
Placebo
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
PLX3397
Intervention Description
Once-daily oral capsules
Primary Outcome Measure Information:
Title
To assess the drug-drug interaction of PLX3397 and Methotrexate in patients with rheumatoid arthritis
Description
Blood samples will be taken at multiple time points during the 2 week time frame plus a 2 week follow up time frame to study the pharmacokinetics of PLX3397 and Methotrexate in patients.
Time Frame
2 weeks + 2 weeks follow up
Secondary Outcome Measure Information:
Title
To assess the safety and tolerability of PLX3397 when taken once daily with concomitant methotrexate administration
Description
Adverse events and safety lab tests (including a hematology panel, blood chemistry panel, coagulation and urinalysis) will be monitored throughout the study time frame.
Time Frame
4 weeks
Title
To assess the pharmacokinetics of PLX3397 when taken once daily for 2 weeks at either a 25, 50, 100, 200 or 300 mg dose.
Description
The pharmacokinetic profile of plasma PLX3397 will be analyzed by measurement of area under the plasma concentration-time curve (AUC0-t, AUC0-inf), peak concentration (Cmax), time to peak concentration (Tmax), half-life (t1/2), and terminal elimination rate constant (Kel).
Time Frame
2 weeks
Title
To assess the pharmacodynamics of PLX3397 when taken once daily for 2 weeks at either a 25, 50, 100, 200 or 300 mg dose.
Description
Measured by looking at the factors in the blood that may include, but are not limited to pro- and anti-inflammatory cytokines and mediators of the inflammatory process that may correlate with the activity of the disease and the response to PLX3397 in combination with methotrexate
Time Frame
4 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male or female patients ≥ 18 years old with a diagnosis of rheumatoid arthritis by ACR criteria for ≥ 3 months. Prior to Baseline, patients must be on oral or subcutaneous methotrexate (≥ 10 mg/week and ≤ 25 mg/week) for at least 12 weeks (with a stable dose for at least 4 weeks) and folate (≥ 5 mg/week) for at least 6 weeks, and willing to continue on this regimen for the duration of the study. Adequate hematologic, hepatic, and renal function (absolute neutrophil count ≥ 1.5 X 109/L, Hgb > 9 g/dL, platelet count ≥ 100 X 109/L, AST/ALT WNL, albumin ≥ 3 g/dL, calculated CrCl>60 mL/min using Cockcroft-Gault formula). Women of child-bearing potential must have a negative pregnancy test within 7 days prior to initiation of dosing and must agree to use a double barrier method of birth control from the time of the negative pregnancy test up to 30 days after the last dose of study drug. Women of non-childbearing potential may be included if they are either surgically sterile or have been postmenopausal for ≥1 year. Fertile men must agree to use an acceptable method of birth control while on study drug. Acceptable methods of contraception must include either abstinence from the first dose of study drug through 4 weeks after the last dose of study drug, or use of a condom with instructions to the female partner of child-bearing potential to also be protected as above. Willing and able to provide written informed consent prior to any study related procedures and to comply with all study requirements. Exclusion Criteria: Use of biologic response modifiers within the following periods prior to Day 1 Baseline: 4 weeks for Kineret (anakinra) and Enbrel (etanercept); 12 weeks for Remicade (infliximab), Humira (adalimumab), Simponi (golimumab), Orencia (abatacept), Actemra (tocilizumab), or Cimzia (certolizumab); 12 months for Rituxan. Use of Arava (leflunomide) within 12 weeks prior to Day 1 Baseline or any immunosuppressive agents other then hydroxychloroquine or sulfasalazine within 4 weeks of Day 1 Baseline. Investigational drug use within 4 weeks of Day 1 Baseline. Concomitant use of DMARDs (other than methotrexate), biological response modifiers, or known strong inducers or inhibitors of CYP3A4. Positive HepBsAg or HCV, or presence of clinically significant hepatic or biliary disease. Uncontrolled intercurrent illness. Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude adequate absorption. QTc ≥ 450 msec at Screening. The presence of a medical or psychiatric condition that, in the opinion of the Principal Investigator, makes the patient inappropriate for inclusion in this study.
Facility Information:
City
Tuscaloosa
State/Province
Alabama
Country
United States
City
Little Rock
State/Province
Arkansas
Country
United States
City
San Francisco
State/Province
California
Country
United States
City
Altoona
State/Province
Pennsylvania
Country
United States
City
Dallas
State/Province
Texas
Country
United States

12. IPD Sharing Statement

Learn more about this trial

Safety, Pharmacokinetic (PK), Pharmcodynamic (PD), and Drug-Drug Interaction of PLX3397 in Patients With Rheumatoid Arthritis Who Are Receiving Methotrexate

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