Clinical Trials /

Study of PTC299 in Relapsed/Refractory Acute Leukemias

NCT03761069

Description:

This is an open-label, non-randomized, Phase 1b study to evaluate the safety, pharmacokinetics (PK) profiles, and preliminary evidence of antitumor activity of PTC299 and the metabolite, O-desmethyl PTC299, in participants with relapsed/refractory acute myeloid leukemia (AML) who have exhausted standard available therapies known to provide clinical benefit. The study is designed as a series of cohort-based dose escalations. For each cohort, a minimum of 3 evaluable participants with PK and safety data will be assessed. Additional participants will be recruited if additional PK data are needed to assess mean exposure based on the observed variability.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of PTC299 in Relapsed/Refractory Acute Leukemias
  • Official Title: Phase 1B Study of PTC299 in Relapsed/Refractory Acute Leukemias

Clinical Trial IDs

  • ORG STUDY ID: PTC299-HEM-001-LEU
  • NCT ID: NCT03761069

Conditions

  • Leukemia, Myeloid, Acute
  • AML

Interventions

DrugSynonymsArms
PTC299PTC299

Purpose

This is an open-label, non-randomized, Phase 1b study to evaluate the safety, pharmacokinetics (PK) profiles, and preliminary evidence of antitumor activity of PTC299 and the metabolite, O-desmethyl PTC299, in participants with relapsed/refractory acute myeloid leukemia (AML) who have exhausted standard available therapies known to provide clinical benefit. The study is designed as a series of cohort-based dose escalations. For each cohort, a minimum of 3 evaluable participants with PK and safety data will be assessed. Additional participants will be recruited if additional PK data are needed to assess mean exposure based on the observed variability.

Trial Arms

NameTypeDescriptionInterventions
PTC299ExperimentalPTC299 will be administered orally once daily (QD) for each 28-day cycle.
  • PTC299

Eligibility Criteria

        Inclusion Criteria:

          -  Participant must have relapsed/refractory AML and exhausted standard available
             therapies known to provide clinical benefit.

          -  Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to (≤)
             2

          -  Women of childbearing potential must be willing to practice a highly-effective method
             of birth control for up to 50 days after the last dose of study drug.

          -  A man who is sexually active with a woman of childbearing potential and has not had a
             vasectomy must agree to use a barrier method of birth control during the study and for
             up to 50 days after the last dose of study drug.

          -  Participants must be willing to participate to the study, have the ability to
             understand and adhere to study visit schedule and other protocol procedures, and be
             able and willing to sign a written informed consent form.

        Exclusion Criteria:

        Medical history:

          -  Women who are or plan to become pregnant, or who are currently breastfeeding.

          -  Persistence of any clinically relevant (Common Terminology Criteria for Adverse Events
             [CTCAE] Grade 2 or above) toxicities from previous therapy.

          -  Active alcohol or drug abuse.

          -  Previous drug-induced liver injury.

        Cardiac assessments:

          -  Uncontrolled congestive heart failure, unstable angina pectoris.

          -  History or current evidence of a myocardial infarction during the last 6 months.

          -  QTc prolongation greater than (>) 500 milliseconds (msec) (Fridericia formula).

          -  Congenitally long QT syndrome or has received any marketed or experimental compound in
             the last 4 weeks or 5 half-lives (whichever is shorter) prior to entering the study
             with possible or known effects of QT prolongation. (If equivalent medication is not
             available, QTc will be closely monitored.)

        Laboratory assessments:

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) greater than or
             equal to (≥) 1 * upper limit of normal (ULN).

          -  Serum bilirubin ≥ 1 * ULN (except those known to have Gilbert's syndrome).

          -  Creatinine clearance ≤45 milliliters per minute (mL/min) (estimated by Cockcroft-Gault
             or by 24-hour urine collection).

          -  Any laboratory abnormality, which in the opinion of the investigator, places the
             participant at an unacceptably high risk for toxicities.

        Gastrointestinal (GI) assessments:

          -  Liver malignancy (including metastases) or chronic liver disease.

          -  History of GI surgery or procedures or conditions that might interfere with the
             absorption or swallowing of the study drug.

        Immunologic:

          -  Known hypersensitivity to study drug or its excipients.

        Miscellaneous:

          -  Any sign of active uncontrolled infections; any severe chronic disease potentially
             interfering with the protocol, including human immunodeficiency virus (HIV) infection,
             or active hepatitis B or C or those with a positive screen for hepatitis A
             Immunoglobulin M (IgM).

          -  Any other malignancies within the past 2 years other than basal cell skin cancer or
             carcinoma in situ of the cervix.

          -  Participant concomitantly receiving any other investigational agents.

          -  Systemic chemotherapy within 2 weeks or investigational therapy within 5 half-lives
             prior to first dose of study drug, unless there is evidence of rapidly progressive
             disease (in which case the shorter washout of 2 weeks will be followed). For
             monoclonal antibodies, the washout from prior therapy will be 4 weeks, unless there is
             evidence of rapidly progressive disease, in which case, the shorter washout period of
             2 weeks will be followed. Persistent chronic clinically significant toxicities from
             prior chemotherapy must not be >Grade 1. Use of hydroxyurea (Hydrea) is permitted up
             to 24 hours prior to start of study drug for control of proliferative disease. Hydrea
             treatment may be reinstated during study for control of proliferative disease, as
             needed, at the discretion of investigator.

          -  Participants with AML that has advanced with central nervous system (CNS) involvement.

          -  Participant is pregnant or breastfeeding or expecting to conceive or father children
             within the projected duration of the study.

          -  Participants receiving CYP2B6 substrates such as bupropion and methadone.

          -  Participants receiving strong CYP3A4 inducers such as carbamazepine, enzalutamide,
             mitotane, phenytoin, rifampin, and St. John's wort (hypericin) or drugs that are
             exclusively substrates of CYP3A4.

          -  Participant is receiving moderate or strong CYP3A4 inhibitors.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of Participants Who Discontinued Study Drug Due to Adverse Event (AE)
Time Frame:From Screening to 50 days post treatment
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Time to Maximum Plasma Concentration (Tmax) of both PTC299 and O-desmethyl PTC299 when PTC299 is Given as Tablet with Food
Time Frame:Days 1, 15, 28, 57, 71 and 99
Safety Issue:
Description:
Measure:Maximum Plasma Concentration (Cmax) of both PTC299 and O-desmethyl PTC299 when PTC299 is Given as Tablet with Food
Time Frame:Days 1, 15, 28, 57, 71 and 99
Safety Issue:
Description:
Measure:Area Under the Concentration-Time Curve (AUC) of both PTC299 and O-desmethyl PTC299 when PTC299 is Given as Tablet with Food
Time Frame:Days 1, 15, 28, 57, 71 and 99
Safety Issue:
Description:
Measure:Half-life (t1/2) of both PTC299 and O-desmethyl PTC299 when PTC299 is Given as Tablet with Food
Time Frame:Days 1, 15, 28, 57, 71 and 99
Safety Issue:
Description:
Measure:Estimate t1/2 of of both PTC299 and O-desmethyl PTC299 During 14-Day Washout Period
Time Frame:Day 29 through Day 42
Safety Issue:
Description:
Measure:Apparent Clearance (CL/F) of both PTC299 and O-desmethyl PTC299 when PTC299 is Given as Tablet with Food
Time Frame:Days 1, 15, 28, 57, 71 and 99
Safety Issue:
Description:
Measure:Apparent Volume of Distribution (Vz/F) of both PTC299 and O-desmethyl PTC299 when PTC299 is Given as Tablet with Food
Time Frame:Days 1, 15, 28, 57, 71 and 99
Safety Issue:
Description:
Measure:Accumulation Ratio (R) of both PTC299 and O-desmethyl PTC299 when PTC299 is Given as Tablet with Food
Time Frame:Days 1, 15, 28, 57, 71 and 99
Safety Issue:
Description:
Measure:Percentage of Participants Achieving Response Rate/Overall Response Rate Utilizing International Working Group (IWG) Response Criteria for AML
Time Frame:Up to 6 Months
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:PTC Therapeutics

Trial Keywords

  • Leukemia, Myeloid
  • Neoplasms by Histologic Type
  • Neoplasms
  • Dihydroorotate dehydrogenase (DHODH) inhibitor

Last Updated

January 13, 2020