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Study of PTC299 in Relapsed/Refractory Acute Leukemias

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ClinicalTrials.gov Identifier: NCT03761069
Recruitment Status : Recruiting
First Posted : December 3, 2018
Last Update Posted : December 4, 2018
Sponsor:
Information provided by (Responsible Party):
PTC Therapeutics

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Leukemia, Myeloid, Acute AML Drug: PTC299 Phase 1

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1b Study of PTC299 in Relapsed/Refractory Acute Leukemias
Actual Study Start Date : October 29, 2018
Estimated Primary Completion Date : May 29, 2020
Estimated Study Completion Date : November 25, 2020


Arm Intervention/treatment
Experimental: PTC299

PTC299 will be administered orally once daily (QD) for each 28-day cycle. There will be a total of 3 cycles with a 14-day washout period between Cycle 1 and Cycle 2.

Cycle 1: 20 milligrams (mg)/day on Day 1 followed by 40 mg/day on Days 2-8 and 20 mg/day on Days 9-28.

Washout Period: 14-day washout from Day 29-42.

Cycle 2: 40 mg/day from Days 43-50 followed by 20 mg/day through Day 70.

Cycle 3: 20 mg/day for the last 28 day cycle.

Drug: PTC299
PTC299 will be administered per the treatment arm description




Primary Outcome Measures :
  1. Number of Participants Who Discontinued Study Drug Due to Adverse Event (AE) [ Time Frame: From 21 days before treatment to 50 days post treatment ]

Secondary Outcome Measures :
  1. Time to Maximum Plasma Concentration (Tmax) for PTC299 and for O-desmethyl PTC299 [ Time Frame: Hours 0 (predose), 1, 2, 3, 4, 6, 8, and 24 hours postdose on Days 1, 3, 4, 9, and 11 of each Cycle ]
  2. Maximum Plasma Concentration (Cmax) for PTC299 and for O-desmethyl PTC299 [ Time Frame: Hours 0 (predose), 1, 2, 3, 4, 6, 8, and 24 hours postdose on Days 1, 3, 4, 9, and 11 of each Cycle ]
  3. Area Under the Concentration-Time Curve (AUC) for PTC299 and for O-desmethyl PTC299 [ Time Frame: Hours 0 (predose), 1, 2, 3, 4, 6, 8, and 24 hours postdose on Days 1, 3, 4, 9, and 11 of each Cycle ]
  4. Half-life (t1/2) of PTC299 and of O-desmethyl PTC299 [ Time Frame: Hours 0 (predose), 1, 2, 3, 4, 6, 8, and 24 hours postdose on Days 1, 3, 4, 9, and 11 of each Cycle ]
  5. Apparent Clearance (CL/F) of PTC299 and of O-desmethyl PTC299 [ Time Frame: Hours 0 (predose), 1, 2, 3, 4, 6, 8, and 24 hours postdose on Days 1, 3, 4, 9, and 11 of each Cycle ]
  6. Apparent Volume of Distribution (Vz/F) of PTC299 and of O-desmethyl PTC299 [ Time Frame: Hours 0 (predose), 1, 2, 3, 4, 6, 8, and 24 hours postdose on Days 1, 3, 4, 9, and 11 of each Cycle ]
  7. Accumulation Ratio (R) of PTC299 and of O-desmethyl PTC299 [ Time Frame: Hours 0 (predose), 1, 2, 3, 4, 6, 8, and 24 hours postdose on Days 1, 3, 4, 9, and 11 of each Cycle ]
  8. Estimate of t1/2 for PTC299 and of O-desmethyl PTC299 During the 14-Day Washout Period Between Cycle 1 and Cycle 2 (Days 29-42) [ Time Frame: Day 29 (26 plus or minus [±4] hours [hr] and 28±4 hr postdose from Day 28), Day 36 (170±4 hr and 172±4 hr postdose from Day 28), and Day 43 (338±4 hr and 340±4 hr postdose from Day 28). ]
  9. Percentage of Participants Achieving Response Rate/Overall Response Rate Utilizing International Working Group (IWG) Response Criteria for AML [ Time Frame: Up to Day 70 (Cycle 3) ]


Information from the National Library of Medicine

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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:

  • 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 practicing 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 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 (≥) upper limit of normal (ULN).
  • Serum bilirubin ≥ ULN (except those known to have Gilbert's syndrome).
  • Creatinine clearance ≤ 45 milliliters per minute (mL/min).
  • Any laboratory abnormality, which in the opinion of the investigator, places the subject 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; persistent chronic clinically significant toxicities from prior chemotherapy must not be >Grade 1. For monoclonal antibodies, the washout from prior therapy will be 4 weeks. Use of hydroxyurea (Hydrea) is permitted up to 24 hours prior to start of study drug for control of proliferative disease.
  • Participant 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.
  • Participant is receiving CYP2B6 substrates such as bupropion and methadone.
  • Participant is 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.

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): NCT03761069


Locations
United States, Michigan
Henry Ford Health System Not yet recruiting
Detroit, Michigan, United States, 48202
Contact: Ahmad Mattour    313-916-3721    amattou1@hfhs.org   
United States, New Jersey
Rutgers, Cancer Institute of NJ Not yet recruiting
New Brunswick, New Jersey, United States, 08903
Contact: Dale Schaar    732-235-2465    scharrdg@cinj.rutgers.edu   
United States, New York
Columbia Not yet recruiting
New York, New York, United States, 10032
Contact: Joseph Jurcic    212-317-4224    jgj2110@cumc.columbia.edu   
University of Rochester MC Not yet recruiting
Rochester, New York, United States, 14642
Contact: Michael Becker    545-275-4099    michael_becker@urmc.rochester.edu   
United States, Ohio
Gabrail Cancer Center Recruiting
Canton, Ohio, United States, 44718
Contact: Nashat Gabrail    330-492-3345    ngabrail@gabrailcancercenter.com   
Cleveland Clinic Foundation Not yet recruiting
Cleveland, Ohio, United States, 44195
Contact: Aziz Nazha    216-445-7009    NAZHAA@ccf.org   
United States, Rhode Island
Rhode Island, Miriam Hospital Not yet recruiting
Providence, Rhode Island, United States, 02903
Contact: John Reagan    401-444-3234    Jreagan@lifespan.org   
United States, Tennessee
SCRI Tennessee Oncology Not yet recruiting
Nashville, Tennessee, United States, 37203
Contact: William Donnellan    615-986-7604    wdonnellan@tnonc.com   
United States, Washington
Swedish Cancer Institute Not yet recruiting
Seattle, Washington, United States, 91804
Contact: Raya Mawad    206-215-2658    Raya.Mawad@swedish.org   
Sponsors and Collaborators
PTC Therapeutics

Responsible Party: PTC Therapeutics
ClinicalTrials.gov Identifier: NCT03761069     History of Changes
Other Study ID Numbers: PTC299-HEM-001-LEU
First Posted: December 3, 2018    Key Record Dates
Last Update Posted: December 4, 2018
Last Verified: November 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by PTC Therapeutics:
Leukemia, Myeloid
Neoplasms by Histologic Type
Neoplasms
Dihydroorotate dehydrogenase (DHODH) inhibitor

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
6-(4-fluorophenyl)-2,3-dihydro-5-(4-pyridinyl)imidazo(2,1-b)thiazole
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action