A Phase I, Open-Label, Multicenter, Dose Escalation, Dose Expansion Study of PRT543 in Patients with Advanced Solid Tumors and Hematologic Malignancies
This is a Phase 1 cohort, dose-escalation, dose-expansion study of PRT543 in patients with advanced cancers who have exhausted available treatment options. The purpose of this study is to define a safe dose and schedule to be used in subsequent development of PRT543.
Primary: To describe any dose limiting toxicities (DLT) of PRT543, and to determine the maximally tolerated dose (MTD) and recommended phase II dose (RP2D) and schedule of PRT543, in patients with advanced solid tumors and certain hematologic malignancies
1.To describe the adverse event profile and tolerability of PRT543
2.To describe the pharmacokinetic profile of PRT543
3.To describe any anti-tumor activity of PRT543 based on the measurement of objectiveresponses to PRT543 according to the RECIST 1.1 criteria for patients with solid tumorsand the disease-specific response criteria for patients with hematologic malignancies
Metastatic or advanced solid tumor; or advanced diffuse large B-cell lymphoma; or advanced mantle cell lymphoma; or relapsed myelodysplastic syndrome; or relapsed myelofibrosis. All malignancies must be refractory to established therapies
Eastern Cooperative Oncology Group (ECOG) Performance Score of 0 or 1
Adequate organ function (bone marrow, hepatic, renal, cardiovascular)
Female patients of childbearing potential must have a negative pregnancy test within 7 days of the start of treatment and must agree to use an effective method of contraception during the trial
Patients with known hypersensitivity to any of the components of PRT543 (the components of PRT543 are: PRT543 Maleate, microcrystalline cellulose, mannitol, crospovidone, and magnesium stearate)
Primary malignancies of the Central Nervous System(CNS) or uncontrolled CNS metastases, including impending spinal cord compression. NOTE: Patients with radiographically visible CNS oligometastases that do not require treatment may participate in the trial.
Requirement of pharmacologic doses of glucocorticoids (>/=10 mg of prednisone or equivalent) require Sponsor consultation and approval prior to enrollment.
Patients who are pregnant or lactating.
Patients with inflammatory disorders of the gastrointestinal tract, or patients with GI malabsorption
Mean QTcF interval of >470 msec following 3 ECGs conducted 5 minutes apart, unless NCS per Investigator
Patients known to be HIV positive; patients with known active hepatitis B or C
NOTE: Patients with hepatitis C on anti-viral therapy or who have completed a course of anti-viral therapy are eligible. Specific screening is not required
Any clinically significant graft-versus-host disease (GVHD) secondary to prior allogenic transplant. Patients must be >90 days from transplant.
NOTE: Topical corticosteroids for minor skin rash is acceptable. Prior solid organ transplant is acceptable provided the patient is on no immunosuppressive therapy. Should the patient be on immunosuppressive therapy for GVHD, Sponsor consultation is required.
Patients with uncontrolled intercurrent illnesses including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, poorly controlled hypertension despite medical therapy, uncontrolled seizures, myocardial infarction or stroke within the past 6 months, or psychiatric illness/social situations that would limit compliance with study requirements or render the patient at high risk during study participation
Patients who require treatment with strong inhibitors or inducers of CYP3A4 for which there are no therapeutic substitutions
Patients who require treatment with MAO inhibitors
Prior exposure to a PRMT5 inhibitor
Patients with untreated concurrent malignancies or patients with malignancies that have been in complete remission for less than one year
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