A Phase 1, Open-Label, Multicenter, Dose-Escalation Study of PRT1419 in Patients With Relapsed/Refractory Hematologic Malignancies
A Phase 1, Open-Label, Multicenter, Dose-Escalation Study of PRT1419 in Patients With Relapsed/Refractory Hematologic Malignancies
This is a Phase 1 dose-escalation study of PRT1419, a myeloid cell leukemia 1 (MCL1) inhibitor, in patients with relapsed/refractory hematologic malignancies. The purpose of this study is to define the dosing schedule, maximally tolerated dose and/or estimate the optimal biological dose to be used in subsequent development of PRT1419.
This is a multicenter, open-label, dose-escalation Phase 1 study of PRT1419, a MCL1 inhibitor, evaluating patients in two cohorts as part of a 28-day treatment cycle in adult patients with multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML), high-risk myelodysplastic syndrome (MDS) or MDS/myeloproliferative neoplasm (MPN) overlap syndrome. Cohort A will evaluate PRT1419 administered as monotherapy in patients with either AML, CMML and/or high-risk MDS or MDS/MPN overlap. Cohort B will evaluate PRT1419 administered as monotherapy in patients with NHL or MM. The study will employ a "3+3" dose escalation design. The dose may be escalated until a dose limiting toxicity is identified.
Inclusion Criteria:
Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
Adequate organ function (bone marrow, hepatic, renal, cardiovascular)
Left ventricular ejection fraction of ≥50%
Female patients of childbearing potential must have a negative pregnancy test within 7 days of the start of treatment and must agree to use a highly effective method of contraception during the trial
Patients must have recovered from the effects of any prior cancer related therapy, radiotherapy or surgery (toxicity ≤ Grade 1)
All patients on prior investigational agents must wait at least 5 half-lives of the agent in question, or 14 days, whichever is longer before study entry
AML patients only: Pathologically confirmed diagnosis of AML as defined by the WHO Classification and patients with targeted mutations must have been treated with appropriate therapy for their disease
CMML patients only: intermediate-2 or high risk per CMML-specific prognostic scoring system (CPSS) or clinical/molecular CPSS (CPSS-mol) criteria. Must have failed prior therapy with a hypomethylating agent.
MDS patients only: Intermediate, high, or very high risk by International Prognostic Scoring System-Revised [IPSS-R] criteria that is relapsed or refractory to approved therapies or MDS/MPN Overlap Syndrome (displaying both fibrosis and dysplastic features).
NHL patients only: Histologically or cytologically confirmed NHL, including B- and T-cell lymphomas that is relapsed or refractory or intolerant to approved therapies. Must have one lesion that can be measured for response
MM patients only: Measurable disease defined by one or more of the following: Serum M-protein ≥ 0.5 g/dL, Urine M-protein ≥ 200 mg/24 hours, Serum Free Light Chain (sFLC) > 10 mg/dL with normal serum FLC ratio. Presence of soft tissue plasmacytoma confirmed by imaging
NHL and MM patients only: must have the following lab values within 14 days prior to study Day 1:
Exclusion Criteria:
Known hypersensitivity to any of the components of PRT1419
Female patients who are pregnant or lactating
Mean QTcF interval of >480 msec
History of heart failure, additional risk factors for arryhthmias or requiring concomitant medications that prolong the QT/QTc interval
Hematopoietic stem-cell transplant < 90 days or have GVHD Grade >1 at study entry
Uncontrolled intercurrent illnesses
Treatment with strong inhibitors of CYP2C8 and/or P-glycoprotein for which there are no therapeutic substitutions
Inflammatory disorders of the gastrointestinal tract, or subjects with GI malabsorption
HIV positive; known active hepatitis B or C
Prior exposure to an MCL1 inhibitor
History of another malignancy except: