A Study of PRT1419 in Patients With Relapsed/Refractory Hematologic Malignancies

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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.

Official Title
-----------------
A Phase 1, Open-Label, Multicenter, Dose-Escalation Study of PRT1419 in Patients With Relapsed/Refractory Hematologic Malignancies

Conditions
-----------------
Multiple Myeloma, Acute Myeloid Leukemia, Non Hodgkin Lymphoma, Myelodysplastic Syndromes

Intervention / Treatment
-----------------
* Drug: PRT1419


Participation Criteria
=================
Eligibility Criteria
-----------------
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 White blood cell count < 25 x 10^9/L. Hydrea or leukapheresis are permitted to meet this criterion. 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: ANC ≥1.0 x 10^3 μL Platelet count ≥50,000 μL 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: Malignancy treated with curative intent with no known active disease for >2 years at study entry Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease Adequately treated carcinoma in situ without evidence of disease Other concurrent low-grade malignancies (i.e chronic lymphocytic leukemia (Rai 0)) may be considered after consultation with Sponsor.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PRT1419<br>PRT1419 will be administered orally | Drug: PRT1419<br>* PRT1419 will be administered orally<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To describe dose limiting toxicities (DLT) of PRT1419 | Dose limiting toxicities will be evaluated through the first cycle | Baseline through Day 28 | 
| To determine the maximally tolerated dose (MTD) and/or optimal biological dose (OBD) | The MTD and/or OBD will be established for further investigation in participants with multiple myeloma, Non-Hodgkin's Lymphoma, acute myeloid leukemia and myelodysplastic syndrome | Baseline through approximately 2 years | 
| To determine the recommended phase 2 dose (RP2D) and schedule of PRT1419 | The RP2D will be established for further investigation in participants with multiple myeloma, Non-Hodgkin's Lymphoma, acute myeloid leukemia and myelodysplastic syndrome | Baseline through approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To describe the adverse event profile and tolerability of PRT1419 | Adverse events as characterized by type, frequency, severity, timing, seriousness and relationship to study therapy | Baseline through approximately 2 years | 
| To describe the pharmacokinetic profile of PRT1419 | PRT1419 pharmacokinetics will be calculated including the maximum observed plasma concentration | Baseline through approximately 2 years | 
| To describe any anti-tumor activity of PRT1419 | Anti-tumor activity of PRT1419 will be based on the measurement of objective responses | Baseline through approximately 2 years |