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

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.