PRT1419 as Monotherapy or in Combination With Azacitidine or Venetoclax in R/R Myeloid or B-cell Malignancies

Inclusion Criteria:

* Willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations (including contraception requirements), and other study procedures
* Refractory/relapsed disease, having progressed on prior treatment, and without access to further approved therapies or ineligible for approved therapies, in one of the following disease categories: AML, CMML, MDS, MDS/MPN Overlap Syndrome, CLL/SLL, and B-cell NHLs
* Eastern Cooperative Oncology Group (ECOG) Performance Score of 0 to 2
* Adequate organ function (hematology, hepatic, renal, and coagulation)

Exclusion Criteria:

* Active inflammatory disorders of the gastrointestinal tract, a history of bariatric surgery or other disorders with the potential for GI malabsorption
* Cardiac function compromise, as assessed by echocardiogram or protocol-specified biochemical markers of cardiac damage, or protocol-defined clinically significant heart disease
* History of cerebrovascular accident or transient ischemic attack, within 6 months of screening. Participants with a history of pulmonary embolism must not be symptomatic at enrollment
* Undergone hematopoietic stem-cell transplantation (HSCT) within the last 90 days or have graft-versus-host disease (GVHD) Grade \> 1 at study entry
* Uncontrolled intercurrent illnesses, poorly controlled hypertension or dyslipidemias, Unstable central nervous system (CNS) metastases
* Treatment with either OATP1B1, OATP1B3 substrates or strong inhibitors of CYP2C8, CYP3A4, and any medication contraindicated in combination with AZA or VEN
* Prior exposure to an MCL-1 inhibitor
* Within 5 half-lives or 14 days (whichever is longer) following the last systemic anti-cancer therapy
* History of another malignancy except for:

  1. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
  2. Adequately treated cervical or breast carcinoma in situ without evidence of disease
  3. Asymptomatic prostate cancer without known metastatic disease and no requirement for therapy or requiring only hormonal therapy and with normal prostate specific antigen for \>1 year prior to enrollment
  4. Other malignancy treated with curative intent with no known active disease for \> 2 years prior to enrollment