Dosing completed in all cohorts. Planning underway for potential additional patient cohorts.

This is a multicenter, open-label, Phase 1/2a dose escalation and expansion study of orally administered emavusertib (CA-4948) monotherapy in adult patients with AML or higher- risk Myelodysplastic Syndrome (hrMDS).

Patients enrolling in the Phase 1 dose escalation of the study must meet one of the following criteria prior to consenting to the study:

• Relapse/refractory (R/R) AML with FMS-like tyrosine kinase-3 (FLT3) mutations who have been previously treated with a FLT3 inhibitor
• R/R AML with spliceosome mutations of splicing factor 3B subunit 1 (SF3B1) or U2AF1
• R/R hrMDS with spliceosome mutations of SF3B1 or U2 small nuclear RNA auxiliary factor 1 (U2AF1)
• Number of pretreatments: 1 or 2

The Phase 2a Dose Expansion will be in 3 Cohorts of patients:

1. R/R AML with FLT3 mutations who have been previously treated with a FLT3 inhibitor;
2. R/R AML with spliceosome mutations of SF3B1 or U2AF1; and
3. R/R hrMDS (Revised International Prognostic Scoring System [IPSS-R] score > 3.5) with spliceosome mutations of SF3B1 or U2AF1.

All patients above have had ≤ 2 lines of prior systemic anticancer treatment. In previous versions of this protocol there was a Phase 1b portion of the study, in which patients with AML or hrMDS received CA-4948 in combination with venetoclax. This part of the study is no longer open for enrollment.

The primary objective of the Phase 1 portion of the study is to determine the maximum tolerated dose (MTD) and Recommended Phase 2 Dose (RP2D) for emavusertib in monotherapy in patients with AML, intermediate-2, high risk, or every high risk MDS based on the safety and tolerability, dose-limiting toxicities (DLTs), and Pharmacokinetic (PK)/Pharmacodynamic (PD) findings.

The primary objective of the Phase 1b portion of the study is to determine MTD and RP2D for emavusertib in combination with azacitidine (AZA) in treatment naïve patients with hrMDS or in combination with venetoclax (VEN) in R/R patients with AML or hrMDS after first line treatment based on the safety and tolerability, DLTs and PK and pharmacodynamic findings. Note, this portion of the study is no longer enrolling patients.

The primary objective of the Phase 2a portion of the study (emavusertib monotherapy expansion) is to assess anti-cancer activity of CA-4948 at the RP2D in patients with R/R AML with FMS-like tyrosine kinase-3 (FLT3) mutations, or patients with R/R hrMDS or R/R AML with spliceosome mutations of SF3B1 or U2AF1.

Emavusertib is formulated as tablets for twice daily oral administration. Each treatment cycle will be 28 days in length and repeated in the absence of toxicity. Patients who tolerate emavusertib may continue to receive emavusertib until progression of disease, intolerable toxicity, lack of clinical benefit, withdrawal from the trial, or study termination.

The emavusertib starting dose level will be 200 milligrams (mg) twice daily (BID) which was determined to be safe, capable of achieving relevant levels of drug exposure as well as demonstrating signs of biologic activity and clinical efficacy in an ongoing study (Study CA-4948-101). For phase 1, emavusertib is taken daily for 28 days of a 28 day cycle. For Phase 1b, emavusertib is taken daily for 21 days of a 28 day cycle in combination with venetoclax.

Venetoclax will be administered at 100 mg orally (Day 1) per the product label at the same time each day with a ramp up over 3 days to 400 mg for 21 days of the 28-day Cycle. Second and subsequent cycles start with the target dose level.

In each of the Phase 1/1b cohorts, three patients with AML or MDS were enrolled at the designated dose. If none of the first 3 patients experience a DLT during the first cycle, patients may be enrolled into the next higher dose level. If 1 patient out of the first 3 experiences a DLT, the dose level may be expanded with an additional 3 patients. If 2 or 3 patients out of the first six experienced a DLT, this will be considered a DLT rate above the MTD (> 33%), and additional enrollment will proceed at a lower dose level. Any adverse reaction that led to dose reduction or discontinuation is considered a DLT unless the adverse reaction is clearly and solely related to disease.

The RP2D will be determined by the Clinical Safety Committee (CSC) in consultation with the Sponsor, considering all aspects of safety, tolerability, biologic activity, pharmacokinetics and preliminary efficacy in the trial population. The intent of the RP2D is to provide a dose and schedule that will maximize the opportunity for clinical benefit, while minimizing the risk of toxicity. The RP2D may be below the MTD. The CSC may request enrollment of additional patients at any previously-explored dose level in order to make an appropriate RP2D or MTD determination.

The expansion phase will begin once the RP2D from Phase 1 Dose Escalation phase has been identified. There will be 3 Cohorts and patients will be assigned to each Cohort based on baseline disease:

1. R/R AML with FLT3 mutations who have been previously treated with a FLT3 inhibitor; or
2. R/R AML with spliceosome mutations of SF3B1 or U2AF1; or
3. R/R hrMDS (IPSS-R score > 3.5) with spliceosome mutations of SF3B1 or U2AF1

All patients have had ≤ 2 lines of prior systemic anticancer treatment. This part of the study is no longer open for enrollment.

Inclusion Criteria:

1. Males and females ≥18 years of age

2. Life expectancy of at least 3 months

3. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤1

4. Cytomorphology based confirmed diagnosis of MDS or AML (as per World Health Organisation [WHO] 2016 classification) with the following characteristics.

   Phase 1 Dose Escalation (Monotherapy)

   • AML (primary or secondary, including treatment-related) after failing at least 1 standard treatment (may include chemotherapy, re induction therapy or stem cell transplantation).

   OR

   • Higher-risk R/R MDS that are considered resistant/refractory following at least 2 to 3 cycles of hypomethylating agent (HMA) or evidence of early progression

   Phase 2a Dose Expansion (Monotherapy)

   Patients with:

   • R/R AMLwith FLT3 mutations who have been previously treated with a FLT3 inhibitor
   • R/R AML with spliceosome mutations of SF3B1 or U2AF1
   • R/R hrMDS (IPSS-R score > 3.5) with spliceosome mutations of SF3B1 or U2AF1
   • Number of prior treatments: 1 or 2

5. Acceptable organ function at screening

6. Ability to swallow and retain oral medications

7. Negative serum pregnancy test in women of childbearing potential

8. Women of childbearing potential and men who partner with a woman of childbearing potential must agree to use highly effective contraceptive methods for the duration of the study and for 180 days after the last dose of emavusertib

9. Willing and able to provide written informed consent and comply with the requirements of the trial

10. Able to undergo serial bone marrow sampling and peripheral blood sampling

Exclusion Criteria:

1. Diagnosed with acute promyelocytic leukemia (APL, M3)

2. Has known active central nervous system (CNS) leukemia

3. Allogeneic hematopoietic stem cell transplant (Allo-HSCT) within 60 days of the first dose of emavusertib, or clinically significant graft-versus-host disease (GVHD) requiring ongoing up titration of immunosuppressive medications prior to start of emavusertib

4. Chronic myeloid leukemia (CML)

5. Any prior systemic anti-cancer treatment such as chemotherapy, immunomodulatory drug therapy, etc., received within 3 weeks (or 5 half-lives) prior to start of emavusertib.

   Localized radiation or surgical resection of skin cancers allowed.

6. Use of any investigational agent within 3 weeks or 5 half-lives, whichever is shorter, prior to start of emavusertib

7. Presence of an acute or chronic toxicity resulting from prior anti-cancer therapy, with the exception of alopecia that has not resolved to Grade ≤ 1 within 7 days prior to start of emavusertib.

8. Known allergy or hypersensitivity to any component of the formulation of emavusertib

9. Major surgery, other than diagnostic surgery, <28 days from the start of emavusertib; minor surgery <14 days from the start of emavusertib

10. Patients with active advanced malignant solid tumors

11. Known to be human immunodeficiency virus (HIV) positive or have an acquired immunodeficiency syndrome-related illness

12. Hepatitis B virus (HBV) deoxyribonucleic acid (DNA) positive or Hepatitis C virus (HCV) infection <6 months prior to start of emavusertib unless viral load is undetectable, or HCV with cirrhosis

13. Uncontrolled or severe cardiovascular disease including myocardial infarction or unstable angina within 6 months prior to CA-4948, New York Heart Association Class II or greater congestive heart failure, or left ventricular ejection fraction < 50% by echocardiogram or multi-gated acquisition scan, serious arrhythmias uncontrolled on treatment, clinically significant pericardial disease, cardiac amyloidosis, congenital long QT syndrome, or QTc with Fridericia's correction (QTcF) that is unmeasurable or > 450 milliseconds (msec) on Screening electrocardiogram (ECG)

14. Gastrointestinal disease or disorder that could interfere with the swallowing, oral absorption, or tolerance of emavusertib

15. Pregnant or lactating

16. Systemic fungal, bacterial, viral, or other infection that is not controlled

17. Any other severe, acute, or chronic medical, psychiatric or social condition, or laboratory abnormality that may increase the risk of trial participation or emavusertib administration