A Phase 1/2A, Open Label Dose Escalation and Cohort Expansion Study of Orally Administered CA-4948 (IRAK4I) as a Monotherapy in Patients with Acute Myelogenous Leukemia or Myelodysplastic Syndrome

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 Acute Myelogenous
Leukemia (AML) or high risk Myelodysplastic Syndrome (MDS).

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

- R/R AML with FLT3 mutations who have been previously treated with a FLT3 inhibitor

- R/R AML with spliceosome mutations of SF3B1 or U2AF1

- R/R hrMDS with spliceosome mutations of SF3B1 or 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 (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.

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 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 hypermethylating 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 pretreatments: 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 90 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 ≤ 1within 7 days prior
to start of emavusertib; presence of any acute or chronic non-hematological toxicity ≥
Grade 3 at Screening, or prior to start of emavusertib must resolve to ≤ Grade 2.

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) 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 diseaseincluding 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 < 40% 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 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