Summary

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.

Objectives

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.

Eligibility

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 hypermethylating agent (HMA) or evidence of early progression Phase 2a Dose Expansion (Monotherapy) Patients with:
5. R/R AMLwith FLT3 mutations who have been previously treated with a FLT3 inhibitor
6. R/R AML with spliceosome mutations of SF3B1 or U2AF1
7. R/R hrMDS (IPSS-R score > 3.5) with spliceosome mutations of SF3B1 or U2AF1
8. Number of pretreatments: 1 or 2
9. Acceptable organ function at screening
10. Ability to swallow and retain oral medications
11. Negative serum pregnancy test in women of childbearing potential
12. 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
13. Willing and able to provide written informed consent and comply with the requirements of the trial
14. Able to undergo serial bone marrow sampling and peripheral blood sampling

Treatment Sites in Georgia