Dose Escalation/ Expansion Study of CA-4948 as Monotherapy in Patients With AML or MDS

Summary

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 high risk, 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 relapsed/ refractory (R/R) patients with AML or high
risk myelodysplastic syndrome (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 (FLT-3) 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 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 lead 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;

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 have had = 2 lines of prior systemic anticancer treatment.