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

Cancer Categories

Hematologic (Blood Cancers)

Karmanos Trial ID

2023-095

NCT ID

NCT04278768

Age Group

Adult

Scope

National

Phase

Phase I/II

Principal Investigator

Jay
Yang, M.D.
Oncology - Hematology, Oncology - Medical View Profile

Objective:

Phase 1 Dose Escalation

Primary Objectives:

To evaluate the safety and tolerability of CA-4948 in patients with R/R AML and
hrMDS
To identify the MTD and RP2D

Secondary Objectives:

To characterize the PK parameters of CA-4948 using non-compartmental analysis
and appropriate PK modelling
To assess anti-cancer activity

Phase 2a Dose Expansion

Primary Objective:

To assess anti-cancer activity of CA-4948 at RP2D in patients with R/R AML with
FLT-3 mutations, and patients with R/R hrMDS or R/R AML with spliceosome
mutations of SF3B1 or U2AF1

Secondary Objectives:

To assess tolerability and long-term safety
To further assess anti-cancer activity of CA-4948 at RP2D

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Eligibility

Inclusion Criteria:

Males and females ≥18 years of age
Life expectancy of at least 3 months
Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤1
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).

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

Acceptable organ function at screening
Ability to swallow and retain oral medications
Negative serum pregnancy test in women of childbearing potential
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
Willing and able to provide written informed consent and comply with the requirements of the trial
Able to undergo serial bone marrow sampling and peripheral blood sampling

Exclusion Criteria:

Diagnosed with acute promyelocytic leukemia (APL, M3)
Has known active central nervous system (CNS) leukemia
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
Chronic myeloid leukemia (CML)
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.

Use of any investigational agent within 3 weeks or 5 half-lives, whichever is shorter, prior to start of emavusertib
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.
Known allergy or hypersensitivity to any component of the formulation of emavusertib
Major surgery, other than diagnostic surgery, <28 days from the start of emavusertib; minor surgery <14 days from the start of emavusertib
Patients with active advanced malignant solid tumors
Known to be human immunodeficiency virus (HIV) positive or have an acquired immunodeficiency syndrome-related illness
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
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)
Gastrointestinal disease or disorder that could interfere with the swallowing, oral absorption, or tolerance of emavusertib
Pregnant or lactating
Systemic fungal, bacterial, viral, or other infection that is not controlled
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

Locations

Karmanos Cancer Institute - Detroit Headquarters

4100 John R
Detroit, MI 48201
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Phone: 800-527-6266

Karmanos Cancer Institute at Weisberg Cancer Center - Farmington Hills

31995 Northwestern Hwy
Farmington Hills, MI 48334
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Phone: 800-527-6266

Applicable Disease Site

Therapies, Drugs, Devices