Acute Myelogenous LeukemiaPhase 1/2NCT04278768
Dose Escalation/ Expansion Study of CA-4948 as Monotherapy in Patients With Acute Myelogenous Leukemia (AML) or Myelodysplastic Syndrome (MDS)
A Phase 1/2 study testing Emavusertib and Venetoclax in people with Acute Myelogenous Leukemia and Myelodysplastic Syndrome, run by Curis, Inc. at 32 sites in 8 countries.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Acute Myelogenous Leukemia, Myelodysplastic Syndrome
- What is being tested?
- Emavusertib and Venetoclax
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 366 participants
- Where
- 32 sitesin 8 countries
- Study dates
- 6 Jul 2020to 1 Apr 2026
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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 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).
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- 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
- 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 180 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
Who cannot join
- 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.
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- 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 ≤ 1 within 7 days prior to start of emavusertib.
- 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) 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
- 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)
- 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
Trial locations and contacts
32 sites in 8 countries.
32 sites in 8 countries
United States12 sites
Winship Cancer Institute
Atlanta, Georgia, 30322
Dana Farber Cancer Institute
Boston, Massachusetts, 02215
Northwestern Memorial Hospital
Chicago, Illinois, 60611
University of Chicago Medical Center
Chicago, Illinois, 60637
The Ohio State University Wexner Medical Center - James Cancer Hospital
Columbus, Ohio, 43210
Karmanos Cancer Institute
Detroit, Michigan, 48201
The University of Texas MD Anderson Cancer Center
Houston, Texas, 77030
Oncology Hematology West, PC dba Nebraska Cancer Specialists
Omaha, Nebraska, 68130
University of Rochester Medical Center
Rochester, New York, 14642
Moffitt Cancer Center
Tampa, Florida, 33612
Albert Einstein Medical College
The Bronx, New York, 10461
Novant Health Hematology - Forsyth
Winston-Salem, North Carolina, 27103
Germany5 sites
Marien Hospital Dusseldorf; Klinik fur Onkologie und Hamatologie, Palliativmedizin
Düsseldorf, 40479
Universitätsklinikum Hamburg-Eppendorf (UKE)
Hamburg, 20246
Universitatsklinikum Leipzig; Medizinische Klinik und Poliklinik I
Leipzig, 04103
Klinikum rechts der Isar der Technischen Universitat Munchen
München, 81675
Universitatsklinikum Munster
Münster, 48149
Spain4 sites
Hospital de la Santa Creu I Sant Pau (Neuvo Hospital)
Barcelona
Hospital Universitaro del a Princesa
Madrid, 28006
MD Anderson Cancer Center Madrid
Madrid
Hospital Universitario Virgen del Rocio
Seville
France3 sites
Service d'hématologie clinique CHU de Nice
Nice, 6200
APHP - Sorbonne Universite
Paris, 75012
APHP - Hopital Saint Louis
Paris, 75475
Israel3 sites
Soroka University MC
Beersheba, 84100
Edith Wolfson Medical Center
Holon, 5822012
Hadassah University MC
Jerusalem, 9112001
Italy2 sites
Azienda Ospedaliera Santa Croce e Carle
Cuneo
Instituto Romagnolo per lo Studio dei Tumori "Dino Amadori"
Meldola
Poland2 sites
Uniwersyteckie Centrum Kliniczne Osrodek Badan Klinicznych Wczesnych Faz
Gdansk, 80-214
University Hospital in Krakow
Krakow, 31 501
About this study
Official title: A Phase 1/2A, Open Label Dose Escalation and Expansion Study of Orally Administered CA-4948 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 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:
Read more
- 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:
- 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; and
- 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.
Read the detailed description
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:
- R/R AML with FLT3 mutations who have been previously treated with a FLT3 inhibitor; or
- R/R AML with spliceosome mutations of SF3B1 or U2AF1; or
- 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.
- Being tested
- Emavusertib, Venetoclax
- Keywords
- Acute Myelogenous Leukemia, Myelodysplastic Syndrome, AML, MDS, Interleukin-1 receptor-associated kinase 4 (IRAK4), FLT3-ITD or TKD mutant, FLT3 Wild Type (WT), Relapse/refractory to hypomethylating agent (HMA), spliceosome mutation, SF3B1, U2AF1, Serine/arginine-rich splicing factor 2 (SRSF2), Zinc finger CCCH-type, RNA binding motif and serine/arginine rich 2 (ZRSR2), higher-risk MDS, failing prior treatment, R/R AML or relapse/refractory AML, R/R hrMDS or relapse/refractory hrMDS, FLT3 mutation, FLT3 inhibitor
- Medical subject headings
- Leukemia, Myeloid, Acute, Myelodysplastic Syndromes, Hereditary Sensory and Autonomic Neuropathies, Recurrence
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EmavusertibDrug
Also called CA-4948
Emavusertib is formulated as a tablet for oral administration for BID dosing in consecutive 28-day cycles. Emavusertib is a novel small molecule inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4). IRAK4 kinase plays an essential role in toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathways and these pathways are frequently dysregulated in non-Hodgkin's lymphoma and AML/MDS malignancies.
VenetoclaxDrug
Ventoclax is B-cell lymphoma-2 (BCL-2) inhibitor. 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 21days of a 28-day Cycle. Second and subsequent cycles start with target dose level.
This arm of the study has been closed to enrollment.
EmavusertibDrug
Also called CA-4948
Emavusertib is formulated as a tablet for oral administration for BID dosing for 21 days (Days 1-21) of a 28-day Cycle.
| Study group | Role | What they receive |
|---|---|---|
| Emavusertib (CA-4948) dose escalation | Experimental | Patients receive emavusertib monotherapy BID daily. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Receives: Drug: Emavusertib |
| Emavusertib dose escalation + Venetoclax | Experimental | The starting dose for emavusertib will be 200 mg BID for 21 days of a 28-day Cycle. Anticipated emavusertib doses will be 200 and 300 mg BID. 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 21days of a 28-day Cycle. Second and subsequent cycles start with target dose level. Receives: Drug: Venetoclax; Drug: Emavusertib |
| Emavusertib monotherapy dose expansion | Experimental | 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. Receives: Drug: Emavusertib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Determine Maximum Tolerated Dose (MTD) of emavusertib (CA-4948) monotherapy (Phase 1)
The highest dose at which there is <33% Dose Limiting Toxicity rate in the first cycle of treatment in a minimum of 6 patients.
Measured: 28 days
Determine the Recommended Phase 2 Dose (RP2D) of emavusertib monotherapy (Phase 1)
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 an RP2D is to provide a dose and schedule that will maximize the opportunity for clinical benefit, while minimizing the risk of toxicity.
Measured: 24 months
Determine Maximum Tolerated Dose (MTD) of emavusertib in combination with venetoclax (Phase 1b)
The highest dose at which there is <33% Dose Limiting Toxicity rate in the first cycle of treatment in a minimum of 6 patients.
Measured: 28 days
Determine the Recommended Phase 2 Dose (RP2D) of emavusertib in combination with venetoclax (Phase 1b)
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 an RP2D is to provide a dose and schedule that will maximize the opportunity for clinical benefit, while minimizing the risk of toxicity.
Measured: 24 months
To assess anti-cancer activity (Phase 2a - AML patients)
Proportion of patients who achieve complete response (CR) + complete response with partial hematological recovery (CRh)
Measured: 24 months
To assess anti-cancer activity (Phase 2a - hrMDS patients)
Overall response rate: proportion of patients who achieve CR+ partial response (PR)
Measured: 24 months
To assess safety (Phase 1b)
Clinical safety assessments including frequency of adverse events (AEs)
Measured: 24 months
Secondary outcomes (14)
To characterize the pharmacokinetic (PK) parameters of emavusertib measured by maximum plasma concentration (Cmax) (Phase 1 and 1b)
maximum plasma concentration (Cmax)
Measured: 24 months
To characterize the pharmacokinetic (PK) parameters of emavusertib measured by trough plasma concentration (Cmin) (Phase 1 and Phase 1b)
trough plasma concentration (Cmin)
Measured: 24 months
To characterize the pharmacokinetic (PK) parameters of emavusertib measured by Time to maximum plasma concentration (Tmax) (Phase 1 and 1b)
Time to maximum plasma concentration
Measured: 24 months
To characterize the pharmacokinetic (PK) parameters of emavusertib measured by Area under the plasma concentration versus time curve(AUC) [0-24] (Phase 1 and 1b)
Area under the plasma concentration-time curve from 0 to 24 hours
Measured: 24 months
To characterize the pharmacokinetic (PK) parameters of emavusertib measured by Area under the plasma concentration-time curve from 0 to infinity (AUC[INF]) (Phase 1 and 1b)
Area under the plasma concentration-time curve from 0 to infinity
Measured: 24 months
To characterize the pharmacokinetic (PK) parameters of emavusertib measured by Plasma terminal elimination half-life (T 1/2) (Phase 1 and 1b)
Plasma terminal elimination half-life (T 1/2)
Measured: 24 months
To assess clinical response (Phase 1 and 1b)
For AML: assessed by proportion of patients who reach complete response (CR) + complete response with partial hematological recovery (CRh) assessed by proportion of patients who reach complete response with incomplete hematologic recovery (CRi) or CR or CRh For hrMDS: overall response rate of CR+partial response (PR)
Measured: 24 months
To assess clinical response (Phase 1 and 1b)
Assessed by transfusion independence
Measured: 24 months
To assess tolerability and long term safety (Phase 2a)
Clinical safety assessments including frequency of adverse events (AEs)
Measured: 24 months
To assess clinical response (Phase 2a)
For AML - assessed by proportion of patients who achieve CR or CRh or CRi; For hrMDS - assessed by proportion of patients who achieve CR or PR or marrow complete response (mCR)
Measured: 24 months
To assess clinical response (Phase 2a)
Assessed by duration of response (DOR)
Measured: 24 months
To assess clinical response (Phase 2a)
Assessed by time to response
Measured: 24 months
To assess clinical response (Phase 2a)
Assessed by transfusion independence
Measured: 24 months
To assess clinical response (Phase 2a)
Assessed by overall survival (OS)
Measured: 24 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Feb 2020
- Study start6 Jul 2020
- Primary completion1 Apr 2026 (estimated)
- Study completion1 Apr 2026 (estimated)
Why it stopped: Dosing completed in all cohorts. Planning underway for potential additional patient cohorts.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Acute Myelogenous LeukemiaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Model description
- Phase 1 and 1b follow a 3 + 3 design where 3 patients will be enrolled at the starting dose level. If none of the first 3 patients experience a DLT during the 1st 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 experience a DLT, this will be considered a DLT rate above the max tolerated dose (\> 33%), and additional enrollment will proceed at a lower dose level. The Phase 2a Dose Expansion will be enrolled after the RP2D is determined from Phase 1. It will be in 3 Cohorts of patients: (1) R/R AML with FTLT-3 mutation 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 \>3.5) with spliceosome mutations of SF3B1 or U2AF1; AND all patients have ≤ 2 lines of prior systemic anti-cancer therapy.
- Masking
- None (open label)
- Enrolment
- 366 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Curis, Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04278768
- Sponsor's protocol ID
- CA-4948-102
- Status last verified
- Mar 2026
- First submitted
- 10 Feb 2020
- Last updated
- 19 Mar 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 19 Mar 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 1/2A, Open Label Dose Escalation and Expansion Study of Orally Administered CA-4948 as a Monotherapy in Patients With Acute Myelogenous Leukemia or Myelodysplastic Syndrome
- ClinicalTrials.gov ID
- NCT04278768
- Acronym / sponsor ID
- CA-4948-102
- Keywords
- Acute Myelogenous Leukemia, Myelodysplastic Syndrome, AML, MDS, Interleukin-1 receptor-associated kinase 4 (IRAK4), FLT3-ITD or TKD mutant, FLT3 Wild Type (WT), Relapse/refractory to hypomethylating agent (HMA)
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- SuspendedReason stopped: Dosing completed in all cohorts. Planning underway for potential additional patient cohorts.
- Enrolment
- 366 participants (estimated)
- Lead sponsor
- Curis, Inc.Industry (pharma, biotech, devices)
- Study start
- 6 Jul 2020 (actual)
- Primary completion
- 1 Apr 2026 (estimated)
- Study completion
- 1 Apr 2026 (estimated)
- First posted
- 20 Feb 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- 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; and
- 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.
Detailed description
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:
- R/R AML with FLT3 mutations who have been previously treated with a FLT3 inhibitor; or
- R/R AML with spliceosome mutations of SF3B1 or U2AF1; or
- 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 3
- Model description
- Phase 1 and 1b follow a 3 + 3 design where 3 patients will be enrolled at the starting dose level. If none of the first 3 patients experience a DLT during the 1st 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 experience a DLT, this will be considered a DLT rate above the max tolerated dose (> 33%), and additional enrollment will proceed at a lower dose level. The Phase 2a Dose Expansion will be enrolled after the RP2D is determined from Phase 1. It will be in 3 Cohorts of patients: (1) R/R AML with FTLT-3 mutation 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 >3.5) with spliceosome mutations of SF3B1 or U2AF1; AND all patients have ≤ 2 lines of prior systemic anti-cancer therapy.
| Arm | Type | Receives |
|---|---|---|
| Emavusertib (CA-4948) dose escalation | Experimental | Drug: EmavusertibPatients receive emavusertib monotherapy BID daily. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. |
| Emavusertib dose escalation + Venetoclax | Experimental | Drug: Venetoclax, Drug: EmavusertibThe starting dose for emavusertib will be 200 mg BID for 21 days of a 28-day Cycle. Anticipated emavusertib doses will be 200 and 300 mg BID. 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 21days of a 28-day Cycle. Second and subsequent cycles start with target dose level. |
| Emavusertib monotherapy dose expansion | Experimental | Drug: EmavusertibThe 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (20 listed)
- 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 World Health Organisation [WHO] 2016 classification) with the following characteristics.
- Phase 1 Dose Escalation (Monotherapy)
Key exclusion criteria (18 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| EmavusertibAlso: CA-4948Emavusertib is formulated as a tablet for oral administration for BID dosing in consecutive 28-day cycles. Emavusertib is a novel small molecule inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4). IRAK4 kinase plays an essential role in toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathways and these pathways are frequently dysregulated in non-Hodgkin's lymphoma and AML/MDS malignancies. | Drug | Emavusertib (CA-4948) dose escalation, Emavusertib monotherapy dose expansion |
| VenetoclaxVentoclax is B-cell lymphoma-2 (BCL-2) inhibitor. 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 21days of a 28-day Cycle. Second and subsequent cycles start with target dose level. This arm of the study has been closed to enrollment. | Drug | Emavusertib dose escalation + Venetoclax |
| EmavusertibAlso: CA-4948Emavusertib is formulated as a tablet for oral administration for BID dosing for 21 days (Days 1-21) of a 28-day Cycle. | Drug | Emavusertib dose escalation + Venetoclax |
Primary outcome
Determine Maximum Tolerated Dose (MTD) of emavusertib (CA-4948) monotherapy (Phase 1)
Time frame: 28 days
The highest dose at which there is <33% Dose Limiting Toxicity rate in the first cycle of treatment in a minimum of 6 patients.
Determine the Recommended Phase 2 Dose (RP2D) of emavusertib monotherapy (Phase 1)
Time frame: 24 months
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 an RP2D is to provide a dose and schedule that will maximize the opportunity for clinical benefit, while minimizing the risk of toxicity.
Determine Maximum Tolerated Dose (MTD) of emavusertib in combination with venetoclax (Phase 1b)
Time frame: 28 days
The highest dose at which there is <33% Dose Limiting Toxicity rate in the first cycle of treatment in a minimum of 6 patients.
Determine the Recommended Phase 2 Dose (RP2D) of emavusertib in combination with venetoclax (Phase 1b)
Time frame: 24 months
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 an RP2D is to provide a dose and schedule that will maximize the opportunity for clinical benefit, while minimizing the risk of toxicity.
To assess anti-cancer activity (Phase 2a - AML patients)
Time frame: 24 months
Proportion of patients who achieve complete response (CR) + complete response with partial hematological recovery (CRh)
To assess anti-cancer activity (Phase 2a - hrMDS patients)
Time frame: 24 months
Overall response rate: proportion of patients who achieve CR+ partial response (PR)
To assess safety (Phase 1b)
Time frame: 24 months
Clinical safety assessments including frequency of adverse events (AEs)
14 secondary outcomes
To characterize the pharmacokinetic (PK) parameters of emavusertib measured by maximum plasma concentration (Cmax) (Phase 1 and 1b)
Time frame: 24 months
To characterize the pharmacokinetic (PK) parameters of emavusertib measured by trough plasma concentration (Cmin) (Phase 1 and Phase 1b)
Time frame: 24 months
To characterize the pharmacokinetic (PK) parameters of emavusertib measured by Time to maximum plasma concentration (Tmax) (Phase 1 and 1b)
Time frame: 24 months
To characterize the pharmacokinetic (PK) parameters of emavusertib measured by Area under the plasma concentration versus time curve(AUC) [0-24] (Phase 1 and 1b)
Time frame: 24 months
To characterize the pharmacokinetic (PK) parameters of emavusertib measured by Area under the plasma concentration-time curve from 0 to infinity (AUC[INF]) (Phase 1 and 1b)
Time frame: 24 months
To characterize the pharmacokinetic (PK) parameters of emavusertib measured by Plasma terminal elimination half-life (T 1/2) (Phase 1 and 1b)
Time frame: 24 months
To assess clinical response (Phase 1 and 1b)
Time frame: 24 months
To assess clinical response (Phase 1 and 1b)
Time frame: 24 months
To assess tolerability and long term safety (Phase 2a)
Time frame: 24 months
To assess clinical response (Phase 2a)
Time frame: 24 months
To assess clinical response (Phase 2a)
Time frame: 24 months
To assess clinical response (Phase 2a)
Time frame: 24 months
To assess clinical response (Phase 2a)
Time frame: 24 months
To assess clinical response (Phase 2a)
Time frame: 24 months
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Mar 2026.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
32 sites in 8 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Emavusertib and Venetoclax in people with Acute Myelogenous Leukemia and Myelodysplastic Syndrome, run by Curis, Inc. at 32 sites in 8 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 20 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: paused, as of the sponsor's last update on 19 Mar 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 32 sites in United States, Germany, Spain, France, Israel and 3 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Determine Maximum Tolerated Dose (MTD) of emavusertib (CA-4948) monotherapy (Phase 1) (time frame: 28 days). The study lists 7 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Mar 2026.