Dose Escalation/ Expansion Study of CA-4948 as Monotherapy in Patients With Acute Myelogenous Leukemia (AML) or Myelodysplastic Syndrome (MDS)

NCT04278768 | Suspended Phase 1 DMC FDA Drug

• 1 other identifier: CA-4948-102
• Study Type: interventional
• Target: 366
• Locations: 8 countries
• Sites: 32

Brief 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:
• 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.

Conditions

Acute Myelogenous Leukemia; Myelodysplastic Syndrome

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

Outcome Measures

Primary Outcomes (7)

• 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.

  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.

  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.

  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.

  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)

  24 months

• To assess anti-cancer activity (Phase 2a - hrMDS patients)

  Overall response rate: proportion of patients who achieve CR+ partial response (PR)

  24 months

• To assess safety (Phase 1b)

  Clinical safety assessments including frequency of adverse events (AEs)

  24 months

Secondary Outcomes (14)

• To characterize the pharmacokinetic (PK) parameters of emavusertib measured by maximum plasma concentration (Cmax) (Phase 1 and 1b)

  24 months

• To characterize the pharmacokinetic (PK) parameters of emavusertib measured by trough plasma concentration (Cmin) (Phase 1 and Phase 1b)

  24 months

• To characterize the pharmacokinetic (PK) parameters of emavusertib measured by Time to maximum plasma concentration (Tmax) (Phase 1 and 1b)

  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)

  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)

  24 months

Study Arms (3)

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.

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.

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.

Drug: Emavusertib

Interventions

Emavusertib DRUG

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.

Also known as: CA-4948

Emavusertib (CA-4948) dose escalation; Emavusertib monotherapy dose expansion

Venetoclax DRUG

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.

Emavusertib dose escalation + Venetoclax

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).
• 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

You may not qualify if:

• 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 ≤ 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

Sponsors & Collaborators

• Curis, Inc.: lead

Study Sites (32)

Moffitt Cancer Center

Tampa, Florida, 33612, United States

Location

Winship Cancer Institute

Atlanta, Georgia, 30322, United States

Location

Northwestern Memorial Hospital

Chicago, Illinois, 60611, United States

Location

University of Chicago Medical Center

Chicago, Illinois, 60637, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Karmanos Cancer Institute

Detroit, Michigan, 48201, United States

Location

Oncology Hematology West, PC dba Nebraska Cancer Specialists

Omaha, Nebraska, 68130, United States

Location

University of Rochester Medical Center

Rochester, New York, 14642, United States

Location

Albert Einstein Medical College

The Bronx, New York, 10461, United States

Location

Novant Health Hematology - Forsyth

Winston-Salem, North Carolina, 27103, United States

Location

The Ohio State University Wexner Medical Center - James Cancer Hospital

Columbus, Ohio, 43210, United States

Location

The University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Vseobecna Fakultni nemocnice v Praze

Prague, 12 808, Czechia

Location

Service d'hématologie clinique CHU de Nice

Nice, 6200, France

Location

APHP - Sorbonne Universite

Paris, 75012, France

Location

APHP - Hopital Saint Louis

Paris, 75475, France

Location

Marien Hospital Dusseldorf; Klinik fur Onkologie und Hamatologie, Palliativmedizin

Düsseldorf, 40479, Germany

Location

Universitätsklinikum Hamburg-Eppendorf (UKE)

Hamburg, 20246, Germany

Location

Universitatsklinikum Leipzig; Medizinische Klinik und Poliklinik I

Leipzig, 04103, Germany

Location

Klinikum rechts der Isar der Technischen Universitat Munchen

München, 81675, Germany

Location

Universitatsklinikum Munster

Münster, 48149, Germany

Location

Soroka University MC

Beersheba, 84100, Israel

Location

Edith Wolfson Medical Center

Holon, 5822012, Israel

Location

Hadassah University MC

Jerusalem, 9112001, Israel

Location

Azienda Ospedaliera Santa Croce e Carle

Cuneo, Italy

Location

Instituto Romagnolo per lo Studio dei Tumori "Dino Amadori"

Meldola, Italy

Location

Uniwersyteckie Centrum Kliniczne Osrodek Badan Klinicznych Wczesnych Faz

Gdansk, 80-214, Poland

Location

University Hospital in Krakow

Krakow, 31 501, Poland

Location

Hospital de la Santa Creu I Sant Pau (Neuvo Hospital)

Barcelona, Spain

Location

Hospital Universitaro del a Princesa

Madrid, 28006, Spain

Location

MD Anderson Cancer Center Madrid

Madrid, Spain

Location

Hospital Universitario Virgen del Rocio

Seville, Spain

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Hereditary Sensory and Autonomic Neuropathies; Recurrence

Interventions

CA-4948; venetoclax

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Diseases; Nervous System Malformations; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Polyneuropathies; Peripheral Nervous System Diseases; Neuromuscular Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: February 10, 2020
• First Posted: February 20, 2020
• Study Start: July 6, 2020
• Primary Completion: April 1, 2026
• Study Completion: April 1, 2026
• Last Updated: March 19, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

IL (3); CZ (1); IT (2); PL (2); ES (4); FR (3); DE (5); US (12)