Dose Escalation/ Expansion Trial of CA-4948 as Monotherapy and in Combination With Azacitidine or Venetoclax in Patients With AML or MDS
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ClinicalTrials.gov Identifier: NCT04278768 |
Recruitment Status :
Recruiting
First Posted : February 20, 2020
Last Update Posted : February 2, 2023
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This is a multicenter, open-label, Phase 1/2a dose escalation and expansion study of orally administered emavusertib (CA-4948) monotherapy and in combination with azacitidine or venetoclax in adult patients with Acute Myelogenous Leukemia (AML) or high risk Myelodysplastic Syndrome (MDS).
- R/R AML with FLT3 mutations, R/R including a FLT3 inhibitor
- R/R AML with sliceosome mutations of SF3B1 or U2AF1
- R/R hrMDS with spliceosome mutations of SF3B1 or U2AF1; bone marrow blast count >/= 8%; ineligible for intensive chemotherapy
- Number of pretreatments: 1 or 2
Condition or disease | Intervention/treatment | Phase |
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Acute Myelogenous Leukemia Myelodysplastic Syndrome | Drug: Emavusertib Drug: Azacitidine Drug: Venetoclax | Phase 1 Phase 2 |

Study Type : | Interventional (Clinical Trial) |
Estimated Enrollment : | 325 participants |
Allocation: | Non-Randomized |
Intervention Model: | Sequential Assignment |
Intervention 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 Dose Limiting Toxicity (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 siz 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. In Phase 2a Dose Expansion (Monotherapy), for each Cohort a Simon-2-Stage design will be employed with a minimum of 9 patients enrolled in each cohort (Stage 1). If a response is observed, a total of 30 patients will be enrolled in each Cohort. If the clinical response rate is ≥ 30% in any Cohort, additional patients (max of 35) may be entered to provide a tighter estimate of the 95% confidence interval around the clinical response rate. |
Masking: | None (Open Label) |
Primary Purpose: | Treatment |
Official Title: | TakeAim Leukemia: 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 and in Combination With Azacitidine or Venetoclax |
Actual Study Start Date : | July 6, 2020 |
Estimated Primary Completion Date : | April 1, 2026 |
Estimated Study Completion Date : | April 1, 2026 |

Arm | Intervention/treatment |
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Experimental: Emavusertib (CA-4948) dose escalation
Patients receive emavusertib monotherapy PO BID daily. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
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Drug: Emavusertib
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.
Other Name: CA-4948 |
Experimental: Emavusertib dose escalation + Azacitidine
The starting dose level for emavusertib will be 200 mg BID for 21 days (Days 1-21) of a 28-day Cycle. Anticipated emavusertib doses will be 200 and 300 mg BID. Azacitidine 75 mg/m2 intravenous (IV) or subcutaneously (SC) will be administered as 7 doses on a 28-day Cycle (e.g., 7 consecutive doses or split doses with weekend break 5-2, starting at Day 1)
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Drug: Azacitidine
Azacitidine is a chemotherapy drug. Azacitidine 75 mg/m2 intravenous (IV) or subcutaneously (SC) will be administered as 7 doses on a 28-day Cycle. Drug: Emavusertib Emavusertib is formulated as a tablet for oral administration for BID dosing for 21 days (Days 1-21) of a 28-day Cycle.
Other Name: CA-4948 |
Experimental: Emavusertib dose escalation + Venetoclax
The starting dose level for emavusertib will be 200 mg BID for 21 days of a 28-day Cycle. Anticipated emavusertib doses will 200and 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.
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Drug: Venetoclax
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. Drug: Emavusertib Emavusertib is formulated as a tablet for oral administration for BID dosing for 21 days (Days 1-21) of a 28-day Cycle.
Other Name: CA-4948 |
Experimental: Emavusertib monotherapy dose expansion
The Expansion phase will begin once the RP2D from Phase 1 Dose Escalation phase has been identified. There will be 4 Cohorts and patients will be assigned to each Cohort based on baseline disease.
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Drug: Emavusertib
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.
Other Name: CA-4948 |
- 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 azacitidine (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 azacitidine (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.
- 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 complete response (Phase 2a - AML patients) [ Time Frame: 24 months ]Clinical response: A Simon 2-stage design will be followed to determine if further evaluation is needed.
- To assess overall response rate (Phase 2a - hrMDS patients) [ Time Frame: 24 months ]Clinical response: A Simon 2-stage design will be followed to determine if further evaluation is needed.
- To assess safety (Phase 1b) [ Time Frame: 24 months ]Clinical safety assessments including frequency of adverse events (AEs)
- To characterize the pharmacokinetic (PK) parameters of emavusertib measured by Cmax (Phase 1 and 1b) [ Time Frame: 24 months ]maximum plasma concentration (Cmax)
- To characterize the pharmacokinetic (PK) parameters of emavusertib measured by Cmin (Phase 1 and Phase 1b) [ Time Frame: 24 months ]trough plasma concentration (Cmin)
- To characterize the pharmacokinetic (PK) parameters of emavusertib measured by Tmax (Phase 1 and 1b) [ Time Frame: 24 months ]Time to maximum plasma concentration
- 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 ]area under the plasma concentration-time curve from 0 to 24 hours
- To characterize the pharmacokinetic (PK) parameters of emavusertib measured by AUC[INF] (Phase 1 and 1b) [ Time Frame: 24 months ]area under the plasma concentration-time curve from 0 to infinity
- To characterize the pharmacokinetic (PK) parameters of emavusertib measured by T 1/2 (Phase 1 and 1b) [ Time Frame: 24 months ]Plasma terminal elimination half-life (T 1/2)
- To assess clinical response (Phase 1 and 1b) [ Time Frame: 24 months ]For AML: assessed by proportion of patients who reach complete response (CR) + complete response with partial hematological recovery (CRh) For AML: 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) + marrow complete response (mCR) Assessed by transfusion independence
- To assess clinical response (Phase 1 and 1b) [ Time Frame: 24 months ]Assessed by transfusion independence
- To assess tolerability and long term safety (Phase 2a) [ Time Frame: 24 months ]Clinical safety assessments including frequency of adverse events (AEs)
- To assess clinical response (Phase 2a) [ Time Frame: 24 months ]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 mCR
- To assess clinical response (Phase 2a) [ Time Frame: 24 months ]Assessed by duration of response (DOR)
- To assess clinical response (Phase 2a) [ Time Frame: 24 months ]Assessed by time to response
- To assess clinical response (Phase 2a) [ Time Frame: 24 months ]Assessed by transfusion independence
- To assess clinical response (Phase 2a) [ Time Frame: 24 months ]Assessed by overall survival (OS)

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Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
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
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Cytomorphology based confirmed diagnosis of MDS or AML 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
• High-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 1b (Combination Therapy) Doublet Arm: emavusertib + AZA
Patients:
- with International Prognostic Scoring System- revised (IPSS- R) High, high risk myelodysplastic syndrome (hrMDS)
- ineligible for intensive chemotherapy
Doublet Arm: emavusertib + Venetoclax
Patients with:
• R/R AML or hrMDS, after first line therapy
Phase 2a Dose Expansion (Monotherapy)
Patients with:
- R/R AMLwith FLT3 mutations, R/R including a FLT3 inhibitor
- R/R AML with spliceosome mutations of SF3B1 or U2AF1
- R/R hrMDS with spliceosome mutations of SF3B1 or U2AF1; bone marrow blast count >/= 8%; ineligible for intensive chemotherapy
- 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 14 days prior to start of emavusertib. Localized radiation or surgical resection of skin cancers allowed.
- Use of any investigational agent within 28 days 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
- Known hypersensitivity to azacitidine or mannitol, as stated per label (Phase 1b only)
- 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 disease
- Gastrointestinal disease or disorder that could interfere with the swallowing, oral absorption, or tolerance of emavusertib
- History of other invasive malignancy, unless definitively treated with curative intent, provided it is deemed to be at low risk for recurrence by the treating physician
- 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

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04278768
Contact: Reinhard von Roemeling, MD | 617-503-6500 | clinicaltrials@curis.com |
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Principal Investigator: Katharina Gotze, Prof. Dr. med |
Responsible Party: | Curis, Inc. |
ClinicalTrials.gov Identifier: | NCT04278768 |
Other Study ID Numbers: |
CA-4948-102 |
First Posted: | February 20, 2020 Key Record Dates |
Last Update Posted: | February 2, 2023 |
Last Verified: | February 2023 |
Individual Participant Data (IPD) Sharing Statement: | |
Plan to Share IPD: | No |
Studies a U.S. FDA-regulated Drug Product: | Yes |
Studies a U.S. FDA-regulated Device Product: | No |
Acute Myelogenous Leukemia Myelodysplastic Syndrome AML MDS IRAK4 FLT3-ITD mutant FLT3 Wild Type (WT) resistant/refractory to HMA spliceosome mutation |
SF3B1 U2AF1 SRSF2 ZRSR2 high risk AML high risk MDS resistant/refractory to r/r to HMA failing prior treatment |
Leukemia Preleukemia Leukemia, Myeloid Leukemia, Myeloid, Acute Myelodysplastic Syndromes Syndrome Disease Pathologic Processes Neoplasms by Histologic Type Neoplasms |
Bone Marrow Diseases Hematologic Diseases Precancerous Conditions Azacitidine Venetoclax Antimetabolites, Antineoplastic Antimetabolites Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Enzyme Inhibitors |