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Dose Escalation/ Expansion Trial of CA-4948 as Monotherapy and in Combination With Azacitidine or Venetoclax in Patients With AML or MDS

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04278768
Recruitment Status : Recruiting
First Posted : February 20, 2020
Last Update Posted : February 2, 2023
Sponsor:
Information provided by (Responsible Party):
Curis, Inc.

Brief Summary:

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
Acute Myelogenous Leukemia Myelodysplastic Syndrome Drug: Emavusertib Drug: Azacitidine Drug: Venetoclax Phase 1 Phase 2

Show Show detailed description

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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
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.
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)
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.
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.
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




Primary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. To assess safety (Phase 1b) [ Time Frame: 24 months ]
    Clinical safety assessments including frequency of adverse events (AEs)


Secondary Outcome Measures :
  1. To characterize the pharmacokinetic (PK) parameters of emavusertib measured by Cmax (Phase 1 and 1b) [ Time Frame: 24 months ]
    maximum plasma concentration (Cmax)

  2. To characterize the pharmacokinetic (PK) parameters of emavusertib measured by Cmin (Phase 1 and Phase 1b) [ Time Frame: 24 months ]
    trough plasma concentration (Cmin)

  3. To characterize the pharmacokinetic (PK) parameters of emavusertib measured by Tmax (Phase 1 and 1b) [ Time Frame: 24 months ]
    Time to maximum plasma concentration

  4. 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

  5. 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

  6. 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)

  7. 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

  8. To assess clinical response (Phase 1 and 1b) [ Time Frame: 24 months ]
    Assessed by transfusion independence

  9. To assess tolerability and long term safety (Phase 2a) [ Time Frame: 24 months ]
    Clinical safety assessments including frequency of adverse events (AEs)

  10. 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

  11. To assess clinical response (Phase 2a) [ Time Frame: 24 months ]
    Assessed by duration of response (DOR)

  12. To assess clinical response (Phase 2a) [ Time Frame: 24 months ]
    Assessed by time to response

  13. To assess clinical response (Phase 2a) [ Time Frame: 24 months ]
    Assessed by transfusion independence

  14. To assess clinical response (Phase 2a) [ Time Frame: 24 months ]
    Assessed by overall survival (OS)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Males and females ≥18 years of age
  2. Life expectancy of at least 3 months
  3. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤1
  4. 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
  5. Acceptable organ function at screening
  6. Ability to swallow and retain oral medications
  7. Negative serum pregnancy test in women of childbearing potential
  8. 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
  9. Willing and able to provide written informed consent and comply with the requirements of the trial
  10. Able to undergo serial bone marrow sampling and peripheral blood sampling

Exclusion Criteria:

  1. Diagnosed with acute promyelocytic leukemia (APL, M3)
  2. Has known active central nervous system (CNS) leukemia
  3. 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
  4. Chronic myeloid leukemia (CML)
  5. 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.
  6. Use of any investigational agent within 28 days or 5 half-lives, whichever is shorter, prior to start of emavusertib
  7. 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
  8. Known allergy or hypersensitivity to any component of the formulation of emavusertib
  9. Major surgery, other than diagnostic surgery, <28 days from the start of emavusertib; minor surgery <14 days from the start of emavusertib
  10. Known hypersensitivity to azacitidine or mannitol, as stated per label (Phase 1b only)
  11. Patients with active advanced malignant solid tumors
  12. Known to be human immunodeficiency virus (HIV) positive or have an acquired immunodeficiency syndrome-related illness
  13. 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
  14. Uncontrolled or severe cardiovascular disease
  15. Gastrointestinal disease or disorder that could interfere with the swallowing, oral absorption, or tolerance of emavusertib
  16. 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
  17. Pregnant or lactating
  18. Systemic fungal, bacterial, viral, or other infection that is not controlled
  19. 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

Information from the National Library of Medicine

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


Contacts
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Contact: Reinhard von Roemeling, MD 617-503-6500 clinicaltrials@curis.com

Locations
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United States, Florida
Moffitt Cancer Center Recruiting
Tampa, Florida, United States, 33612
Principal Investigator: Chetasi Talati, MD         
United States, Massachusetts
Dana Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Principal Investigator: Eric S Winer, MD         
United States, Nebraska
Oncology Hematology West, PC dba Nebraska Cancer Specialists Recruiting
Omaha, Nebraska, United States, 68130
Principal Investigator: Stefano Tarantolo, MD         
United States, New York
Albert Einstein Medical College Recruiting
Bronx, New York, United States, 10461
Principal Investigator: Amit K Verma, MD         
United States, North Carolina
Novant Health Hematology - Forsyth Recruiting
Winston-Salem, North Carolina, United States, 27103
Principal Investigator: James P Dugan, MD         
United States, Texas
The University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Principal Investigator: Guillermo Garcia-Manero, MD         
Germany
Marien Hospital Dusseldorf; Klinik fur Onkologie und Hamatologie, Palliativmedizin Recruiting
Düsseldorf, Germany, 40479
Principal Investigator: Stefanie Gropper, Dr. med.         
Universitatsklinikum Leipzig; Medizinische Klinik und Poliklinik I Recruiting
Leipzig, Germany, 04103
Principal Investigator: Uwe Platzbecker, Prof. Dr. med.         
Klinikum rechts der Isar der Technischen Universitat Munchen Recruiting
München, Germany, 81675
Principal Investigator: Katharina Gotze, Prof. Dr. med         
Sponsors and Collaborators
Curis, Inc.
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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

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Curis, Inc.:
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
Additional relevant MeSH terms:
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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