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Dose Escalation/ Expansion Study of CA-4948 as Monotherapy in Patients With AML or MDS

Primary Purpose

Acute Myelogenous Leukemia, Myelodysplastic Syndrome

Status
Recruiting
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Emavusertib
Venetoclax
Emavusertib
Sponsored by
Curis, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Myelogenous Leukemia focused on measuring 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

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Moffitt Cancer CenterRecruiting
  • Northwestern Memorial HospitalRecruiting
  • Dana Farber Cancer InstituteRecruiting
  • Oncology Hematology West, PC dba Nebraska Cancer SpecialistsRecruiting
  • Albert Einstein Medical CollegeRecruiting
  • University of Rochester Medical CenterRecruiting
  • Novant Health Hematology - ForsythRecruiting
  • The University of Texas MD Anderson Cancer CenterRecruiting
  • Vseobecna Fakultni nemocnice v Praze
  • Service d'hématologie clinique CHU de Nic
  • APHP - Sorbonne Universite
  • APHP - Hopital Saint Louis
  • Marien Hospital Dusseldorf; Klinik fur Onkologie und Hamatologie, PalliativmedizinRecruiting
  • Universitatsklinikum Leipzig; Medizinische Klinik und Poliklinik IRecruiting
  • Klinikum rechts der Isar der Technischen Universitat MunchenRecruiting
  • Universitatsklinikum MunsterRecruiting
  • Soroka University MC
  • Edith Wolfson Medical Center
  • Hadassah University MC
  • Uniwersyteckie Centrum Kliniczne Osrodek Badan Klinicznych Wczesnych FazRecruiting
  • University Hospital in KrakowRecruiting
  • Hospital de la Santa Creu I Sant Pau (Neuvo Hospital)
  • Hospital Universitaro del a Princesa
  • MD Anderson Cancer Center MadridRecruiting
  • Hospital Universitario Virgen del RocioRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Emavusertib (CA-4948) dose escalation

Emavusertib dose escalation + Venetoclax

Emavusertib monotherapy dose expansion

Arm Description

Patients receive emavusertib monotherapy BID daily. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

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. This arm of the study has been closed to enrollment.

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.

Outcomes

Primary Outcome Measures

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.
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.
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.
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.
To assess anti-cancer activity (Phase 2a - AML patients)
Proportion of patients who achieve CR + CRh
To assess anti-cancer activity (Phase 2a - hrMDS patients)
Overall response rate: proportion of patients who achieve CR+PR
To assess safety (Phase 1b)
Clinical safety assessments including frequency of adverse events (AEs)

Secondary Outcome Measures

To characterize the pharmacokinetic (PK) parameters of emavusertib measured by Cmax (Phase 1 and 1b)
maximum plasma concentration (Cmax)
To characterize the pharmacokinetic (PK) parameters of emavusertib measured by Cmin (Phase 1 and Phase 1b)
trough plasma concentration (Cmin)
To characterize the pharmacokinetic (PK) parameters of emavusertib measured by Tmax (Phase 1 and 1b)
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)
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)
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)
Plasma terminal elimination half-life (T 1/2)
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)
To assess clinical response (Phase 1 and 1b)
Assessed by transfusion independence
To assess tolerability and long term safety (Phase 2a)
Clinical safety assessments including frequency of adverse events (AEs)
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 mCR
To assess clinical response (Phase 2a)
Assessed by duration of response (DOR)
To assess clinical response (Phase 2a)
Assessed by time to response
To assess clinical response (Phase 2a)
Assessed by transfusion independence
To assess clinical response (Phase 2a)
Assessed by overall survival (OS)

Full Information

First Posted
February 10, 2020
Last Updated
September 12, 2023
Sponsor
Curis, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT04278768
Brief Title
Dose Escalation/ Expansion Study of CA-4948 as Monotherapy in Patients With AML or MDS
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
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
July 6, 2020 (Actual)
Primary Completion Date
April 1, 2026 (Anticipated)
Study Completion Date
April 1, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Curis, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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 Acute Myelogenous Leukemia (AML) or high risk Myelodysplastic Syndrome (MDS). Patients enrolling in the Phase 1 portion of the study must meet one of the following criteria prior to consenting to the study: 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 R/R hrMDS with spliceosome mutations of SF3B1 or 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 (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 high risk, 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 relapsed/ refractory (R/R) patients with AML or high risk myelodysplastic syndrome (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 (FLT-3) 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 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 lead 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; R/R AML with spliceosome mutations of SF3B1 or U2AF1; and 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myelogenous Leukemia, Myelodysplastic Syndrome
Keywords
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
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 sixz 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)
Allocation
Non-Randomized
Enrollment
366 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Emavusertib (CA-4948) dose escalation
Arm Type
Experimental
Arm Description
Patients receive emavusertib monotherapy BID daily. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Arm Title
Emavusertib dose escalation + Venetoclax
Arm Type
Experimental
Arm Description
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. This arm of the study has been closed to enrollment.
Arm Title
Emavusertib monotherapy dose expansion
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Emavusertib
Other Intervention Name(s)
CA-4948
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Venetoclax
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Emavusertib
Other Intervention Name(s)
CA-4948
Intervention Description
Emavusertib is formulated as a tablet for oral administration for BID dosing for 21 days (Days 1-21) of a 28-day Cycle.
Primary Outcome Measure Information:
Title
Determine Maximum Tolerated Dose (MTD) of emavusertib (CA-4948) monotherapy (Phase 1)
Description
The highest dose at which there is <33% Dose Limiting Toxicity rate in the first cycle of treatment in a minimum of 6 patients.
Time Frame
28 days
Title
Determine the Recommended Phase 2 Dose (RP2D) of emavusertib monotherapy (Phase 1)
Description
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.
Time Frame
24 months
Title
Determine Maximum Tolerated Dose (MTD) of emavusertib in combination with venetoclax (Phase 1b)
Description
The highest dose at which there is <33% Dose Limiting Toxicity rate in the first cycle of treatment in a minimum of 6 patients.
Time Frame
28 days
Title
Determine the Recommended Phase 2 Dose (RP2D) of emavusertib in combination with venetoclax (Phase 1b)
Description
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.
Time Frame
24 months
Title
To assess anti-cancer activity (Phase 2a - AML patients)
Description
Proportion of patients who achieve CR + CRh
Time Frame
24 months
Title
To assess anti-cancer activity (Phase 2a - hrMDS patients)
Description
Overall response rate: proportion of patients who achieve CR+PR
Time Frame
24 months
Title
To assess safety (Phase 1b)
Description
Clinical safety assessments including frequency of adverse events (AEs)
Time Frame
24 months
Secondary Outcome Measure Information:
Title
To characterize the pharmacokinetic (PK) parameters of emavusertib measured by Cmax (Phase 1 and 1b)
Description
maximum plasma concentration (Cmax)
Time Frame
24 months
Title
To characterize the pharmacokinetic (PK) parameters of emavusertib measured by Cmin (Phase 1 and Phase 1b)
Description
trough plasma concentration (Cmin)
Time Frame
24 months
Title
To characterize the pharmacokinetic (PK) parameters of emavusertib measured by Tmax (Phase 1 and 1b)
Description
Time to maximum plasma concentration
Time Frame
24 months
Title
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)
Description
Area under the plasma concentration-time curve from 0 to 24 hours
Time Frame
24 months
Title
To characterize the pharmacokinetic (PK) parameters of emavusertib measured by AUC[INF] (Phase 1 and 1b)
Description
Area under the plasma concentration-time curve from 0 to infinity
Time Frame
24 months
Title
To characterize the pharmacokinetic (PK) parameters of emavusertib measured by T 1/2 (Phase 1 and 1b)
Description
Plasma terminal elimination half-life (T 1/2)
Time Frame
24 months
Title
To assess clinical response (Phase 1 and 1b)
Description
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)
Time Frame
24 months
Title
To assess clinical response (Phase 1 and 1b)
Description
Assessed by transfusion independence
Time Frame
24 months
Title
To assess tolerability and long term safety (Phase 2a)
Description
Clinical safety assessments including frequency of adverse events (AEs)
Time Frame
24 months
Title
To assess clinical response (Phase 2a)
Description
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
Time Frame
24 months
Title
To assess clinical response (Phase 2a)
Description
Assessed by duration of response (DOR)
Time Frame
24 months
Title
To assess clinical response (Phase 2a)
Description
Assessed by time to response
Time Frame
24 months
Title
To assess clinical response (Phase 2a)
Description
Assessed by transfusion independence
Time Frame
24 months
Title
To assess clinical response (Phase 2a)
Description
Assessed by overall survival (OS)
Time Frame
24 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Males and females ≥18 years of age Life expectancy of at least 3 months Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤1 Cytomorphology based confirmed diagnosis of MDS or AML (as per WHO 2016 classification) with the following characteristics. Phase 1 Dose Escalation (Monotherapy) • AML (primary or secondary, including treatment-related) after failing at least 1 standard treatment (may include chemotherapy, re induction therapy or stem cell transplantation). OR • Higher-risk R/R MDS that are considered resistant/refractory following at least 2 to 3 cycles of hypermethylating agent (HMA) or evidence of early progression Phase 2a Dose Expansion (Monotherapy) Patients with: R/R AMLwith FLT3 mutations who have been previously treated with a FLT3 inhibitor R/R AML with spliceosome mutations of SF3B1 or U2AF1 R/R hrMDS (IPSS-R score > 3.5) with spliceosome mutations of SF3B1 or U2AF1 Number of pretreatments: 1 or 2 Acceptable organ function at screening Ability to swallow and retain oral medications Negative serum pregnancy test in women of childbearing potential Women of childbearing potential and men who partner with a woman of childbearing potential must agree to use highly effective contraceptive methods for the duration of the study and for 90 days after the last dose of emavusertib Willing and able to provide written informed consent and comply with the requirements of the trial Able to undergo serial bone marrow sampling and peripheral blood sampling Exclusion Criteria: Diagnosed with acute promyelocytic leukemia (APL, M3) Has known active central nervous system (CNS) leukemia Allogeneic hematopoietic stem cell transplant (Allo-HSCT) within 60 days of the first dose of emavusertib, or clinically significant graft-versus-host disease (GVHD) requiring ongoing up titration of immunosuppressive medications prior to start of emavusertib Chronic myeloid leukemia (CML) Any prior systemic anti-cancer treatment such as chemotherapy, immunomodulatory drug therapy, etc., received within 3 weeks (or 5 half-lives) prior to start of emavusertib. Localized radiation or surgical resection of skin cancers allowed. Use of any investigational agent within 3 weeks or 5 half-lives, whichever is shorter, prior to start of emavusertib Presence of an acute or chronic toxicity resulting from prior anti-cancer therapy, with the exception of alopecia that has not resolved to Grade ≤ 1within 7 days prior to start of emavusertib; presence of any acute or chronic non-hematological toxicity ≥ Grade 3 at Screening, or prior to start of emavusertib must resolve to ≤ Grade 2. Known allergy or hypersensitivity to any component of the formulation of emavusertib Major surgery, other than diagnostic surgery, <28 days from the start of emavusertib; minor surgery <14 days from the start of emavusertib Patients with active advanced malignant solid tumors Known to be human immunodeficiency virus (HIV) positive or have an acquired immunodeficiency syndrome-related illness Hepatitis B virus (HBV) DNA positive or Hepatitis C virus (HCV) infection <6 months prior to start of emavusertib unless viral load is undetectable, or HCV with cirrhosis Uncontrolled or severe cardiovascular diseaseincluding myocardial infarction or unstable angina within 6 months prior to CA-4948, New York Heart Association Class II or greater congestive heart failure, or left ventricular ejection fraction < 40% by echocardiogram or multi-gated acquisition scan, serious arrhythmias uncontrolled on treatment, clinically significant pericardial disease, cardiac amyloidosis, congenital long QT syndrome, or QTc with Fridericia's correction (QTcF) that is unmeasurable or > 450 msec on Screening electrocardiogram (ECG) Gastrointestinal disease or disorder that could interfere with the swallowing, oral absorption, or tolerance of emavusertib Pregnant or lactating Systemic fungal, bacterial, viral, or other infection that is not controlled Any other severe, acute, or chronic medical, psychiatric or social condition, or laboratory abnormality that may increase the risk of trial participation or emavusertib administration
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Reinhard von Roemeling, MD
Phone
617-503-6500
Email
clinicaltrials@curis.com
Facility Information:
Facility Name
Moffitt Cancer Center
City
Tampa
State/Province
Florida
ZIP/Postal Code
33612
Country
United States
Individual Site Status
Recruiting
Facility Name
Northwestern Memorial Hospital
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Individual Site Status
Recruiting
Facility Name
Dana Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Individual Site Status
Recruiting
Facility Name
Oncology Hematology West, PC dba Nebraska Cancer Specialists
City
Omaha
State/Province
Nebraska
ZIP/Postal Code
68130
Country
United States
Individual Site Status
Recruiting
Facility Name
Albert Einstein Medical College
City
Bronx
State/Province
New York
ZIP/Postal Code
10461
Country
United States
Individual Site Status
Recruiting
Facility Name
University of Rochester Medical Center
City
Rochester
State/Province
New York
ZIP/Postal Code
14642
Country
United States
Individual Site Status
Recruiting
Facility Name
Novant Health Hematology - Forsyth
City
Winston-Salem
State/Province
North Carolina
ZIP/Postal Code
27103
Country
United States
Individual Site Status
Recruiting
Facility Name
The University of Texas MD Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Individual Site Status
Recruiting
Facility Name
Vseobecna Fakultni nemocnice v Praze
City
Praha 2
ZIP/Postal Code
12 808
Country
Czechia
Individual Site Status
Not yet recruiting
Facility Name
Service d'hématologie clinique CHU de Nic
City
Nice
ZIP/Postal Code
6200
Country
France
Individual Site Status
Not yet recruiting
Facility Name
APHP - Sorbonne Universite
City
Paris
ZIP/Postal Code
75012
Country
France
Individual Site Status
Not yet recruiting
Facility Name
APHP - Hopital Saint Louis
City
Paris
ZIP/Postal Code
75475
Country
France
Individual Site Status
Not yet recruiting
Facility Name
Marien Hospital Dusseldorf; Klinik fur Onkologie und Hamatologie, Palliativmedizin
City
Düsseldorf
ZIP/Postal Code
40479
Country
Germany
Individual Site Status
Recruiting
Facility Name
Universitatsklinikum Leipzig; Medizinische Klinik und Poliklinik I
City
Leipzig
ZIP/Postal Code
04103
Country
Germany
Individual Site Status
Recruiting
Facility Name
Klinikum rechts der Isar der Technischen Universitat Munchen
City
München
ZIP/Postal Code
81675
Country
Germany
Individual Site Status
Recruiting
Facility Name
Universitatsklinikum Munster
City
Münster
ZIP/Postal Code
48149
Country
Germany
Individual Site Status
Recruiting
Facility Name
Soroka University MC
City
Be'er Sheva
ZIP/Postal Code
84100
Country
Israel
Individual Site Status
Not yet recruiting
Facility Name
Edith Wolfson Medical Center
City
H̱olon
ZIP/Postal Code
5822012
Country
Israel
Individual Site Status
Not yet recruiting
Facility Name
Hadassah University MC
City
Jerusalem
ZIP/Postal Code
9112001
Country
Israel
Individual Site Status
Not yet recruiting
Facility Name
Uniwersyteckie Centrum Kliniczne Osrodek Badan Klinicznych Wczesnych Faz
City
Gdańsk
ZIP/Postal Code
80-214
Country
Poland
Individual Site Status
Recruiting
Facility Name
University Hospital in Krakow
City
Kraków
ZIP/Postal Code
31 501
Country
Poland
Individual Site Status
Recruiting
Facility Name
Hospital de la Santa Creu I Sant Pau (Neuvo Hospital)
City
Barcelona
Country
Spain
Individual Site Status
Not yet recruiting
Facility Name
Hospital Universitaro del a Princesa
City
Madrid
ZIP/Postal Code
28006
Country
Spain
Individual Site Status
Not yet recruiting
Facility Name
MD Anderson Cancer Center Madrid
City
Madrid
Country
Spain
Individual Site Status
Recruiting
Facility Name
Hospital Universitario Virgen del Rocio
City
Sevilla
Country
Spain
Individual Site Status
Recruiting

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Dose Escalation/ Expansion Study of CA-4948 as Monotherapy in Patients With AML or MDS

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