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

• ClinicalTrials.gov Identifier: NCT04278768
• Recruitment Status: Recruiting
• First Posted: February 20, 2020
• Last Update Posted: February 2, 2023
• Sponsor: Curis, Inc.
• Information provided by (Responsible Party): Curis, Inc.

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 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

Detailed Description:

The primary objective of Phase 1 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 Phase 1b 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.

The primary objective of Phase 2a of the study (emavusertib monotherapy expansion) is to assess complete response (CR) and duration of response in patients with R/R FLT-3 AML, R/R AML with sliceosome mutations of SF3B1 or U2AF1 and R/R hrMDS with sliceosome mutations of SF3B1 or U2AF1 and to assess tolerability, and long-term safety.

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, 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.

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 the target dose level.

Azacitidine 75 mg/m2 intravenous (IV) or subcutaneously (SC) will be administered as 7 doses on a 28 Cycle (e.g., 7 consecutive doses or split doses with weekend break 5-2), starting at Day 1, and in accordance with local prescribing information.

In each of the Phase 1/1b cohorts, three patients with AML or MDS will be 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 experience 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 leads 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 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

Study Design

• 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

Arms and Interventions

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

Outcome Measures

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)

Eligibility Criteria

• 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

Contacts and Locations

Contacts

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

Locations

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.

More Information

• Responsible Party: Curis, Inc.
• ClinicalTrials.gov Identifier: NCT04278768
• Other Study ID Numbers: CA-4948-102
• First Posted: February 20, 2020
• 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

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:

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