Study of Orally Administered CA-4948(IRAK4i) as a Monotherapy in patients with Acute Myelogenous Leukemia or Myelodysplastic Syndrome

Phase 1/2

Completed

• Conditions: Acute Myelogenous Leukemia (AML) or higher-risk Myelodysplastic Syndrome (MDS).
• Interventions: Drug: Venetoclax; Drug: Emavusertib

• Registration Number: 2024-513313-13-00
• Lead Sponsor: Curis Inc.

Brief Summary

Phase 1

• To evaluate the safety and tolerability of CA-4948 in patients with relapsed / refractory (R/R) acute myelogenous leukemia (AML) and higher-risk myelodysplastic syndrome (hrMDS)

• To identify maximum tolerated dose (MTD) and recommended Phase 2 Dose (RP2D)

Phase 2a:

To assess anti-cancer activity of CA-4948 at RP2D in patients with R/R AML with FMS-like tyrosine kinase-3 (FLT-3) mutations, and patients with R/R hrMDS or R/R AML with spliceosome mutations of SF3B1 or U2AF1

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-2, high risk, or every 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 R/R patients with AML or 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 (FLT3) 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 milligrams (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 led 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:

1. R/R AML with FLT3 mutations who have been previously treated with a FLT3 inhibitor; or

2. R/R AML with spliceosome mutations of SF3B1 or U2AF1; or

3. 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.

Study Timeline

• Study First Posted: 2024-09-04
• Last Update Posted: 2024-09-30

Recruitment & Eligibility

• Status: Ended
• Sex: Not specified
• Target Recruitment: 70

Inclusion Criteria

1. Males and females >=18 years of age

2. Negative serum pregnancy test in women of childbearing potential (WOCP)

3. WOCP and men who partner with a WOCP must agree to use highly effective contraceptive methods for the duration of the study and for 180 days after the last dose of CA-4948

4. Willing and able to provide written informed consent and comply with the requirements of the study

5. Biopsy requirement for AML and MDS: patients must be willing to have serial bone marrow sampling and peripheral blood sampling during the study. The diagnosis and evaluation of AML and MDS will be made by bone marrow aspiration and/or biopsy. If an aspirate is unobtainable (ie, a “dry tap”), the diagnosis is made from the core biopsy.

6. Life expectancy of at least 3 months

7. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 1

8. Cytomorphology based confirmed diagnosis of MDS or AML (as per the World Health Organization 2016 classification) with the following characteristics: -Phase 1 Dose Escalation Patients that meet 1 of the following criteria: • 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 (IPSS-R score > 3.5) with spliceosome mutations of SF3B1 or U2AF1 And • Have had ≤ 2 lines of prior systemic anti-cancer treatment (see Appendix M for guidelines)

9. Cytomorphology based confirmed diagnosis of MDS or AML (as per the World Health Organization 2016 classification) with the following characteristics: Phase 2a Dose Expansion Patients with: • R/R AML with FLT-3 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 And • Have had ≤ 2 lines of prior systemic anti-cancer treatment (see Appendix M for guidelines)

10. Acceptable organ function at Screening as described below: a. Estimated creatinine clearance of ≥ 35 mL/min b. Aspartate aminotransferase or alanine aminotransferase ≤ 2 × ULN c. Total bilirubin ≤ 1.5 × ULN or ≤ 3 × ULN in patients with documented Gilbert’s syndrome d. White blood cell count ≤ 25,000/µL (hydroxyurea is allowed during Screening and Cycle 1 for cytoreduction, if needed, for patients with AML per Investigator’s discretion. However, hydroxyurea must stop prior to Cycle 2)

11. CPK < Grade 2

12. For patients on a cholesterol lowering agent that has been associated with CPK elevations, such as statins or fibrates, the agent should be discontinued or replaced with an alternative if medically feasible. Otherwise, it should be reduced to the lowest dose that is biologically effective (ie, the lowest dose required to achieve the desired clinical effect).

13. Ability to swallow and retain oral medications

Exclusion Criteria

1. Diagnosed with acute promyelocytic leukemia (APL, M3)

2. Patients with active advanced malignant solid tumors

3. Viral Infections: a. Known to be human immunodeficiency virus (HIV) positive or have an acquired immunodeficiency syndrome-related illness. If HIV virus is undetectable and maintained on treatment, enrollment may be allowed after discussion with the Sponsor b. Hepatitis B virus (HBV) DNA positive or hepatitis C virus (HCV) infection < 6 months prior to start of CA-4948 unless viral load is undetectable, or HCV with cirrhosis Note: testing only required in patients with history of HBV or history of HCV < 6 months prior to start of CA-4948.

4. Concomitant illnesses that would preclude safe participation in study, identified within approximately 28 days of C1D1, including: a. Uncontrolled or severe cardiovascular disease, including myocardial infarction or unstable angina within 6 months prior to CA-4948, New York Heart Association Class II or greater congestive heart failure, or left ventricular ejection fraction < 50% by echocardiogram or multi-gated acquisition scan, serious arrhythmias uncontrolled on treatment, clinically significant pericardial disease, cardiac amyloidosis, congenital long QT syndrome, or QTc with Fridericia’s correction (QTcF) that is unmeasurable or > 450 msec on Screening electrocardiogram (ECG) Note: for QTcF > 450 msec on the Screening ECG, the ECG may be repeated twice at least 24 hours apart; the mean QTcF from the 3 Screening ECGs must be ≤ 450 msec in order to meet eligibility for study participation. Patients with bundle branch block and/or ventricular paced rhythms should be reviewed by the Medical Monitor for potential inclusion. b. Gastrointestinal disease or disorder that could interfere with the swallowing, oral absorption, or tolerance of CA-4948. This includes major abdominal surgery and/or significant bowel resection and/or gastrointestinal diseases that could alter the assessment of PK or safety c. Any other severe, acute, or chronic medical, psychiatric or social condition, or laboratory abnormality that may increase the risk of study participation or CA-4948 administration, may interfere with the informed consent process and/or with compliance with the requirements of the study or may interfere with the interpretation of the study results and, in the Investigator's opinion, would make the patient inappropriate for entry into this study d. Systemic fungal, bacterial, viral, or other infection that is not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment)

5. Pregnant or lactating

6. History of ≥ Grade 3 rhabdomyolysis without complete recovery

7. Known active central nervous system (CNS) leukemia; patients with previously treated CNS disease may participate if asymptomatic as determined by treating physician (without symptomatic active disease for at least 4 weeks prior to the first dose of treatment, and any neurologic symptoms have returned to baseline)

8. Allogeneic SCT within 60 days of the first dose of CA 4948, or clinically significant graft-versus-host disease (GVHD) requiring ongoing up titration of immunosuppressive medications prior to start of CA-4948 Note: The use of a stable or tapering dose of immunosuppressive therapy post-SCT and/or topical steroids for ongoing skin GVHD is permitted with Medical Monitor approval.

9. Chronic myelogenous leukemia

10. Any prior systemic anti-cancer treatment such as chemotherapy, immunomodulatory drug therapy, etc, received within 3 weeks (or 5 half-lives), whichever is shorter, or radiotherapy received 2 weeks prior to the start of CA-4948. Note: Localized radiation or surgical resection of skin cancers is allowed.

11. Use of any investigational agent within 3 weeks (or 5 half-lives), whichever is shorter, prior to start of CA 4948

12. 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, as determined by NCI-CTCAE v 4.03 within 7 days prior to start of CA-4948, unless approved by the Medical Monitor

13. Known allergy or hypersensitivity to any component of the formulation of CA-4948 used in this study

14. Major surgery, other than diagnostic surgery, < 28 days from the start of CA-4948; minor surgery < 14 days from the start of CA-4948 Note: Insertion of a vascular access device is not considered minor surgery.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Emavusertib dose escalation + Venetoclax	Venetoclax	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.
Emavusertib dose escalation + Venetoclax	Emavusertib	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.
Emavusertib (CA-4948) dose escalation	Emavusertib	Patients receive emavusertib monotherapy BID daily. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Emavusertib monotherapy dose expansion	Emavusertib	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.

Primary Outcome Measures

Name	Time	Method
Phase 1: Safety measured by adverse events (AEs), dose-limiting toxicities (DLTs) electrocardiograms (ECGs), chemistry and hematology laboratory values, vital signs, and physical examinations		Phase 1: Safety measured by adverse events (AEs), dose-limiting toxicities (DLTs) electrocardiograms (ECGs), chemistry and hematology laboratory values, vital signs, and physical examinations
Phase 2a: Clinical response in AML or hrMDS assessed as follows: • AML: Proportion of patients who achieve CR + CRh • hrMDS: ORR (CR + PR)		Phase 2a: Clinical response in AML or hrMDS assessed as follows: • AML: Proportion of patients who achieve CR + CRh • hrMDS: ORR (CR + PR)

Secondary Outcome Measures

Name	Time	Method
Phase 1: PK parameters of CA 4948 measured by maximum plasma concentration (Cmax), trough plasma concentration (Cmin), time to Cmax (Tmax,) area under the concentration-time curve from 0-24 hours (AUC 0-24), area under the concentration-time curve from 0 to infinity (AUC 0-inf), and half-life (T ½)		Phase 1: PK parameters of CA 4948 measured by maximum plasma concentration (Cmax), trough plasma concentration (Cmin), time to Cmax (Tmax,) area under the concentration-time curve from 0-24 hours (AUC 0-24), area under the concentration-time curve from 0 to infinity (AUC 0-inf), and half-life (T ½)
Phase 1: Clinical response in AML :- Proportion of patients who achieve complete response (CR) + complete response with partial hematological recovery (CRh) - Proportion of patients who achieve complete response with incomplete hematological recovery (CRi), or CR, or CRh, or partial response (PR), or morphologic leukemia-free state (MLFS) - Duration of response (DOR) - Time to response		Phase 1: Clinical response in AML :- Proportion of patients who achieve complete response (CR) + complete response with partial hematological recovery (CRh) - Proportion of patients who achieve complete response with incomplete hematological recovery (CRi), or CR, or CRh, or partial response (PR), or morphologic leukemia-free state (MLFS) - Duration of response (DOR) - Time to response
Phase 1: Clinical response in hrMDS: - Overall response rate (ORR): proportion of patients who achieve CR or PR - DOR - Time to response		Phase 1: Clinical response in hrMDS: - Overall response rate (ORR): proportion of patients who achieve CR or PR - DOR - Time to response
Phase I: Transfusion independence in AML or hrMDS		Phase I: Transfusion independence in AML or hrMDS
Phase 2a: Safety measured by AEs, ECGs, chemistry and hematology laboratory values, vital signs, and physical examinations		Phase 2a: Safety measured by AEs, ECGs, chemistry and hematology laboratory values, vital signs, and physical examinations
Phase 2a: Clinical response in AML or hrMDS assessed as follows:- Proportion of patients with AML who achieve CR, or CRh, or CRi - Proportion of patients with hrMDS who achieve CR, or PR, or mCR, with or without hematological improvement - DOR - Time to responses - Transfusion independence - Overall survival (OS)		Phase 2a: Clinical response in AML or hrMDS assessed as follows:- Proportion of patients with AML who achieve CR, or CRh, or CRi - Proportion of patients with hrMDS who achieve CR, or PR, or mCR, with or without hematological improvement - DOR - Time to responses - Transfusion independence - Overall survival (OS)

Trial Locations

Locations (11)

Assistance Publique Hopitaux De Paris; 🇫🇷 Paris Cedex 10, France

Centre Hospitalier Universitaire De Nice; 🇫🇷 Nice, France

Hopital Saint Antoine; 🇫🇷 Paris Cedex 12, France

Universitaetsklinikum Leipzig AöR; 🇩🇪 Leipzig, Germany

Klinikum rechts der Isar der TU Muenchen AöR; 🇩🇪 Munich, Germany

Marien Hospital Duesseldorf GmbH; 🇩🇪 Duesseldorf, Germany

University Medical Center Hamburg-Eppendorf; 🇩🇪 Hamburg, Germany

Universitaet Muenster; 🇩🇪 Muenster, Germany

Hospital Universitario De La Princesa; 🇪🇸 Madrid, Spain

MD Anderson Cancer Center; 🇪🇸 Madrid, Spain

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Assistance Publique Hopitaux De Paris

🇫🇷Paris Cedex 10, France

Lionel Ades

Site contact

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lionel.ades@aphp.fr