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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Curis Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

9 Dec 2020 → 24 Mar 2026

Decision date (initial)

2024-09-30

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Curis, Inc.

External identifiers

EU CT number

2024-513313-13-00

EudraCT number

2019-004839-23

ClinicalTrials.gov

NCT04278768

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Pharmacogenetic, Dose response, Pharmacogenomic, Safety, Others, Pharmacokinetic, Pharmacodynamic

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

Secondary objectives 4

1. Phase 1: To characterize the pharmacokinetic (PK) parameters of CA 4948 using non-compartmental analysis and appropriate PK modelling
2. Phase 1: To assess anti-cancer activity
3. Phase 2a: To assess tolerability and long-term safety
4. Phase 2a: To further assess anti-cancer activity of CA-4948 at RP2D

Conditions and MedDRA coding

Acute Myelogenous Leukemia (AML) or higher-risk Myelodysplastic Syndrome (MDS).

Study design 2 periods

Regulatory references

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. 01. Males and females >=18 years of age
2. 02. Life expectancy of at least 3 months
3. 03. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 1
4. 04. 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)
5. 04. 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)
6. 05. 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)
7. 06. CPK < Grade 2
8. 07. 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).
9. 08. Ability to swallow and retain oral medications
10. 09. Negative serum pregnancy test in women of childbearing potential (WOCP)
11. 10. 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
12. 11. Willing and able to provide written informed consent and comply with the requirements of the study
13. 12. 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.

Exclusion criteria 14

1. 01. Diagnosed with acute promyelocytic leukemia (APL, M3)
2. 02. 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)
3. 03. 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.
4. 04. Chronic myelogenous leukemia
5. 05. 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.
6. 06. Use of any investigational agent within 3 weeks (or 5 half-lives), whichever is shorter, prior to start of CA 4948
7. 07. 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
8. 08. Known allergy or hypersensitivity to any component of the formulation of CA-4948 used in this study
9. 09. 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.
10. 10. Patients with active advanced malignant solid tumors
11. 11. 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.
12. 12. 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)
13. 13. Pregnant or lactating
14. 14. History of ≥ Grade 3 rhabdomyolysis without complete recovery

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

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

Secondary endpoints 6

1. 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)
2. 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
3. Phase 1: Clinical response in hrMDS: - Overall response rate (ORR): proportion of patients who achieve CR or PR - DOR - Time to response
4. Phase I: Transfusion independence in AML or hrMDS
5. Phase 2a: Safety measured by AEs, ECGs, chemistry and hematology laboratory values, vital signs, and physical examinations
6. 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)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Curis Inc.

Sponsor organisation

Curis Inc.

Address

128 Spring Street Suite 500 Building C

City

Lexington

Postcode

02421-7800

Country

United States

Scientific contact point

Organisation

Curis Inc.

Contact name

Catherine Wang

Public contact point

Organisation

Curis Inc.

Contact name

Catherine Wang

Third parties 8

Locations

3 EU/EEA countries · 11 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 15 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications