Phase 2 Study of Emavusertib and Zanubrutinib in Patients with Chronic Lymphocytic Leukemia and Other B-cell Malignancies
- Trial ID
- 2025-523600-68-00
- Protocol
- CA-4948-203
- Sponsor
- Curis Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the anticancer activity of emavusertib in combination with zanubrutinib in patients diagnosed with chronic lymphocytic leukemia and other B-cell malignancies. Secondary objectives include:
- Further evaluation of anticancer activity.
- Assessment of safety and tolerability.
- Determination of the exposure profile.
Participants
This study involves 80 participants diagnosed with chronic lymphocytic leukemia. The study population consists of both male and female patients within specific age ranges. Inclusion criteria require a histopathologically confirmed diagnosis according to the World Health Organization classification and an Eastern Cooperative Oncology Group performance status of ≤2. Participants must have a life expectancy of at least 3 months and measurable disease per iwCLL criteria. For Cohort 1, patients must exhibit minimal residual disease positivity as determined by the ClonoSEQ assay and have been receiving zanubrutinib for a minimum of 12 months. For Cohort 2, the population includes patients with relapsed disease who have exhausted standard of care options or are ineligible for such treatments, specifically demonstrating progression while on zanubrutinib. All participants must demonstrate acceptable organ function and maintain specific creatine phosphokinase levels below the upper limit of normal. Women of childbearing potential must have a negative serum pregnancy test and adhere to highly effective contraceptive methods.
Plans and Procedures
This Phase 2 study evaluates the anticancer activity of emavusertib in combination with zanubrutinib in patients diagnosed with chronic lymphocytic leukemia and other B-cell malignancies. The research is organized into two distinct cohorts to assess efficacy through specific clinical endpoints. Cohort 1 focuses on the rate of undetectable measurable residual disease in peripheral blood mononuclear cells, while Cohort 2 evaluates the overall response rate according to iwCLL response criteria. Study procedures involve a screening visit to confirm eligibility, including assessments of organ function and measurable disease. Following the initiation of treatment, participants undergo regular follow-up monitoring to evaluate progression-free survival, overall survival, and the incidence of treatment-emergent adverse events. Clinical assessments include physical examinations, vital signs, electrocardiograms, and laboratory evaluations to monitor pharmacokinetic parameters. The study includes requirements for bone marrow aspirate to confirm specific response rates in certain cohorts.
Treatment
The experimental medication emavusertib, referred to as CA-4948, is administered as a coated tablet via oral use.
The study includes the administration of zanubrutinib, marketed as BRUKINSA, which is provided in two pharmaceutical forms: hard capsules at a dose of 80 mg or film-coated tablets at a dose of 160 mg. This substance is administered via oral use.
Efficacy
The efficacy of the combination of emavusertib and zanubrutinib will be evaluated through specific endpoints in two cohorts of patients with chronic lymphocytic leukemia and other B-cell malignancies. In Cohort 1, the primary endpoint is the rate of undetectable measurable residual disease (uMRD) in peripheral blood mononuclear cells (PBMCs) as measured by the ClonoSEQ assay. Confirmation of complete response (CR) and uMRD via peripheral blood requires a bone marrow aspirate. Secondary assessments for Cohort 1 include the duration of uMRD, time to measurable residual disease conversion, CR rate, duration of CR, and time to CR.
In Cohort 2, the primary efficacy endpoint is the overall response rate (ORR), defined as the percentage of patients achieving CR or partial response (PR) according to the iwCLL Response Criteria. Secondary endpoints for Cohort 2 consist of duration of response (DOR) and time to response. For both cohorts, efficacy and safety are further characterized by progression-free survival (PFS), overall survival (OS), and the incidence of treatment-emergent adverse events (TEAEs). Additionally, pharmacokinetic (PK) parameters, including Cmax, Tmax, AUC0-t, and Cmin for both emavusertib and zanubrutinib, will be evaluated.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age ≥18 years of age with life expectancy of ≥ 3 months.
- Eastern Cooperative Oncology Group Performance Status of ≤2;
- Histopathologically confirmed diagnosis of CLL per the World Health Organization 2016 classification;
- At least 1 criterion for measurable disease per iwCLL; creatine phosphokinase (CPK) < 2.5 × upper limit of normal (ULN);
- Ability to tolerate contrast-enhanced computed tomography (CT) scan;
- Ability to swallow/retain oral medications;
- Negative serum pregnancy test in women of childbearing potential (WOCP);
- WOCP and men who partner with WOCP must use highly effective contraceptive methods during study and 180 days after the last dose of study treatment;
- Ability to understand/sign a written informed consent document.
- For Cohort 1 only: Patient must be in a PR or PR-L and MRD+, must have detectable MRD as determined by the ClonoSEQ assay, actively taking zanubrutinib for at least 12 months, acceptable organ function (protocol-defined) at Screening within 28 days prior to Cycle 1 Day 1 (C1D1)
- For Cohort 2 only: Relapsed disease (protocol-defined) for which patients are ineligible for or exhausted standard of care options; Actively taking zanubrutinib and with direct progression on zanubrutinib and no other anticancer therapy administered since; Acceptable organ function (protocol-defined) at Screening within 28 days prior to C1D1.
Exclusion Criteria
- Active second malignancy unless in remission with life expectancy > 2 years;
- Active malignancy other than CLL requiring systemic therapy;
- high-risk CLL TP53 mutations and 17P deletion;
- History of Grade ≥ 3 rhabdomyolysis without complete recovery;
- Prior chimeric antigen receptor-T cell therapy;
- Prior investigational drugs within 28 days or 5 half-lives, whichever is shorter, prior to C1D1: allogeneic hematopoietic stem cell transplant (HSCT) within 60 days prior to C1D1, or clinically significant graft-versus-host disease (GVHD) requiring ongoing uptitration of immunosuppressive medications prior to Screening: Prior systemic anticancer treatment received within 21 days or 5 half-lives, whichever is shorter, prior to C1D1 (with the exception of zanubrutinib, which may be continued until the day before C1D1);
- Receiving the following medications within 7 days or 5 half-lives, whichever is shorter, prior to C1D1: Medications that have a high risk of causing prolonged QT interval, corrected (QTc) and/or Torsades de Pointes, Peg-filgrastim or equivalent, St John’s Wort;
- History of or ongoing drug-induced pneumonitis, History of stroke or intracranial hemorrhage within 6 months prior to C1D1, Requirement for anticoagulation with warfarin or equivalent vitamin K antagonists, including dual antiplatelet agents, within 5 half-lives of the anticoagulant or 7 days, whichever is longer, prior to C1D1;
- Vaccinated with a live-attenuated vaccine within 4 weeks prior to C1D1: History of hypersensitivity or anaphylaxis to ema, approved BTKi, or any of their excipients;
- History of Stevens-Johnson syndrome or toxic epidermal necrolysis;
- Intolerance to contrast-enhanced CT scan: Major surgery < 28 days prior to C1D1, minor surgery < 7 days prior to C1D1. Viral infections (protocol-defined);
- Concomitant illness that would preclude safe participation in the study.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Recruiting | 20 Apr 2026 | 20 |
 Spain | Recruiting | 20 Apr 2026 | 20 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
CA-4948 | Test | COATED TABLET | ORAL USE | 00 | 9999999 | PRD10459565 |
BRUKINSA 80 mg hard capsules | Test | HARD CAPSULES | ORAL USE | 00 | 9999999 | PRD9341336 |
BRUKINSA 160 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 00 | 9999999 | PRD12846027 |
BRUKINSA 160 mg film-coated tablets | Test | FILM COATED TABLET | ORAL USE | 00 | 9999999 | PRD12846028 |
CA-4948 | Test | COATED TABLET | ORAL USE | 00 | 9999999 | PRD7988755 |