CA-4948-101: Open-Label, Dose Escalation and Expansion Trial of Emavusertib (CA-4948) in Relapsed or Refractory Primary Central Nervous System Lymphoma (R/R PCNSL)

An Open-Label, Dose Escalation and Dose Expansion Trial Evaluating the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of Orally Administered CA-4948 in Patients With Relapsed or Refractory Primary Central Nervous System Lymphoma

This is a multi-center, open-label study to evaluate the safety, pharmacokinetics (PK), and anti-cancer activity of oral administration of emavusertib alone or in combination with ibrutinib in adult participants with relapsed or refractory (R/R) hematologic malignancies.

This trial will be completed in four parts. In Part A1, emavusertib will be evaluated first in a dose escalating monotherapy setting to establish the safety and tolerability (complete). In Part A2, emavusertib will be evaluated in combination with ibrutinib at 560 milligrams (mg) once daily (QD) or 420 mg QD as indicated by disease (Part A2 complete).

Part B will comprise 2 cohorts to assess safety and efficacy of emavusertib in combination with ibrutinib in participants with R/R primary central nervous system lymphoma (PCNSL) who have directly progressed on a bruton tyrosine kinase inhibitor (BTKi). In this part of the study, emavusertib will be dosed at 100 mg or 200 mg twice daily (BID) in combination with ibrutinib in 28-day treatment cycles.

Part C will comprise 3 treatment arms in the second-line setting to assess the efficacy and safety of emavusertib monotherapy, ibrutinib monotherapy, and emavusertib in combination with ibrutinib in participants with R/R PCNSL who are naïve to BTKi treatment. In this part of the study, eligible second-line participants with R/R PCNSL who are naïve to BTKi treatment will be randomized 1:1:1 to 1 of 3 treatment arms: (1) emavusertib 200 mg BID, (2) ibrutinib 560 mg QD, or (3) emavusertib 200 mg BID in combination with ibrutinib 560 mg QD.

Study Overview

• Status: Recruiting
• Conditions: Relapsed Primary Central Nervous System Lymphoma; Refractory Hematologic Malignancy; Relapsed Hematologic Malignancy; Refractory Primary Central Nervous System Lymphoma
• Intervention / Treatment: Drug: Emavusertib; Drug: Ibrutinib

• Study Type: Interventional
• Enrollment (Estimated): 152
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Ahmed Hamdy, MD; Phone Number: 617-503-6500; Email: clinicaltrials@curis.com

Study Locations

• Czechia
  • Prague, Czechia
    • Recruiting
    • Vseobecna Fakultni Nemocnice V Praze
• France
  • Bordeaux, France
    • Recruiting
    • Institut Bergonie
  • Marseille, France
    • Recruiting
    • Hopital de la Timone
  • Paris, France
    • Recruiting
    • Hospital Pitie Salpetriere
  • Paris, France
    • Recruiting
    • Institut Curie Hospital
• Israel
  • Beersheba, Israel
    • Recruiting
    • Hematology Department Soroka UMC / Heanatology Department
  • Haifa, Israel
    • Recruiting
    • Rambam Medical Center
  • Jerusalem, Israel
    • Recruiting
    • Hadassah Medical Center / Ein-Carem
• Italy
  • Cuneo, Italy
    • Recruiting
    • Università di Torino Croce e Carle
  • Florence, Italy
    • Recruiting
    • SODc Ematologia Azienda Ospedaliera Universitaria Careggi
  • Meldola, Italy
    • Recruiting
    • IRST - Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori
  • Milan, Italy
    • Recruiting
    • IRCCS San Raffaele Scientific Institute
• Poland
  • Gdansk, Poland
    • Recruiting
    • Uniwersyteckie Centrum Kliniczne Osrodek Badan Klinicznych Wczesnych Faz
  • Krakow, Poland
    • Withdrawn
    • Oddzial Kliniczny Hematologii
  • Warsaw, Poland
    • Recruiting
    • NarodowyInstytutu Onkologii im. Marii Sklodowskiej-Curie-Panstwowy Instytutu Badawczy
• Spain
  • Barcelona, Spain
    • Recruiting
    • University Hospital Vall d'Hebron
  • Madrid, Spain
    • Recruiting
    • MD Anderson Cancer Center Madrid
  • Seville, Spain
    • Recruiting
    • Hospital Universitario Virgen del Rocio
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • Recruiting
      • St. Joseph's Hospital and Medical Center
    • Phoenix, Arizona, United States, 85054
      • Completed
      • Mayo Clinic
  • California
    • Duarte, California, United States, 91010
      • Recruiting
      • City of Hope
    • Santa Monica, California, United States, 90404
      • Recruiting
      • Providence St. John's Health Center
    • Santa Monica, California, United States, 90404
      • Withdrawn
      • UCLA Department of Medicine - Hematology/Oncology
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Completed
      • Smilow Cancer Hospital at Yale-New Haven
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Recruiting
      • Mayo Clinic
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Recruiting
      • Northwestern Memorial Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Recruiting
      • Dana Farber Cancer Institute
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Recruiting
      • Mayo Clinic
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • Recruiting
      • Fred and Pamela Buffett Cancer Center
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Completed
      • Hackensack University Medical Center
  • New York
    • Buffalo, New York, United States, 14263
      • Recruiting
      • Roswell Park Comprehensive Cancer Center
    • New York, New York, United States, 10065
      • Recruiting
      • Memorial Sloan Kettering Cancer Center
    • New York, New York, United States, 10032
      • Withdrawn
      • Columbia University Irving Medical Center
    • New York, New York, United States, 10029
      • Recruiting
      • Mt Sinai
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Recruiting
      • Duke University Medical Center, Duke Cancer Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Recruiting
      • Cleveland Clinic
  • Oregon
    • Portland, Oregon, United States, 97225
      • Recruiting
      • Providence Neurological Specialties West
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Completed
      • Hospital of the University of Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • Recruiting
      • UPMC Hilman Cancer Center
  • Tennessee
    • Knoxville, Tennessee, United States, 37920
      • Completed
      • University of Tennessee Medical Center
  • Texas
    • Dallas, Texas, United States, 75235
      • Active, not recruiting
      • UT Southwestern Medical Center
    • Houston, Texas, United States, 77030
      • Recruiting
      • The University of Texas MD Anderson Cancer Center
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Recruiting
      • Huntsman Cancer Institute, University of Utah
  • Washington
    • Seattle, Washington, United States, 98195
      • Recruiting
      • University of Washington Medical Center
    • Seattle, Washington, United States, 98104
      • Completed
      • Swedish Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Males and females greater than or equal to 18 years of age
2. Life expectancy of at least 3 months
3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1 or 2

4. Histopathologically confirmed diagnosis of PCNSL (medical record is acceptable). Cerebral biopsies are not required if imaging reveals typical images of PCNSL.

   1. Participants with parenchymal lesions must have unequivocal evidence of disease progression (e.g., presence of at least 1 measurable target lesion [≥ 10 millimeters (mm) and ≤ 40 mm in the longest diameter on brain magnetic resonance imaging [MRI] or head computed tomography [CT] on imaging within 28 days prior to Cycle 1 Day 1]). In cases where the tumor size is smaller but still measurable and located at a critical central nervous system (CNS) location, disabling the participant and/or causing symptoms, this participant may be eligible following a discussion with the Sponsor Medical Monitor.
   2. For participants limited to leptomeningeal involvement, cerebrospinal fluid (CSF) analysis (cytology and/or flow cytometry) with or without additional imaging (MRI) of the spine as clinically indicated is required to document abnormal cells within 28 days prior to Cycle 1 Day 1.

Exclusion Criteria for Part B and Part C

1. Participants with only intraocular PCNSL without brain lesion or CSF involvement, T-cell lymphoma, systemic presence of lymphoma, or non-CNS lymphoma metastatic to the CNS
2. Evidence of systemic lymphoma. This must be demonstrated by a positron emission tomography (PET) scan (or CT scan with contrast if applicable) of the chest, abdomen, and pelvis at Screening (testicular ultrasound may be considered to exclude a testicular lymphoma disseminated to the brain).
3. Prior history of malignancies other than lymphoma (except for basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or breast) or prior history of systemic lymphoma, unless the participant has been free of the disease for ≥ 3 years.
4. Active malignancy other than PCNSL requiring systemic therapy
5. Previous BTKi treatment (Part C only).
6. History of Grade ≥ 3 rhabdomyolysis without complete recovery
7. Requirement for urgent therapy due to uncontrolled tumor mass/edema effects.
8. Received external beam radiation therapy to the CNS within 28 days prior to Cycle 1 Day 1.

9. Received prior investigational drugs (including treatment in clinical research, unapproved combination products, and new dosage forms) within 28 days or 5 half-lives, whichever is shorter, prior to Cycle 1 Day 1; allogeneic hematopoietic stem cell transplant (HSCT) within 60 days prior to Cycle 1 Day 1; or had clinically significant graft-versus-host disease (GVHD) requiring ongoing up-titration of immunosuppressive medications prior to Screening (with the exception of a BTKi for Part B only).

   Note: The use of a stable or tapering dose of immunosuppressive therapy post-HSCT and/or topical steroids for ongoing skin GVHD is permitted with Sponsor Medical Monitor approval

10. Any prior systemic anti-cancer treatment such as chemotherapy, immunomodulatory drug therapy, etc., received within 14 days or 5 half-lives, whichever is shorter, prior to Cycle 1 Day 1 (with the exception of ibrutinib or other BTKi for Part B only, which may be continued until the day before Cycle 1 Day 1)
11. Prior history of hypersensitivity or anaphylaxis to emavusertib, ibrutinib or any of their excipients.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Emavusertib (CA-4948) dose escalation; Part A1: Dose-level cohorts with up to approximately 6 participants each will be used to define the Maximum Tolerated Dose (MTD) for emavusertib.	Drug: Emavusertib; Emavusertib will be provided as a tablet dosage form to be taken BID.; Other Names: CA-4948
Experimental: Emavusertib (CA-4948) and ibrutinib dose escalation; Part A2: Evaluate escalating dose levels of oral emavusertib in combination with 560 mg QD or 420 mg QD of oral ibrutinib. The starting dose of emavusertib to be used in combination will be 200 mg BID. It is anticipated that 12 to 20 participants at a potential dose level will be required to establish optimal combination dosing.	Drug: Emavusertib; Emavusertib will be provided as a tablet dosage form to be taken BID.; Other Names: CA-4948; Drug: Ibrutinib; Ibrutinib will be provided as a tablet or capsule dosage form to be taken QD.
Experimental: Emavusertib (CA-4948) and ibrutinib dose expansion; In two Expansion Cohorts (Part B), emavusertib in combination with ibrutinib will be administered in participants with R/R PCNSL who have progressed on a BTKi. In Cohort 1, emavusertib 100 mg BID will be administered with ibrutinib 560 mg QD consecutively in 28-day treatment cycles. In Cohort 2, emavusertib 200 mg BID will be administered with ibrutinib 560 mg QD consecutively in 28-day treatment cycles.	Drug: Emavusertib; Emavusertib will be provided as a tablet dosage form to be taken BID.; Other Names: CA-4948; Drug: Ibrutinib; Ibrutinib will be provided as a tablet or capsule dosage form to be taken QD.
Experimental: Emavusertib (CA-4948) and ibrutinib; In this part of the study (Part C), eligible second-line participants with R/R PCNSL who are naïve to BTKi treatment will receive 1 of 3 treatment arms: (1) emavusertib 200 mg BID, (2) ibrutinib 560 mg QD, or (3) emavusertib 200 mg BID in combination with ibrutinib 560 mg QD. Treatments will be administered continuously in 28-day treatment cycles.	Drug: Emavusertib; Emavusertib will be provided as a tablet dosage form to be taken BID.; Other Names: CA-4948; Drug: Ibrutinib; Ibrutinib will be provided as a tablet or capsule dosage form to be taken QD.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A: Maximum tolerated dose (MTD) of emavusertib as a monotherapy and in combination with ibrutinib measured by dose-limiting toxicities (DLTs)	MTD determined by the highest dose level studied at which fewer than 2 out of 6 subjects (<33%) experience a dose limiting toxicity.	12 months
Part A: To determine the safety and tolerability of emavusertib as a monotherapy and in combination with ibrutinib: dose-limiting toxicity (DLT)	The number of participants with a dose-limiting toxicity (DLT) in the first treatment cycle	12 months
Part A: Recommended Phase 2 Dose (RP2D) of emavusertib as a monotherapy and in combination with ibrutinib based on overall tolerability data	RP2D selected based on overall tolerability data from all participants treated at different dose levels and will not exceed the MTD.	12 months
Part B: Overall Response Rate (ORR) in participants with R/R PCNSL		18 months
Part C: ORR in participants with R/R PCNSL		18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Parts A, B and C: Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by AUC	Area Under the concentration-time curve (AUC)	24- 66 months
Parts A, B and C: Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by Cmax	Maximum plasma concentration (Cmax)	24- 66 months
Parts A, B and C: Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by Cmin	Minimum plasma concentration (Cmin)	24- 66 months
Parts A, B and C: Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by Tmax	Time to maximum plasma concentration (Tmax)	24- 66 months
Parts A, B and C: Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by plasma terminal half-life	Plasma terminal elimination half-life (T 1/2)	24- 66 months
Part A: To assess efficacy of emavusertib as a monotherapy and in combination with ibrutinib measured by ORR	Assessed by ORR	24- 36 months
Parts A, B and C: To assess efficacy of emavusertib as a monotherapy and in combination with ibrutinib and ibrutinib as monotherapy measured by duration of response (DOR)	Assessed by DOR	24- 66 months
Part A: To assess efficacy of emavusertib as a monotherapy and in combination with ibrutinib measured by disease control rate (DCR)	Assessed by DCR	24- 36 months
Parts A, B and C: To assess efficacy of emavusertib as a monotherapy and in combination with ibrutinib and ibrutinib as monotherapy measured by progression free survival (PFS)	Assessed by PFS	24- 66 months
Parts A, B and C: To assess efficacy of emavusertib as a monotherapy, in combination with ibrutinib and ibrutinib as monotherapy measured by overall survival (OS)	Assessed by OS	24 - 66 months
Parts B and C: To assess the safety and tolerability of emavusertib as monotherapy, ibrutinib as monotherapy and emavusertib in combination with ibrutinib in participants with R/R PCNSL	Measured by the number of participants with treatment-emergent adverse events (TEAEs) and treatment-related adverse events	up to 66 months

Collaborators and Investigators

• Sponsor: Curis, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): December 28, 2017
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): October 1, 2026

Study Registration Dates

• First Submitted: October 17, 2017
• First Submitted That Met QC Criteria: October 27, 2017
• First Posted (Actual): November 1, 2017

Study Record Updates

• Last Update Posted (Actual): April 16, 2026
• Last Update Submitted That Met QC Criteria: April 15, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Immune System Diseases; Neoplasms; Lymphoma; NHL; Lymphoma, Non-Hodgkin; Ibrutinib; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphatic Diseases; PCNSL; Primary CNS Lymphoma; IRAK4; MYD88; Relapsed/refractory Central Nervous System (CNS) Lymphoma; Systemic Lymphoma with Concurrent CNS Lymphoma; Systemic Lymphoma with a History of Treated CNS Lymphoma; Bruton tyrosine kinase inhibitor (BTKi)
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Disease Attributes; Neoplasms by Histologic Type; Hematologic Diseases; Pathological Conditions, Signs and Symptoms; Hemic and Lymphatic Diseases; Neoplasms; Recurrence; Hematologic Neoplasms; Lymphoma; Lymphoma, Non-Hodgkin; Lymphoproliferative Disorders; Immune System Diseases; Lymphatic Diseases; Immunoproliferative Disorders; Tyrosine Kinase Inhibitors; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; ibrutinib; CA-4948
• Other Study ID Numbers: CA-4948-101; 2024-513312-95-00 (Ctis); 2022-000891-20 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No