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)

NCT03328078 | Recruiting Phase 1 FDA Drug

• 3 other identifiers: CA-4948-1012024-513312-95-002022-000891-20
• Study Type: interventional
• Target: 152
• Locations: 7 countries
• Sites: 45

Brief Summary

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.

Conditions

Relapsed Hematologic Malignancy; Refractory Hematologic Malignancy; Relapsed Primary Central Nervous System Lymphoma; Refractory Primary Central Nervous System Lymphoma

Keywords

MYD88; IRAK4; NHL; PCNSL; Lymphoma; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Lymphoma, Non-Hodgkin; Relapsed/refractory Central Nervous System (CNS) Lymphoma; Systemic Lymphoma with Concurrent CNS Lymphoma; Systemic Lymphoma with a History of Treated CNS Lymphoma; Ibrutinib; Bruton tyrosine kinase inhibitor (BTKi); Primary CNS Lymphoma

Outcome Measures

Primary Outcomes (5)

• 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: 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: 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 Outcomes (11)

• Parts A, B and C: Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by AUC

  24- 66 months

• Parts A, B and C: Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by Cmax

  24- 66 months

• Parts A, B and C: Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by Cmin

  24- 66 months

• Parts A, B and C: Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by Tmax

  24- 66 months

• Parts A, B and C: Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by plasma terminal half-life

  24- 66 months

Study Arms (4)

Emavusertib (CA-4948) dose escalation

EXPERIMENTAL

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 (CA-4948) and ibrutinib dose escalation

EXPERIMENTAL

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; Drug: Ibrutinib

Emavusertib (CA-4948) and ibrutinib dose expansion

EXPERIMENTAL

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; Drug: Ibrutinib

Emavusertib (CA-4948) and ibrutinib

EXPERIMENTAL

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; Drug: Ibrutinib

Interventions

Ibrutinib DRUG

Ibrutinib will be provided as a tablet or capsule dosage form to be taken QD.

Emavusertib (CA-4948) and ibrutinib; Emavusertib (CA-4948) and ibrutinib dose escalation; Emavusertib (CA-4948) and ibrutinib dose expansion

Emavusertib DRUG

Emavusertib will be provided as a tablet dosage form to be taken BID.

Also known as: CA-4948

Emavusertib (CA-4948) and ibrutinib; Emavusertib (CA-4948) and ibrutinib dose escalation; Emavusertib (CA-4948) and ibrutinib dose expansion; Emavusertib (CA-4948) dose escalation

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Males and females greater than or equal to 18 years of age
• Life expectancy of at least 3 months
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1 or 2
• Histopathologically confirmed diagnosis of PCNSL (medical record is acceptable). Cerebral biopsies are not required if imaging reveals typical images of PCNSL.
• 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.
• 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.

You may not qualify if:

• 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
• 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).
• 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.
• Active malignancy other than PCNSL requiring systemic therapy
• Previous BTKi treatment (Part C only).
• History of Grade ≥ 3 rhabdomyolysis without complete recovery
• Requirement for urgent therapy due to uncontrolled tumor mass/edema effects.
• Received external beam radiation therapy to the CNS within 28 days prior to Cycle 1 Day 1.
• 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
• 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)
• Prior history of hypersensitivity or anaphylaxis to emavusertib, ibrutinib or any of their excipients.

Sponsors & Collaborators

• Curis, Inc.: lead

Study Sites (45)

St. Joseph's Hospital and Medical Center

Phoenix, Arizona, 85013, United States

RECRUITING

Mayo Clinic

Phoenix, Arizona, 85054, United States

COMPLETED

City of Hope

Duarte, California, 91010, United States

RECRUITING

Providence St. John's Health Center

Santa Monica, California, 90404, United States

RECRUITING

UCLA Department of Medicine - Hematology/Oncology

Santa Monica, California, 90404, United States

WITHDRAWN

Smilow Cancer Hospital at Yale-New Haven

New Haven, Connecticut, 06510, United States

COMPLETED

Mayo Clinic

Jacksonville, Florida, 32224, United States

RECRUITING

Northwestern Memorial Hospital

Chicago, Illinois, 60611, United States

RECRUITING

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

RECRUITING

Mayo Clinic

Rochester, Minnesota, 55905, United States

RECRUITING

Fred and Pamela Buffett Cancer Center

Omaha, Nebraska, 68198, United States

RECRUITING

Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

COMPLETED

Roswell Park Comprehensive Cancer Center

Buffalo, New York, 14263, United States

RECRUITING

Mt Sinai

New York, New York, 10029, United States

RECRUITING

Columbia University Irving Medical Center

New York, New York, 10032, United States

WITHDRAWN

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

RECRUITING

Duke University Medical Center, Duke Cancer Center

Durham, North Carolina, 27710, United States

RECRUITING

Cleveland Clinic

Cleveland, Ohio, 44195, United States

RECRUITING

Providence Neurological Specialties West

Portland, Oregon, 97225, United States

RECRUITING

Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

COMPLETED

UPMC Hilman Cancer Center

Pittsburgh, Pennsylvania, 15232, United States

RECRUITING

University of Tennessee Medical Center

Knoxville, Tennessee, 37920, United States

COMPLETED

UT Southwestern Medical Center

Dallas, Texas, 75235, United States

ACTIVE NOT RECRUITING

The University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

RECRUITING

Huntsman Cancer Institute, University of Utah

Salt Lake City, Utah, 84112, United States

RECRUITING

Swedish Cancer Institute

Seattle, Washington, 98104, United States

COMPLETED

University of Washington Medical Center

Seattle, Washington, 98195, United States

RECRUITING

Všeobecná fakultní nemocnice v Praze

Prague, Czechia

RECRUITING

Institut Bergonie

Bordeaux, France

RECRUITING

Hopital de la Timone

Marseille, France

RECRUITING

Hospital Pitie Salpetriere

Paris, France

RECRUITING

Institut Curie Hospital

Paris, France

RECRUITING

Hematology Department Soroka UMC / Heanatology Department

Beersheba, Israel

RECRUITING

Rambam Medical Center

Haifa, Israel

RECRUITING

Hadassah Medical Center / Ein-Carem

Jerusalem, Israel

RECRUITING

Università di Torino Croce e Carle

Cuneo, Italy

RECRUITING

SODc Ematologia Azienda Ospedaliera Universitaria Careggi

Florence, Italy

RECRUITING

IRST - Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori

Meldola, Italy

RECRUITING

IRCCS San Raffaele Scientific Institute

Milan, Italy

RECRUITING

Uniwersyteckie Centrum Kliniczne Osrodek Badan Klinicznych Wczesnych Faz

Gdansk, Poland

RECRUITING

Oddzial Kliniczny Hematologii

Krakow, Poland

WITHDRAWN

NarodowyInstytutu Onkologii im. Marii Sklodowskiej-Curie-Panstwowy Instytutu Badawczy

Warsaw, Poland

RECRUITING

University Hospital Vall d'Hebron

Barcelona, Spain

RECRUITING

MD Anderson Cancer Center Madrid

Madrid, Spain

RECRUITING

Hospital Universitario Virgen del Rocio

Seville, Spain

RECRUITING

MeSH Terms

Conditions

Hematologic Neoplasms; Lymphoma; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Lymphoma, Non-Hodgkin; Recurrence

Interventions

CA-4948; ibrutinib

Condition Hierarchy (Ancestors)

Neoplasms by Site; Hematologic Diseases; Hemic and Lymphatic Diseases; Neoplasms by Histologic Type; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Central Study Contacts

Ahmed Hamdy, MD

CONTACT

617-503-6500; clinicaltrials@curis.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Masking Details: Part B is non-randomized and Part C is randomized.
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Part A will evaluate escalating doses of emavusertib (CA-4948) either as monotherapy (Part A1) or in combination with ibrutinib (Part A2). Enrollment is closed for Part A1 and A2. Part B will comprise two expansion cohorts to assess efficacy and safety of emavusertib in combination with ibrutinib in R/R PCNSL. Part C will comprise three cohorts 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.

Study Record Dates

• First Submitted: October 17, 2017
• First Posted: November 1, 2017
• Study Start: December 28, 2017
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): October 1, 2026
• Last Updated: April 16, 2026

Record last verified: 2026-04

Locations

CZ (1); FR (4); US (27); IT (4); PL (3); IL (3); ES (3)