A Study of CA-4948 in Patients With Relapsed or Refractory Primary Central Nervous System Lymphoma

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 trial to evaluate the safety, pharmacokinetics (PK), and anti-cancer activity of oral administration of emavusertib (CA-4948) in adult patients with relapsed or refractory (R/R) hematologic malignancies. Part A will evaluate the safety and tolerability of escalating doses of emavusertib as monotherapy (Part A1), and in combination with ibrutinib. In Protocol Version (v) 1.0 through v6.0, patients with Waldenström macroglobulinemia/ lymphoplasmacytic lymphoma (WM/LPL) and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) were also enrolled at ibrutinib doses of 420 mg (Part A2). Enrollment into Parts A1 and A2 has been closed. Part B will comprise 2 cohorts to assess safety and efficacy of emavusertib in combination with ibrutinib in patients with primary central nervous system lymphoma (PCNSL).

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): 80
• Phase: Phase 2; Phase 1

Contacts and Locations

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

Study Locations

• Czechia
  • Prague, Czechia
    • Not yet recruiting
    • Všeobecná fakultní nemocnice v Praze
• France
  • Paris, France
    • Not yet recruiting
    • Institut Curie Hospital
• Israel
  • Be'er Sheva, Israel
    • Not yet recruiting
    • Hematology Department Soroka UMC / Heanatology Department
  • Jerusalem, Israel
    • Not yet recruiting
    • Hadassah Medical Center / Ein-Carem
• Italy
  • Cuneo, Italy
    • Not yet recruiting
    • Università di Torino Croce e Carle
  • Firenze, Italy
    • Not yet recruiting
    • SODc Ematologia Azienda Ospedaliera Universitaria Careggi
  • Meldola, Italy
    • Not yet recruiting
    • IRST - Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori
  • Milano, Italy
    • Not yet recruiting
    • IRCCS San Raffaele Scientific Institute
• Poland
  • Gdańsk, Poland
    • Recruiting
    • Uniwersyteckie Centrum Kliniczne Osrodek Badan Klinicznych Wczesnych Faz
  • Kraków, Poland
    • Recruiting
    • Oddzial Kliniczny Hematologii
  • Warsaw, Poland
    • Recruiting
    • NarodowyInstytutu Onkologii im. Marii Sklodowskiej-Curie-Panstwowy Instytutu Badawczy
• Spain
  • Madrid, Spain
    • Recruiting
    • MD Anderson Cancer Center Madrid
  • Sevilla, Spain
    • Recruiting
    • Hospital Universitario Virgen Del Rocio
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Recruiting
      • Mayo Clinic
  • California
    • Santa Monica, California, United States, 90404
      • Withdrawn
      • UCLA Department of Medicine - Hematology/Oncology
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Recruiting
      • Smilow Cancer Hospital at Yale-New Haven
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Recruiting
      • Mayo Clinic
  • 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
      • Recruiting
      • Hackensack University Medical Center
  • New York
    • New York, New York, United States, 10065
      • Recruiting
      • Memorial Sloan Kettering Cancer Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Completed
      • Hospital of the University of Pennsylvania
  • Tennessee
    • Knoxville, Tennessee, United States, 37920
      • Recruiting
      • University of Tennessee Medical Center
  • Texas
    • Dallas, Texas, United States, 75235
      • Recruiting
      • UT Southwestern Medical Center
  • Washington
    • 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. Patients with parenchymal lesions must have unequivocal evidence (e.g., presence of at least 1 bi-dimensionally measurable target lesion on brain magnetic resonance imaging (MRI) or head CT or a new lesion with CSF involvement) of disease progression on imaging within 28 days prior to Cycle 1 Day 1.
   2. For patients with leptomeningeal disease only, CSF cytology must document lymphoma cells or monotypic cells on flowcytometry, and/or imaging findings consistent with CSF disease within 28 days prior to Cycle 1 Day 1 (at the discretion of the Investigator).

Exclusion Criteria for Part B - PCNSL Expansion Cohorts of Combination Therapy

1. Patients with only intraocular PCNSL without brain lesion or CSF involvement or T-cell lymphoma or systemic presence of lymphoma, or non-CNS lymphoma metastatic to the CNS
2. 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 patient has been free of the disease for ≥ 3 years.
3. Active malignancy other than PCNSL requiring systemic therapy
4. History of Grade ≥ 3 rhabdomyolysis without complete recovery
5. Patient has received external beam radiation therapy to the CNS within 28 days prior to Cycle 1 Day 1.
6. 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 C1D1; or clinically significant graft-versus-host disease (GVHD) requiring ongoing up-titration of immunosuppressive medications prior to Screening 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
7. 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, which may be continued as part of this study without interruption)
8. Prior history of hypersensitivity or anaphylaxis to emavusertib or ibrutinib or any 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

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Emavusertib (CA-4948) dose escalation; Part A1: Dose-level cohorts with up to approximately 6 patients each will be used to define the Maximum Tolerated Dose (MTD) for emavusertib.	Drug: Emavusertib; Emavusertib (formulated for oral administration for BID dosing); 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 daily (QD) of oral ibrutinib. The starting dose of emavusertib to be used in combination will be 200 mg twice a day (BID). It is anticipated that 12 to 20 patients at a potential dose level will be required to establish optimal combination dosing.	Drug: Emavusertib; Emavusertib (formulated for oral administration for BID dosing); Other Names: CA-4948; Drug: ibrutinib; 560 mg QD of oral ibrutinib
Experimental: Emavusertib (CA-4948) and ibrutinib dose expansion; In two PCNSL Expansion Cohorts (Part B), emavusertib in combination with ibrutinib will be administered in patients with PCNSL. In Cohort 1, emavusertib 100 mg BID will be administered with ibrutinib 560 mg QD consecutively in a 28-day cycle in approximately 6 to 9 patients. In Cohort 2, CA-4948 200 mg BID will be administered with ibrutinib in at least 9 patients.	Drug: Emavusertib; Emavusertib (formulated for oral administration for BID dosing); Other Names: CA-4948; Drug: ibrutinib; 560 mg QD of oral ibrutinib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 patients 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 patients treated at different dose levels and will not exceed the MTD.	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 B: To assess safety of emavusertib in combination with ibrutinib by incidence of AEs in patients with PCNSL.	Assessed by incidence of AEs	24- 36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by AUC	Area Under the concentration-time curve (AUC)	24- 36 months
Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by Cmax	Maximum plasma concentration (Cmax)	24- 36 months
Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by Cmin	Minimum plasma concentration (Cmin)	24- 36 months
Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by Tmax	Time to maximum plasma concentration (Tmax)	24- 36 months
Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by plasma terminal half-life	Plasma terminal elimination half-life (T 1/2)	24- 36 months
To assess efficacy of emavusertib as a monotherapy and in combination with ibrutinib measured by overall response rate (ORR)	Assessed by ORR	24- 36 months
To assess efficacy of emavusertib as a monotherapy and in combination with ibrutinib measured by duration of response (DOR)	Assessed by DOR	24- 36 months
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
To assess efficacy of emavusertib as a monotherapy and in combination with ibrutinib measured by progression free survival (PFS)	Assessed by PFS	24- 36 months
To assess efficacy of emavusertib as a monotherapy and in combination with ibrutinib measured by overall survival (OS)	Assessed by OS	24 - 36 months
Part B: To estimate the blood-brain barrier penetration in CNS lymphoma patients	CNS liquor with be sampled from an Ommaya reservoir or with a spinal puncture about 3 hours after oral dosing of emavusertib. At approximately the same timepoint, a peripheral blood sample will be taken to obtain a plasma sample. The respective emavusertib concentrations will be measured in the liquor and in plasma samples. The liquor vs plasma concentration ratio will provide a rough estimate of the blood-brain barrier (BBB) penetration of emavusertib following oral dosing.	1 day

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): August 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): September 13, 2023
• Last Update Submitted That Met QC Criteria: September 11, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: DLBCL; AML; NHL; MCL; MZL; PCNSL; IRAK4; MYD88
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Neoplasms by Site; Hematologic Diseases; Neoplasms; Lymphoma; Hematologic Neoplasms
• Other Study ID Numbers: CA-4948-101

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No