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

Relapsed Hematologic Malignancy Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03328078
• Other study ID #: CA-4948-101
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: December 28, 2017
• Est. completion date: August 2026

Study information

• Verified date: September 2023
• Source: Curis, Inc.
• Contact: Reinhard von Roemeling, MD
• Phone: 617-503-6500
• Email: clinicaltrials[@]curis.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 80
• Est. completion date: August 2026
• Est. primary completion date: August 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Hematologic Neoplasms
• Lymphoma
• Neoplasms
• Refractory Hematologic Malignancy
• Relapsed Hematologic Malignancy
• Relapsed Primary Central Nervous System Lymphoma

Intervention

Drug:
• Emavusertib
Emavusertib (formulated for oral administration for BID dosing)
• ibrutinib
560 mg QD of oral ibrutinib

Locations

Country	Name	City	State
Czechia	Všeobecná fakultní nemocnice v Praze	Prague
France	Institut Curie Hospital	Paris
Israel	Hematology Department Soroka UMC / Heanatology Department	Be'er Sheva
Israel	Hadassah Medical Center / Ein-Carem	Jerusalem
Italy	Università di Torino Croce e Carle	Cuneo
Italy	SODc Ematologia Azienda Ospedaliera Universitaria Careggi	Firenze
Italy	IRST - Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori	Meldola
Italy	IRCCS San Raffaele Scientific Institute	Milano
Poland	Uniwersyteckie Centrum Kliniczne Osrodek Badan Klinicznych Wczesnych Faz	Gdansk
Poland	Oddzial Kliniczny Hematologii	Kraków
Poland	NarodowyInstytutu Onkologii im. Marii Sklodowskiej-Curie-Panstwowy Instytutu Badawczy	Warsaw
Spain	MD Anderson Cancer Center Madrid	Madrid
Spain	Hospital Universitario Virgen del Rocio	Sevilla
United States	UT Southwestern Medical Center	Dallas	Texas
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Mayo Clinic	Jacksonville	Florida
United States	University of Tennessee Medical Center	Knoxville	Tennessee
United States	Smilow Cancer Hospital at Yale-New Haven	New Haven	Connecticut
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Fred and Pamela Buffett Cancer Center	Omaha	Nebraska
United States	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania
United States	Mayo Clinic	Phoenix	Arizona
United States	Mayo Clinic	Rochester	Minnesota
United States	UCLA Department of Medicine - Hematology/Oncology	Santa Monica	California
United States	Swedish Cancer Institute	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Curis, Inc.

Countries where clinical trial is conducted

United States,  Czechia,  France,  Israel,  Italy,  Poland,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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	Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by AUC	Area Under the concentration-time curve (AUC)	24- 36 months
Secondary	Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by Cmax	Maximum plasma concentration (Cmax)	24- 36 months
Secondary	Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by Cmin	Minimum plasma concentration (Cmin)	24- 36 months
Secondary	Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by Tmax	Time to maximum plasma concentration (Tmax)	24- 36 months
Secondary	Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by plasma terminal half-life	Plasma terminal elimination half-life (T 1/2)	24- 36 months
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	To assess efficacy of emavusertib as a monotherapy and in combination with ibrutinib measured by overall survival (OS)	Assessed by OS	24 - 36 months
Secondary	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