Clinical Trial Finder

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.

Arms

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.

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.

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.

Interventions

Drug: - Emavusertib

Emavusertib (formulated for oral administration for BID dosing)

Drug: - ibrutinib

560 mg QD of oral ibrutinib