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

Study Overview
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Brief Summary
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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).

Official Title
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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

Conditions
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Relapsed Hematologic Malignancy, Refractory Hematologic Malignancy, Relapsed Primary Central Nervous System Lymphoma, Refractory Primary Central Nervous System Lymphoma

Intervention / Treatment
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* Drug: Emavusertib
* Drug: ibrutinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. 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. 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 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 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. Active malignancy other than PCNSL requiring systemic therapy History of Grade ≥ 3 rhabdomyolysis without complete recovery Patient has received external beam radiation therapy to the CNS within 28 days prior to Cycle 1 Day 1. 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 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) Prior history of hypersensitivity or anaphylaxis to emavusertib or ibrutinib or any excipients.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: 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 and ibrutinib in PCNSL.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Emavusertib (CA-4948) dose escalation<br>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<br>* Emavusertib (formulated for oral administration for BID dosing)<br>* Other names: CA-4948;|
| Experimental: Emavusertib (CA-4948) and ibrutinib dose escalation<br>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<br>* Emavusertib (formulated for oral administration for BID dosing)<br>* Other names: CA-4948;Drug: ibrutinib<br>* 560 mg QD of oral ibrutinib<br>|
| Experimental: Emavusertib (CA-4948) and ibrutinib dose expansion<br>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<br>* Emavusertib (formulated for oral administration for BID dosing)<br>* Other names: CA-4948;Drug: ibrutinib<br>* 560 mg QD of oral ibrutinib<br>|

What is the study measuring?
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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: 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 patients treated at different dose levels and will not exceed the MTD. | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DLBCL, MCL, MYD88, IRAK4, NHL, AML, MZL, PCNSL