Emavusertib +/- Ibrutinib for CNS Lymphoma

Recruiting at 44 trial locations

Overseen By Ahmed Hamdy, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Curis, Inc.

Must be taking: BTKi

Disqualifiers: Intraocular PCNSL, Systemic lymphoma, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

152 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new treatments for primary central nervous system lymphoma (PCNSL), a cancer affecting the brain and spinal cord. The study tests two drugs, emavusertib (CA-4948) and ibrutinib, to evaluate their safety and effectiveness, both individually and in combination. Individuals with PCNSL that has recurred or not responded to treatment, and who have not tried certain similar treatments, might be suitable candidates. The trial seeks to determine which drug combination best controls the disease. As a Phase 1, Phase 2 trial, this research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have received any systemic anti-cancer treatment within 14 days before starting the trial, except for ibrutinib or other similar drugs in Part B, which can be continued until the day before the trial starts.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that emavusertib, whether used alone or with ibrutinib, is generally easy for patients to tolerate. Studies have found this combination safe for individuals with relapsed or hard-to-treat primary central nervous system lymphoma (PCNSL). Participants in earlier studies on PCNSL and similar conditions reported manageable side effects.

Reports indicate that emavusertib alone is well-tolerated, even by patients who have undergone many previous treatments for non-Hodgkin lymphoma. When combined with ibrutinib, emavusertib maintains a good safety record, with most patients experiencing manageable side effects.

Overall, the evidence suggests that this treatment, whether used alone or with ibrutinib, is promising in both effectiveness and safety for patients with certain types of lymphoma. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the treatments involving emavusertib and ibrutinib for CNS lymphoma because they offer unique mechanisms of action compared to standard chemotherapy and radiation options. Emavusertib, also known as CA-4948, targets specific signaling pathways that are crucial for the survival of cancer cells, potentially offering a more targeted and less toxic approach. Meanwhile, ibrutinib works by blocking a protein that helps cancer cells grow, making it a promising partner for emavusertib. Together, these drugs could provide a more effective treatment for patients who have not responded well to existing therapies.

What evidence suggests that this trial's treatments could be effective for CNS lymphoma?

Studies have shown that emavusertib, one of the treatments in this trial, whether used alone or with ibrutinib, shows promise in treating relapsed or refractory primary central nervous system lymphoma (PCNSL). In this trial, participants may receive emavusertib alone, ibrutinib alone, or a combination of both. Research indicates that this combination is generally safe and well-tolerated. Early evidence suggests these treatments can work even for patients who have tried other medications. Emavusertib targets specific proteins that aid cancer cell growth and can effectively reach the brain, crucial for treating PCNSL. Initial results are encouraging, showing potential for shrinking tumors and improving patient health. ^{1 3 4 6 7}

Are You a Good Fit for This Trial?

Adults over 18 with certain types of B-cell blood cancers that have come back or haven't responded to treatment. They should be relatively healthy otherwise, with a life expectancy of at least 3 months and able to perform daily activities with minimal assistance (ECOG ≤1). Specific cancer types include marginal zone lymphoma, activated B-cell type diffuse large B-cell lymphoma, primary central nervous system lymphoma, and others resistant to the drug ibrutinib.

Inclusion Criteria

Life expectancy of at least 3 months

For Part B: Diagnosis of histopathologically confirmed B-cell NHLs, including applicable confirmation as per the WHO 2016 classification (Swerdlow et al. 2016): Cohort 1: Marginal zone lymphoma Cohort 2: ABC-DLBCL, or extranodal subtypes: Leg-, testicular-, or NOS-type. The population will be enriched for MYD88 L265P mutations. As this occurs more frequently in the ABC-DLBCL(activated B-cell (Hans et al. 2004) subtype, all patients with this subtype qualify for enrollment. If the MYD88 mutation status is unknown at baseline, the lymphoma will be tested for MYD88 mutations. Cohort 3: Primary CNS Lymphoma (PCNSL) only. If the MYD88 mutation status is unknown at baseline, the lymphoma will be tested for MYD88 mutations. Cohort 4: Patients receiving ibrutinib monotherapy who have developed adaptive, secondary resistance. Indications include: MCL, MZL Indications for which ibrutinib is NCCN-listed (e.g., PCNSL) Patients with NHL and known myddosome mutations Patients may be candidates for maintaining ibrutinib while emavusertib will be added for resistance reversal. A brief gap of ibrutinib therapy of <3 weeks is acceptable.

I have primary CNS lymphoma and may need testing for the MYD88 mutation.

Exclusion Criteria

I haven't had cancer treatment in the last 2 weeks, except for ibrutinib.

Use of any investigational agent within 21 days or 5 half-lives, whichever is shorter, prior to start of study treatment

I do not have active brain involvement from cancer, except for primary CNS lymphoma.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation (Part A1)

Emavusertib is evaluated in a dose escalating monotherapy setting to establish safety and tolerability

12 months

Dose Expansion (Part A2)

Emavusertib is evaluated in combination with ibrutinib to establish optimal combination dosing

12 months

Treatment (Part B)

Safety and efficacy of emavusertib in combination with ibrutinib are assessed in participants with R/R PCNSL who have progressed on a BTKi

28-day cycles

Treatment (Part C)

Efficacy and safety of emavusertib monotherapy, ibrutinib monotherapy, and their combination are assessed in participants with R/R PCNSL naïve to BTKi treatment

28-day cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

24-66 months

What Are the Treatments Tested in This Trial?

Interventions

• CA-4948
• Emavusertib
• Ibrutinib

Trial Overview The trial is testing emavusertib alone or combined with ibrutinib in patients whose blood cancers have relapsed or are refractory. It's an open-label study which means everyone knows what treatment they're getting. The goal is to see how safe it is and how well it works against these cancers.

How Is the Trial Designed?

Group I: Emavusertib (CA-4948) dose escalation Experimental Treatment 1 Intervention

Part A1: Dose-level cohorts with up to approximately 6 participants each will be used to define the Maximum Tolerated Dose (MTD) for emavusertib.

Group II: Emavusertib (CA-4948) and ibrutinib dose expansion Experimental Treatment 2 Interventions

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.

Group III: Emavusertib (CA-4948) and ibrutinib dose escalation Experimental Treatment 2 Interventions

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.

Group IV: Emavusertib (CA-4948) and ibrutinib Experimental Treatment 2 Interventions

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.

Who Is Running the Clinical Trial?

Curis, Inc.

Lead Sponsor

Trials

17

Recruited

1,100+

Published Research Related to This Trial

A combination treatment of temozolomide, etoposide, doxorubicin, dexamethasone, rituximab, and the BTK inhibitor ibrutinib showed promising responses in patients with primary central nervous system lymphoma.

However, this treatment regimen was linked to significant toxicity, including serious infections like pulmonary and cerebral aspergillosis, highlighting the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib in PCNSL: The Curious Cases of Clinical Responses and Aspergillosis. Grommes, C., Younes, A.[2018]

A 77-year-old patient with primary central nervous system lymphoma (PCNSL) showed good tolerance and sustained remission after receiving ibrutinib as a consolidation therapy following high-dose methotrexate and rituximab plus temozolomide.

This case suggests that ibrutinib, a Bruton's tyrosine kinase inhibitor that can cross the blood-brain barrier, may be an effective option for elderly patients with PCNSL, but further studies are needed to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful Consolidation/Maintenance Therapy with Single Agent Ibrutinib for Primary CNS Lymphoma after Initial Induction Therapy. Du, S., Bota, D., Kong, XT.[2022]

Ibrutinib, an oral Bruton tyrosine kinase inhibitor, demonstrated rapid and dramatic responses in 3 patients with symptomatic CNS relapse of mantle cell lymphoma, leading to almost immediate recovery from symptoms.

Pharmacokinetic analyses confirmed that ibrutinib effectively crosses the blood-brain barrier, with ongoing responses observed in patients from 2 months to 1 year after treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activity of ibrutinib in mantle cell lymphoma patients with central nervous system relapse. Bernard, S., Goldwirt, L., Amorim, S., et al.[2021]

Ibrutinib is a targeted therapy specifically designed for treating chronic lymphocytic leukemia (CLL), which is a type of cancer that affects the blood and bone marrow.

This novel treatment works by inhibiting Bruton's tyrosine kinase (BTK), a key enzyme that helps cancer cells survive and proliferate, leading to improved patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib (imbruvica): a novel targeted therapy for chronic lymphocytic leukemia. Parmar, S., Patel, K., Pinilla-Ibarz, J.[2021]

Ibrutinib (Imbruvica) is an effective treatment for chronic lymphocytic leukemia, targeting specific pathways to inhibit cancer cell growth.

Tasimelteon (Hetlioz) is beneficial for individuals with non-24-hour sleep-wake disorder, helping to regulate sleep patterns, while anti-inhibitor coagulant complex (Feiba) is used to prevent or reduce bleeding episodes in patients with hemophilia A or B, demonstrating its efficacy in managing bleeding risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmaceutical approval update. Goldenberg, MM.[2021]

Ibrutinib is the first FDA-approved drug that inhibits Burton's tyrosine kinase (BTK), effectively reducing B-cell proliferation and promoting apoptosis, making it a significant treatment for relapsed chronic lymphocytic leukemia and Waldenström's macroglobulinemia.

Despite its efficacy, ibrutinib can lead to serious side effects, including rare but severe hemorrhagic events, as demonstrated by a case of back pain caused by iliopsoas muscle hemorrhage in a patient after starting the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spontaneous Iliopsoas Muscle Hemorrhage Secondary to Ibrutinib (Imbruvica; Pharmacyclics): Brief Report. Sarcon, A., Botta, GP., Patel, N., et al.[2018]

Ibrutinib treatment showed a high overall response rate of 75% in patients with relapsed/refractory primary central nervous system lymphoma (PCNSL), with a median progression-free survival of 4 months, indicating its efficacy in this aggressive cancer type.

Genomic analysis revealed that patients with simpler genetic variants and lower tumor mutation burdens (TMB) responded better to ibrutinib, suggesting that genomic profiling could help predict treatment outcomes and tailor therapies for CNS lymphoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The outcome of ibrutinib-based regimens in relapsed/refractory central nervous system lymphoma and the potential impact of genomic variants. Wang, S., Zhu, Y., Qian, X., et al.[2023]

Ibrutinib is an effective oral treatment for patients with relapsed/refractory mantle cell lymphoma (MCL) and chronic lymphocytic leukaemia (CLL), showing a 68% overall response rate in MCL and significant improvements in progression-free survival and overall survival in CLL patients, including those with specific genetic mutations.

The drug has a good safety profile, with less than 10% of patients discontinuing treatment due to adverse effects, making it a promising option for patients with various B-cell malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Ibrutinib: A new drug of B-cell malignancies]. Thieblemont, C.[2021]

In a study of 53 patients with CNS lymphoma receiving ibrutinib-based treatments, higher levels of [18F]FDG uptake on PET scans were found to be inversely related to treatment outcomes, indicating that more aggressive disease may lead to poorer responses.

The study identified that the sum of standardized uptake values (sumSUVmax) was a strong independent prognostic factor, with a 9% increased risk of disease progression for every 5-unit increase in sumSUVmax, suggesting that PET imaging can help predict patient prognosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prognostic value of [18F]FDG PET/CT in patients with CNS lymphoma receiving ibrutinib-based therapies. Krebs, S., Mauguen, A., Yildirim, O., et al.[2022]

Citations

1. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/6020/527681/Preliminary-Safety-and-Efficacy-of-Emavusertib-CA

Preliminary Safety and Efficacy of Emavusertib (CA-4948) in ... We present updated safety and efficacy of emavusertib in combination with ibrutinib in patients with R/R PCNSL most recently treated with BTKi regimen.

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.2087

Emavusertib (CA-4948) in combination with ibrutinib ... Emavusertib in combination with ibrutinib was well tolerated with an acceptable safety profile and promising efficacy in R/R PCNSL patients with previous ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03328078

Study Details | NCT03328078 | CA-4948-101: Open-Label, ... This is a multi-center, open-label study to evaluate the safety, pharmacokinetics (PK), and anti-cancer activity of oral administration of emavusertib alone ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9431264/

P1298: THE IRAK-4 INHIBITOR EMAVUSERTIB (CA-4948 ... Results: Our data confirm elevated IRAK-1, IRAK-4, and NF-κB signaling in patient PCNSL. We also demonstrate that emavusertib can achieve therapeutically ...

5. duke-research.dukehealth.org duke-research.dukehealth.org/studies/pro00115450

Curis CA-4948-101 (Primary Central Nervous System ... We are doing this study to find out if an investigational drug called CA-4948 is a safe and effective option for people with PCNSL.

6. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497124088487

Preliminary Safety and Efficacy of Emavusertib (CA-4948) ... Emavusertib in combination with ibrutinib shows promising efficacy and was well tolerated with an acceptable safety profile in R/R PCNSL patients with prior ...

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.2085

Analysis of genetic mutation profile and CNS ... This study evaluates the molecular and pharmacokinetic (PK) data associated with responses to emavusertib + ibrutinib combination therapy in R/R PCNSL patients.