Emavusertib +/- Ibrutinib for CNS Lymphoma

Recruiting at 39 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

Trial Summary

What is the purpose of this trial?

This is a multi-center, open-label study to evaluate the safety, pharmacokinetics (PK), and anti-cancer activity of oral administration of emavusertib alone or in combination with ibrutinib in adult participants with relapsed or refractory (R/R) hematologic malignancies. This trial will be completed in four parts. In Part A1, emavusertib will be evaluated first in a dose escalating monotherapy setting to establish the safety and tolerability (complete). In Part A2, emavusertib will be evaluated in combination with ibrutinib at 560 milligrams (mg) once daily (QD) or 420 mg QD as indicated by disease (Part A2 complete). Part B will comprise 2 cohorts to assess safety and efficacy of emavusertib in combination with ibrutinib in participants with R/R primary central nervous system lymphoma (PCNSL) who have directly progressed on a bruton tyrosine kinase inhibitor (BTKi). In this part of the study, emavusertib will be dosed at 100 mg or 200 mg twice daily (BID) in combination with ibrutinib in 28-day treatment cycles. Part C will comprise 3 treatment arms in the second-line setting to assess the efficacy and safety of emavusertib monotherapy, ibrutinib monotherapy, and emavusertib in combination with ibrutinib in participants with R/R PCNSL who are naïve to BTKi treatment. In this part of the study, eligible second-line participants with R/R PCNSL who are naïve to BTKi treatment will be randomized 1:1:1 to 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.

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.

What data supports the effectiveness of the drug Emavusertib +/- Ibrutinib for CNS Lymphoma?

Ibrutinib, a component of the treatment, has shown promise in treating central nervous system lymphoma by crossing the blood-brain barrier and providing rapid symptom relief in patients with CNS relapse of mantle cell lymphoma. Additionally, a case study demonstrated that ibrutinib helped maintain remission in a patient with primary CNS lymphoma after initial therapy. ^{1 2 3 4 5}

What safety data exists for Emavusertib and Ibrutinib in humans?

Ibrutinib (Imbruvica) has been shown to be generally safe in humans, with less than 10% of patients stopping treatment due to side effects. However, there have been rare cases of serious bleeding events reported. ^{2 4 6 7 8}

What makes the drug Emavusertib +/- Ibrutinib unique for CNS lymphoma?

This treatment is unique because it combines Emavusertib, a novel drug, with Ibrutinib, which is known to cross the blood-brain barrier and has shown promise in treating central nervous system lymphoma by targeting Bruton tyrosine kinase (BTK), potentially offering a new approach for patients with this aggressive condition. ^{1 2 3 4 9}

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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, 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]

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]

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]

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 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]

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 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]

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]

References

1. Poland 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. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Activity of ibrutinib in mantle cell lymphoma patients with central nervous system relapse. [2021]

3. Germany pubmed.ncbi.nlm.nih.gov

Prognostic value of [18F]FDG PET/CT in patients with CNS lymphoma receiving ibrutinib-based therapies. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Pharmaceutical approval update. [2021]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Successful Consolidation/Maintenance Therapy with Single Agent Ibrutinib for Primary CNS Lymphoma after Initial Induction Therapy. [2022]

6. France pubmed.ncbi.nlm.nih.gov

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

7. United States pubmed.ncbi.nlm.nih.gov

Ibrutinib (imbruvica): a novel targeted therapy for chronic lymphocytic leukemia. [2021]

8. United States pubmed.ncbi.nlm.nih.gov

Spontaneous Iliopsoas Muscle Hemorrhage Secondary to Ibrutinib (Imbruvica; Pharmacyclics): Brief Report. [2018]

9. United States pubmed.ncbi.nlm.nih.gov

Ibrutinib in PCNSL: The Curious Cases of Clinical Responses and Aspergillosis. [2018]