Relapsed Hematologic Malignancy, Refractory Hematologic Malignancy, Relapsed Primary Central Nervous System Lymphoma, Refractory Primary Central Nervous System Lymphoma
Conditions
Keywords
MYD88, IRAK4, NHL, PCNSL, Lymphoma, Neoplasms, Lymphoproliferative Disorders, Lymphatic Diseases, Immunoproliferative Disorders, Immune System Diseases, Lymphoma, Non-Hodgkin, Relapsed/refractory Central Nervous System (CNS) Lymphoma, Systemic Lymphoma with Concurrent CNS Lymphoma, Systemic Lymphoma with a History of Treated CNS Lymphoma, Ibrutinib, Bruton tyrosine kinase inhibitor (BTKi), Primary CNS Lymphoma
Brief summary
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.
Interventions
DRUGEmavusertib
Emavusertib will be provided as a tablet dosage form to be taken BID.
DRUGIbrutinib
Ibrutinib will be provided as a tablet or capsule dosage form to be taken QD.
Sponsors
Curis, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Part B is non-randomized and Part C is randomized.
Intervention 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 in combination with ibrutinib in R/R PCNSL. Part C will comprise three cohorts 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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. Participants with parenchymal lesions must have unequivocal evidence of disease progression (e.g., presence of at least 1 measurable target lesion \[≥ 10 millimeters (mm) and ≤ 40 mm in the longest diameter on brain magnetic resonance imaging \[MRI\] or head computed tomography \[CT\] on imaging within 28 days prior to Cycle 1 Day 1\]). In cases where the tumor size is smaller but still measurable and located at a critical central nervous system (CNS) location, disabling the participant and/or causing symptoms, this participant may be eligible following a discussion with the Sponsor Medical Monitor. 2. For participants limited to leptomeningeal involvement, cerebrospinal fluid (CSF) analysis (cytology and/or flow cytometry) with or without additional imaging (MRI) of the spine as clinically indicated is required to document abnormal cells within 28 days prior to Cycle 1 Day 1.
Exclusion criteria
for Part B and Part C 1. Participants with only intraocular PCNSL without brain lesion or CSF involvement, T-cell lymphoma, systemic presence of lymphoma, or non-CNS lymphoma metastatic to the CNS 2. Evidence of systemic lymphoma. This must be demonstrated by a positron emission tomography (PET) scan (or CT scan with contrast if applicable) of the chest, abdomen, and pelvis at Screening (testicular ultrasound may be considered to exclude a testicular lymphoma disseminated to the brain). 3. 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 participant has been free of the disease for ≥ 3 years. 4. Active malignancy other than PCNSL requiring systemic therapy 5. Previous BTKi treatment (Part C only). 6. History of Grade ≥ 3 rhabdomyolysis without complete recovery 7. Requirement for urgent therapy due to uncontrolled tumor mass/edema effects. 8. Received external beam radiation therapy to the CNS within 28 days prior to Cycle 1 Day 1. 9. Received 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 Cycle 1 Day 1; or had clinically significant graft-versus-host disease (GVHD) requiring ongoing up-titration of immunosuppressive medications prior to Screening (with the exception of a BTKi for Part B only). 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 10. 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 or other BTKi for Part B only, which may be continued until the day before Cycle 1 Day 1) 11. Prior history of hypersensitivity or anaphylaxis to emavusertib, ibrutinib or any of their excipients.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A: To determine the safety and tolerability of emavusertib as a monotherapy and in combination with ibrutinib: dose-limiting toxicity (DLT) | 12 months | The number of participants with a dose-limiting toxicity (DLT) in the first treatment cycle |
| Part A: Maximum tolerated dose (MTD) of emavusertib as a monotherapy and in combination with ibrutinib measured by dose-limiting toxicities (DLTs) | 12 months | MTD determined by the highest dose level studied at which fewer than 2 out of 6 subjects (\<33%) experience a dose limiting toxicity. |
| Part A: Recommended Phase 2 Dose (RP2D) of emavusertib as a monotherapy and in combination with ibrutinib based on overall tolerability data | 12 months | RP2D selected based on overall tolerability data from all participants treated at different dose levels and will not exceed the MTD. |
| Part B: Overall Response Rate (ORR) in participants with R/R PCNSL | 18 months | — |
| Part C: ORR in participants with R/R PCNSL | 18 months | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part A: To assess efficacy of emavusertib as a monotherapy and in combination with ibrutinib measured by ORR | 24- 36 months | Assessed by ORR |
| Parts A, B and C: To assess efficacy of emavusertib as a monotherapy and in combination with ibrutinib and ibrutinib as monotherapy measured by duration of response (DOR) | 24- 66 months | Assessed by DOR |
| Part A: To assess efficacy of emavusertib as a monotherapy and in combination with ibrutinib measured by disease control rate (DCR) | 24- 36 months | Assessed by DCR |
| Parts A, B and C: Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by Tmax | 24- 66 months | Time to maximum plasma concentration (Tmax) |
| Parts A, B and C: To assess efficacy of emavusertib as a monotherapy, in combination with ibrutinib and ibrutinib as monotherapy measured by overall survival (OS) | 24 - 66 months | Assessed by OS |
| Parts B and C: To assess the safety and tolerability of emavusertib as monotherapy, ibrutinib as monotherapy and emavusertib in combination with ibrutinib in participants with R/R PCNSL | up to 66 months | Measured by the number of participants with treatment-emergent adverse events (TEAEs) and treatment-related adverse events |
| Parts A, B and C: To assess efficacy of emavusertib as a monotherapy and in combination with ibrutinib and ibrutinib as monotherapy measured by progression free survival (PFS) | 24- 66 months | Assessed by PFS |
| Parts A, B and C: Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by AUC | 24- 66 months | Area Under the concentration-time curve (AUC) |
| Parts A, B and C: Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by Cmax | 24- 66 months | Maximum plasma concentration (Cmax) |
| Parts A, B and C: Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by Cmin | 24- 66 months | Minimum plasma concentration (Cmin) |
| Parts A, B and C: Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by plasma terminal half-life | 24- 66 months | Plasma terminal elimination half-life (T 1/2) |
Countries
Czechia, France, Israel, Italy, Poland, Spain, United States
Contacts
Primary ContactAhmed Hamdy, MD
Outcome results
None listed