This is a multi-center, open-label trial to evaluate oral administration of CA-4948 in adult patients with relapsed/refractory hematologic malignancies. Part A will evaluate escalating doses of CA-4948 either as monotherapy (Part A1) or in combination with ibrutinib for non- Hodgkin's Lymphoma (NHL), macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) (Part A2). Once the combination dose has been determined, Part B will comprise an expansion phase to assess efficacy (CR rate) and safety of the RP2D of CA-4948 and ibrutinib in 4 Non-Hodgkin Lymphoma (NHL) disease-specific cohorts: - Cohort 1 - Marginal zone lymphoma (MZL) - Cohort 2 - activated B-cell (ABC) diffuse large B-cell lymphoma (DLBCL) or extranodal subtypes: Leg-, testicular-, or not otherwise specified (NOS)-type - Cohort 3 - Primary central nervous system lymphoma (PCNSL) - Cohort 4 - Patients receiving ibrutinib monotherapy who have developed adaptive, secondary resistance. Indications include: - Mantle Cell Lymphoma (MCL), MZL, CLL/SLL, or WM/LPL - Indications for which ibrutinib is National Comprehensive Cancer Network (NCCN)-listed (e.g., PCNSL) - Patients with NHL and known myddosome mutations - Patients may be candidates for maintaining ibrutinib while CA-4948 will be added for resistance reversal. A brief gap of ibrutinib therapy of <3 weeks is acceptable.
Name: CA-4948
Name: ibrutinib
Description: The number of patients with a dose-limiting toxicity (DLT) in the first treatment cycle
Measure: To determine the safety and tolerability of CA-4948 as a monotherapy and in combination with ibrutinib: dose-limiting toxicity (DLT) Time: 12 monthsDescription: MTD determined by the highest dose level studied at which fewer than 2 out of 6 subjects (<33%) experience a dose limiting toxicity
Measure: Part A: Maximum tolerated dose (MTD) of CA-4948 as a monotherapy and in combination with ibrutinib measured by dose-limiting toxicities (DLTs) Time: 12 monthsDescription: RP2D selected based on overall tolerability data from all patients treated at different dose levels and will not exceed the MTD.
Measure: Part A: Recommended Phase 2 Dose (RP2D) of CA-4948 as a monotherapy and in combination with ibrutinib based on overall tolerability data Time: 12 monthsDescription: Assessed by CR
Measure: Part B: To assess complete response (CR) rate of CA-4948 in combination with ibrutinib. Time: 24- 36 monthsDescription: Assessed by ORR
Measure: Part B: To assess overall response rate (ORR) of CA-4948 in combination with ibrutinib. Time: 24- 36 monthsDescription: Area Under the concentration-time curve (AUC)
Measure: Pharmacokinetic (PK) profile of CA-4948 measured by AUC Time: 24- 36 monthsDescription: Maximum plasma concentration (Cmax)
Measure: Pharmacokinetic (PK) profile of CA-4948 measured by Cmax Time: 24- 36 monthsDescription: Trough plasma concentration (Cmin)
Measure: Pharmacokinetic (PK) profile of CA-4948 measured by Cmin Time: 24- 36 monthsDescription: Time to maximum plasma concentration (Tmax)
Measure: Pharmacokinetic (PK) profile of CA-4948 measured by Tmax Time: 24- 36 monthsDescription: Plasma terminal elimination half-life (T 1/2)
Measure: Pharmacokinetic (PK) profile of CA-4948 measured by plasma terminal half-life Time: 24- 36 monthsDescription: Assessed by ORR
Measure: To assess efficacy of CA-4948 as a monotherapy and in combination with ibrutinib measured by overall response rate (ORR) Time: 24- 36 monthsDescription: Assessed by DOR
Measure: To assess efficacy of CA-4948 as a monotherapy and in combination with ibrutinib measured by duration of response (DOR) Time: 24- 36 monthsDescription: Assessed by DCR
Measure: To assess efficacy of CA-4948 as a monotherapy and in combination with ibrutinib measured by disease control rate (DCR) Time: 24- 36 monthsDescription: Assessed by PFS
Measure: To assess efficacy of CA-4948 as a monotherapy and in combination with ibrutinib measured by progression free survival (PFS) Time: 24- 36 monthsDescription: Assessed by OS
Measure: To assess efficacy of CA-4948 as a monotherapy and in combination with ibrutinib measured by overall survival (OS) Time: 24 - 36 monthsDescription: CNS liquor with be sampled from an Ommaya reservoir or with a spinal puncture about 3 hours after oral dosing of CA-4948. At approximately the same timepoint, a peripheral blood sample will be taken to obtain a plasma sample. The respective CA-4948 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 CA-4948 following oral dosing.
Measure: Part B: To estimate the blood-brain barrier penetration in CNS lymphoma patients Time: 1 dayAllocation: Non-Randomized
Sequential Assignment
There is one SNP
The population will be enriched for MYD88 L265P mutations. --- L265P ---