A Study of CA-4948 in Patients With Relapsed or Refractory Primary Central Nervous System Lymphoma
Relapsed Hematologic Malignancy, Refractory Hematologic Malignancy, Relapsed Primary Central Nervous System Lymphoma
About this trial
This is an interventional treatment trial for Relapsed Hematologic Malignancy focused on measuring DLBCL, MCL, MYD88, IRAK4, NHL, AML, MZL, PCNSL
Eligibility Criteria
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 ≤ 1
- For Part A1: Diagnosis of histopathologically confirmed B-cell hematological malignancy (as per the World Health Organization [WHO] 2016 classification; Swedow 2016); eligible subtypes include follicular lymphoma, MZL, DLBCL, mantle cell lymphoma, and WM/LPL without the urgent need for treatment hyperviscosity.
For Part A2: Diagnosis of histopathologically confirmed B-cell NHL, as per the WHO 2016 classification (Swerdlow et al. 2016). Eligible NHL subtypes include follicular lymphoma, MZL, mantle cell lymphoma, DLBCL(including extranodal lymphomas of leg-, testicular-, or NOS type), and primary or secondary CNS lymphoma.
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.
Exclusion Criteria:
- Patient with active central nervous system (CNS) involvement other than PCNSL at study entry are ineligible.
- Radiotherapy delivered to non-target lesions involving >25% of bone marrow within one week prior to starting study treatment or delivered to target lesions that will be followed on the study (NOTE: prior sites of radiation will be recorded)
- Any prior anti-cancer treatment such as chemotherapy, immunomodulatory drug therapy, etc., received within 14 days prior to start of study treatment (with the exception of ibrutinib for Parts A2 and B, which may be continued as part of this study without interruption)
Current or planned glucocorticoid therapy, with the following exceptions:
- Doses ≤ 10 mg/day prednisolone or equivalent is allowed, provided that the steroid dose has been stable or tapering for at least 14 days prior to the first dose of study treatment
- Inhaled, intranasal, intraarticular and topical steroids are permitted
- Use of any investigational agent within 21 days or 5 half-lives, whichever is shorter, prior to start of study treatment
- Presence of an acute or chronic toxicity resulting from prior anti-cancer therapy, with the exception of alopecia, that has not resolved to Grade ≤ 1 within 7 days prior to start of study treatment unless approved by the Medical Monitor
- Known allergy or hypersensitivity to any component of the formulation of emavusertib (or ibrutinib for entry into Parts A2 or B) used in this study
B-cell NHL of the following subtypes:
- Burkitt lymphoma
- Lymphoblastic lymphoma or leukemia
- Post-transplantation lymphoproliferative disorder
- Known primary mediastinal, ocular, or epidural, DLBCL
- WM and LPL
- CLL/SLL
Sites / Locations
- Mayo ClinicRecruiting
- UCLA Department of Medicine - Hematology/Oncology
- Smilow Cancer Hospital at Yale-New HavenRecruiting
- Mayo ClinicRecruiting
- Mayo ClinicRecruiting
- Fred and Pamela Buffett Cancer CenterRecruiting
- Hackensack University Medical CenterRecruiting
- Memorial Sloan Kettering Cancer CenterRecruiting
- Hospital of the University of Pennsylvania
- University of Tennessee Medical CenterRecruiting
- UT Southwestern Medical CenterRecruiting
- Swedish Cancer Institute
- Všeobecná fakultní nemocnice v Praze
- Institut Curie Hospital
- Hematology Department Soroka UMC / Heanatology Department
- Hadassah Medical Center / Ein-Carem
- Università di Torino Croce e Carle
- SODc Ematologia Azienda Ospedaliera Universitaria Careggi
- IRST - Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori
- IRCCS San Raffaele Scientific Institute
- Uniwersyteckie Centrum Kliniczne Osrodek Badan Klinicznych Wczesnych FazRecruiting
- Oddzial Kliniczny HematologiiRecruiting
- NarodowyInstytutu Onkologii im. Marii Sklodowskiej-Curie-Panstwowy Instytutu BadawczyRecruiting
- MD Anderson Cancer Center MadridRecruiting
- Hospital Universitario Virgen del RocioRecruiting
Arms of the Study
Arm 1
Arm 2
Arm 3
Experimental
Experimental
Experimental
Emavusertib (CA-4948) dose escalation
Emavusertib (CA-4948) and ibrutinib dose escalation
Emavusertib (CA-4948) and ibrutinib dose expansion
Part A1: Dose-level cohorts with up to approximately 6 patients each will be used to define the Maximum Tolerated Dose (MTD) for emavusertib.
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.
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.