Acalabrutinib With DA-EPOCH-R or R-CHOP for People With Untreated Diffuse Large B-cell Lymphoma
- Conditions
- Non-Hodgkin's LymphomaDiffuse Large B-Cell LymphomaDLBCLNHL
- Interventions
- Registration Number
- NCT04002947
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
Background:
Diffuse large B-cell lymphoma is the most common type of non-Hodgkin lymphoma. Most people with this cancer can be cured. But those who are not cured have a poor prognosis. Researchers want to add another drug to standard treatment see if it can improve the cure rate.
Objective:
To see if the drug acalabrutinib given with rituximab and standard combination chemotherapy can improve the cure rate of aggressive B-cell lymphomas such as diffuse large B-cell lymphoma.
Eligibility:
People ages 18 and older with an aggressive B-cell lymphomas that have not been treated
Design:
Participants will be screened with:
Blood and urine tests
Physical exam
Medical history
Tumor biopsy
Bone marrow biopsy: A needle will remove marrow from the participant s hipbone.
Lumbar puncture: If necessary, a needle will remove fluid from the participant s spinal canal.
Imaging scans
Participants will take the study drug for up to 14 days. It is a pill taken 2 times a day. Then they will have more scans. They will get rituximab and chemotherapy. They may get these drugs through a needle in an arm vein. Or they may them through a tube placed in a vein in their chest or in their neck. They might also keep taking the study drug. Each treatment cycle lasts 21 days. They will have up to 6 cycles.
Participants may have 4 doses of another drug injected into their spinal fluid.
Participants will have repeats of the screening tests throughout the study.
Participants will have a follow-up visit 30 days after their last treatment, then every 3 months for 2 years, then every 6 months for 3 years, and then yearly.
- Detailed Description
Background:
Gene-expression profiling (GEP) has identified two dominant molecular subtypes, activated B cell like (ABC) and germinal center B cell like (GCB), that arise by distinct mechanisms, have distinct prognoses, and respond differently to targeted therapy
Recently, genetic subtypes of DLBCL have been described within molecular subtypes that have distinct genotypic, epigenetic, and clinical characteristics providing biologic rationale for precision medicine strategies in DLBCL
Frontline treatment of DLBCL is either rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), or infusional rituximab, cyclophosphamide, doxorubicin, etoposide, vincristine, and prednisone (DA-EPOCH-R) but up to 40% of patients are not cured with frontline treatment
Bruton s tyrosine kinase (BTK) is a key component of the B-cell receptor (BCR)-signaling cascade and selective BTK inhibitors have clinical activity preferentially in ABC-DLBCL
Acalabrutinib is a selective, small molecule, next-generation BTK inhibitor approved for relapsed mantle cell lymphoma and demonstrated activity in DLBCL
The molecular characterization of tumors that respond to DLBCL BTK inhibitors is incomplete; although responses occur more commonly in ABC-DLBCL, cases of GCB-DLBCL show minor responses, and no information is available within genetic subtypes of DLBCL
Patients with minor responses during 2-week window of treatment with acalabrutinib (100mg BID) as a single agent may benefit from acalabrutinib added to standard combination therapy as part of frontline therapy
Objectives:
To determine the response rate, including minor response (MR), to acalabrutinib administered for 14 days in molecular and genetic subtypes of untreated DLBLC (ABC, GCB, unclassified, genetic subtypes)
Eligibility:
Histologically confirmed DLBCL or high-grade B-cell lymphoma
Primary mediastinal B-cell lymphoma (PMBL) and CNS involvement excluded
Stages II-IV
HIV negative or positive
Available FFPE or fresh frozen biopsy
Adequate organ function
Age \>= 18 years
Design:
Open-label, single center, non-randomized phase 2 study, with enrollment of 100 untreated DLBCL patients. It is estimated that there may be 50% who are ABC (\~50 patients), and 50% who are GCB or unclassified (\~50 patients). The accrual ceiling will be set at 132 to allow for inevaluable patients and to account for screen fails.
The study will start with an initial 2-week window of treatment with acalabrutinib (100mg BID) as a single agent, with collection and assessment of molecular correlates as well as response rates (by imaging) by molecular subtype
Treatment with chemoimmunotherapy (R-CHOP or DA-EPOCH-R) either alone or in combination with acalabrutinib will depend on response during window; those with less than 25% reduction during window will receive chemoimmunotherapy alone, while those with at least a 25% reduction in tumor lesions (sum of the products of the longest diameter) will receive combination therapy of chemoimmunotherapy with acalabrutinib (100mg BID on days 1-10 of each cycle); those with clinical progression during window will move immediately to chemoimmunotherapy
Secondary objectives include: integrative genomic analysis of all untreated DLBCL that respond or are resistant to acalabrutinib for 14 days, event-free survival (EFS), assessment of progression free survival (PFS) and overall survival (OS) of combination therapy of
acalabrutinib and chemoimmunotherapy and investigation of the safety and tolerability of acalabrutinib added to R-CHOP or DA-EPOCH-R in untreated DLBCL.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 132
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description 1 DA-EPOCH Acalabrutinib 100 mg orally twice a day for 14 days; Following window: patients with \> or = to 25% tumor reduction, treat with DA-EPOCH-R or R-CHOP + acalabrutinib 100mg orally twice a day for the first 10 days, for 6 cycles; whereas, patients with \<25% tumor reduction, treat with DA-EPOCH-R or R-CHOP alone for 6 cycles 1 CHOP Acalabrutinib 100 mg orally twice a day for 14 days; Following window: patients with \> or = to 25% tumor reduction, treat with DA-EPOCH-R or R-CHOP + acalabrutinib 100mg orally twice a day for the first 10 days, for 6 cycles; whereas, patients with \<25% tumor reduction, treat with DA-EPOCH-R or R-CHOP alone for 6 cycles 1 Acalabrutinib Acalabrutinib 100 mg orally twice a day for 14 days; Following window: patients with \> or = to 25% tumor reduction, treat with DA-EPOCH-R or R-CHOP + acalabrutinib 100mg orally twice a day for the first 10 days, for 6 cycles; whereas, patients with \<25% tumor reduction, treat with DA-EPOCH-R or R-CHOP alone for 6 cycles 1 Rituximab Acalabrutinib 100 mg orally twice a day for 14 days; Following window: patients with \> or = to 25% tumor reduction, treat with DA-EPOCH-R or R-CHOP + acalabrutinib 100mg orally twice a day for the first 10 days, for 6 cycles; whereas, patients with \<25% tumor reduction, treat with DA-EPOCH-R or R-CHOP alone for 6 cycles
- Primary Outcome Measures
Name Time Method Response rate every 2 cycles Number of patients who achieve a CR, PR or SD
- Secondary Outcome Measures
Name Time Method Safety and tolerability initiation of study drug until 30 days after last dose Incidence of adverse events (i.e., grade and frequency)
Progression-free survival every 3-6 months for 5 years then yearly The response rate will be determined and reported along with a 95% confidence interval.
Overall survival every 3-6 months for 5 years then yearly The response rate will be determined and reported along with a 95% confidence interval.
Event-free survival every 3-6 months for 5 years then yearly The response rate will be determined and reported along with a 95% confidence interval.
Complete response rate 6 cycles The response rate will be determined and reported along with a 95% confidence interval.
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States