Acalabrutinib With DA-EPOCH-R or R-CHOP for People With Untreated Diffuse Large B-cell Lymphoma
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|ClinicalTrials.gov Identifier: NCT04002947|
Recruitment Status : Recruiting
First Posted : July 1, 2019
Last Update Posted : October 9, 2019
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.
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.
People ages 18 and older with an aggressive B-cell lymphomas that have not been treated
Participants will be screened with:
Blood and urine tests
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.
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.
|Condition or disease||Intervention/treatment||Phase|
|Diffuse Large B-Cell Lymphoma Non Hodgkin's Lymphoma DLBCL NHL||Drug: DA-EPOCH Biological: Rituximab Drug: CHOP Drug: Acalabrutinib||Phase 2|
- 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, second-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 GCBDLBCL 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
-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)
- 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
- 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 112 to allow for inevaluable patients.
- 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), progression free survival (PFS) and overall survival (OS) of combination therapy of acalabrutinib and chemoimmunotherapy will be assessed
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||112 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase 2 Study of Acalabrutinib With DA-EPOCH-R or R-CHOP for Patients With Untreated Diffuse Large B-cell Lymphoma|
|Actual Study Start Date :||August 5, 2019|
|Estimated Primary Completion Date :||May 31, 2023|
|Estimated Study Completion Date :||March 31, 2028|
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 RCHOP + 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 RCHOP alone for 6 cycles
Vincristine 1.4 mg /m2 (2 mg cap) IV on Day 1, Doxorubicin 10 mg/m2/day CIVI on Days 1-4, Etoposide 50 mg/m2 /day CIVI on Days 1-4, Cyclophosphamide 750 mg/m2 IV on Day 5. Prednisone 60 mg/m2 PO BID is administered daily on Days 1-5 of each cycle. Each cycle is 21 days and drugs will be given for 6 cycles.
Rituximab 375 mg /m2 IV on Day 1 of each 21-day cycle for 6 cycles.
Cyclophosphamide 750 mg/m2 IV, Doxorubicin 50 mg /m2 IV, Vincristine 1.4 mg/m2 (2 mg cap) IV are administered on Day 1 of each 21-day cycle for 6 cycles. Prednisone 40 mg/m2 PO is administered daily on Days 1-5 of each cycle.
Acalabrutinib is administered orally at 100 mg twice a day for 14 days during the window period. During combination therapy, acalabrutinib is administered 100 mg twice daily for thefirst 10 days for 6 cycles.
- Response rate [ Time Frame: every 2 cycles ]The response rate will be determined and reported along with a 95% confidence interval.
- Progression-free survival [ Time Frame: 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 [ Time Frame: 6 cycles ]The response rate will be determined and reported along with a 95% confidence interval.
- Event-free survival [ Time Frame: every 3-6 months for 5 years then yearly ]The response rate will be determined and reported along with a 95% confidence interval.
- Safety and tolerability [ Time Frame: initiation of study drug until 30 days after last dose ]Incidence of adverse events (i. e., grade and frequency)
- Overall survival [ Time Frame: every 3-6 months for 5 years then yearly ]The response rate will be determined and reported along with a 95% confidence interval.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04002947
|Contact: Maureen E Edgerly, R.N.||(240) firstname.lastname@example.org|
|United States, Maryland|
|National Institutes of Health Clinical Center||Recruiting|
|Bethesda, Maryland, United States, 20892|
|Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office 888-624-1937|
|Principal Investigator:||Mark J Roschewski, M.D.||National Cancer Institute (NCI)|