Acalabrutinib Plus RICE for Relapsed/Refractory DLBCL
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|ClinicalTrials.gov Identifier: NCT03736616|
Recruitment Status : Not yet recruiting
First Posted : November 9, 2018
Last Update Posted : November 14, 2018
To evaluate the tolerability,feasibility, and efficacy of combining acalabrutinib with RICE chemotherapy as second line therapy in relapsed/refractory DLBCL patients with separate primary objectives in each of in two cohorts:
Cohort A: Hematopoeitic stem cell transplantation (HSCT) eligible patients undergoing second-line salvage chemoimmunotherapy [Rituximab, Ifosfamide, Carboplatin, and Etoposide (RICE)] plus acalabrutinib:.
Cohort B: Individuals not eligible for HSCT undergoing second-line salvage chemoimmunotherapy [Rituximab, Ifosfamide, Carboplatin, and Etoposide (RICE)] plus acalabrutinib followed by acalabrutinib as a maintenance therapy
|Condition or disease||Intervention/treatment||Phase|
|Diffuse Large B Cell Lymphoma||Drug: Carboplatin Drug: Ifosfamide Drug: Etoposide Biological: Rituximab Drug: Carmustine Drug: Cytarabine Drug: Melphalan Other: Autologous HSCT Drug: Acalabrutinib||Phase 2|
This is a phase II study with a safety run-in. There will be two planned cohorts, Cohort A and Cohort B. Cohort A will be open to R/R DLBCL patients who are medically eligible for autologous HSCT (autoHSCT). Cohort B will be open to R/R DLBCL patients who are medically ineligible for autologous transplant. Historical outcomes from completed, published prospective clinical trials using RICE salvage chemotherapy will serve as a comparator population.
Safety run-in: To assess for safety of the combination of acalabrutinib and RICE chemotherapy, we will pause enrollment in both cohorts to assess for any safety concerns once a total 10 patients have been enrolled to either cohort. After the first ten patients have all completed at least one cycle of therapy without unacceptable or unexpected concerns, enrollment will resume. If there are concerns about adverse events or the ability of patients to proceed as expected to HSCT, then the study team will convene to determine whether the protocol should be modified. Data obtained for the first ten patients will be included in the data sample for final analysis.
Cohort A: After confirmation of medical eligibility for autologous HSCT, patients enrolled in Cohort A will receive 2 cycles of standard dose RICE salvage chemotherapy in combination with acalabrutinib 100mg twice daily (BID) day 1-21 of a 21 day cycle. After 2 cycles of therapy, patients will undergo autologous cell collection per standard institutional procedures. Acalabrutinib will be held 3 days before planned placement of an apheresis collection catheter and resumed 3 days after completion of stem cell collection and catheter removal. Patients will then receive a 3rd cycle of RICE chemotherapy in combination with acalabrutinib 100mg BID. For patients with bone marrow disease at enrollment, a repeat bone marrow will be performed after 2 cycles of salvage therapy, prior to autologous stem cell collection. For patients with continued bone marrow disease after 2 cycles of salvage therapy, a 3rd cycle may be given prior to autologous cell collection. PET-CT (PET3) will be performed 14-21 days after day 1 of cycle 3 to assess response. Those patients with complete response (CR) or partial response (PR) after PET3 will move onto autologous transplant with Carmustine, Etoposide, Cytarabine, and Melphalan (BEAM) conditioning within 28-42 days of PET3. After adequate hematopoietic recovery (expected around 30 days after autologous HSCT), patients will restart acalabrutinib 100mg BID as maintenance therapy for a period of 12 months. Patients with a minor response (MR) or stable disease (SD) after PET3 will delay HSCT and will continue acalabrutinib 100mg BID with repeat PET every 6 weeks. If patient converts to CR at subsequent PET-CT, they may proceed with BEAM autologous HSCT within 28-42 days of achieving this response followed by 12 months of post-transplant acalabrutinib maintenance. Patients with continued PR/MR/SD may continue on study, if felt to be clinically benefitting without limiting toxicity, but will not receive a transplant. Patients demonstrating progressive disease (PD) at any stage will be withdrawn from study treatment but their outcomes will be tracked and included in final data analysis.
Cohort B: Patients medically ineligible for autologous HSCT but fit for salvage chemotherapy will receive 3 cycles or RICE salvage chemotherapy in combination with acalabrutinib 100mg BID day 1-21 of a 21 day cycle followed by PET-CT (PET3) 14-21 days after start of Cycle 3. Patients with CR/PR/MR/SD would continue with acalabrutinib maintenance with repeat PET-CT every 3 months until disease progression or toxicity. Patients demonstrating progressive disease (PD) will be withdrawn from study treatment but their outcomes will be tracked and included in final data analysis.
Establishing the feasibility of combining acalabrutinib with RICE chemotherapy in transplant eligible and transplant ineligible patients with R/R DLBCL will provide the foundation for a larger study of efficacy and long-term outcomes of the combination therapy for patients with R/R DLBCL. Such a study, if demonstrative of improvements in the complete response rate to salvage therapy at PET3, could provide evidence to support a new standard of care of for patients with R/R DLBCL.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||47 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Official Title:||Acalabrutinib Plus RICE for Patients With Relapsed/Refractory DLBCL Followed by Autologous Hematopoietic Cell Transplantation and Acalabrutinib Maintenance Therapy|
|Estimated Study Start Date :||November 2018|
|Estimated Primary Completion Date :||September 2021|
|Estimated Study Completion Date :||September 2022|
Experimental: Cohort A: Transplant eligible
Patients receive RICE: Rituximab 375mg/m2 IV d1, Ifosfamide 5000mg/m2, Carboplatin area under curve (AUC) 5 IV d2, Etoposide (VP16) 100mg/m2 IV d1-3 & Acalabrutinib 100mg oral BID d1-21. Cycle is 21 days for up to 3 cycles of treatment.
BEAM chemotherapy & autoHSCT: BEAM given as Carmustine (BCNU) 300mg/m2 IV day -6 respective to stem cell infusion, VP16 200mg/m2 IV BID day -5 to day-2, Cytarabine (Ara-C) 200mg/m2 IV BID day -5 to day -2, and Melphalan 140mg/m2 IV day -1. Autologous hematopoietic stem cell infusion on day 0. Only patients with CR/PR after RICE acalabrutinib will undergo BEAM and autoHSCT
Maintenance therapy: Post autoHSCT patients will receive Acalabrutinib 100mg oral BID starting on day +30 for 12 consecutive months or until progression or intolerance if occurs within those 12 months.
Other Name: VP-16
Other Name: Rituxan
Other Name: BCNU
Other Name: ARA-C
Other: Autologous HSCT
Other Name: Autologous Hematopoeitic Stem Cell Transplantation
Bruton's Tyrosine Kinase Inhibitor
Experimental: Cohort B: Transplant ineligible
Patients receive RICE chemoimmunotherapy + Acalabrutinib Salvage therapy: RICE: Rituximab 375mg/m2 IV d1, Ifosfamide 5000mg/m2, Carboplatin AUC 5 IV d2, Etoposide 100mg/m2 IV d1-3. Acalabrutinib 100mg oral BID d1-21. Cycle is 21 days for up to 3 cycles of treatment.
Maintenance therapy: Patients will receive Acalabrutinib 100mg oral BID for 12 consecutive months or until progression or intolerance if occurs within those 12 months. Maintenance therapy will only be given to patients with stable disease or better response after 3 cycles of RICE+ acalabrutinib
Other Name: VP-16
Other Name: Rituxan
Bruton's Tyrosine Kinase Inhibitor
- Cohort A: Complete Response Rate [ Time Frame: 10 weeks ]To estimate the confirmed complete response (CR) rate (RECIL 2017 criteria) prior to transplant in patients undergoing second-line therapy for relapsed/refractory DLBCL.
- Cohort B: Progression Free Survival [ Time Frame: 1 year ]To estimate the one-year progression free survival rate in patients undergoing second-line induction and maintenance therapy for relapsed/refractory DLBCL.
- Cohort A: Treatment Response [ Time Frame: 10 weeks ]To determine the proportion of patients who complete 3 cycles of acalabrutinib with RICE therapy and achieve treatment response sufficient to continue on to receive planned auto HCT.
- Cohort B: Treatment Completion [ Time Frame: 17 weeks ]To determine the proportion of patients in Cohort B who complete 3 cycles of acalabrutinib with RICE therapy and 2 cycles or more of maintenance acalabrutinib.
- Cohorts A and B: Overall Response Rate [ Time Frame: 1 year ]To measure the overall response rate (ORR) at 1 year following study initiation
- Cohorts A and B: Incidence of treatment-related Grade 3 and 4 Adverse events as assessed by CTCAE v4.0 [ Time Frame: 1.5 years ]Evaluate incidence of grade 3 or grade 4 treatment related adverse events as assessed by CTCAE v4.0
- Cohorts A and B: Incidence of Serious Adverse Events [ Time Frame: 1.5 years ]Evaluate incidence of protocol defined serious adverse events
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): NCT03736616
|Contact: Janell Dueyemail@example.com|
|Contact: Neil Bailey||206-215-1471||Neil.Bailey@swedish.org|
|United States, Washington|
|Swedish Cancer Institute||Not yet recruiting|
|Seattle, Washington, United States, 98104|
|Contact: Neil Bailey|
|Principal Investigator: Krish Patel, MD|
|Principal Investigator:||Krish Patel, MD||Swedish Medical Center|