Mantle Cell Lymphoma
Conditions
Brief summary
This study is designed to evaluate the efficacy and safety of acalabrutinib plus bendamustine and rituximab followed by acalabrutinib plus cytarabine and rituximab in subjects with treatment naïve mantle cell lymphoma (MCL), as a preparation for a larger cooperative group trial with the goal of achieving a standard induction regimen for MCL in transplant eligible patients. The investigators hypothesize that the addition of acalabrutinib to BR/CR regimen will prove safe and increase the complete response (CR) rate as well as minimal residual disease (MRD) negativity pre-transplant, thus improving clinical outcomes.
Interventions
DRUGBendamustine
Bendamustine will be administered at a dose of 90 mg/m\^2 IV over 30 minutes on Days 1 and 2 of Cycles 1-3
DRUGRituximab
In Cycle 1, rituximab will be administered at a dose of 375 mg/m\^2 IV on Day 1 or 2 at the investigator's discretion in order to reduce the risk of a first infusion reaction. Rituximab will be given on Day 1 of Cycles 1 through 6.
DRUGAcalabrutinib
The capsules should be swallowed intact with water and with or without food.
DRUGCytarabine
On Days 1 and 2 of Cycles 4-6, following rituximab dosing, cytarabine will be administered IV every 12 hours for a total of 4 doses.
PROCEDURELeukapheresis
Until collection of ≥ 2 x 106 CD34+ stem cells / kg
PROCEDUREPeripheral blood
-Baseline, end of Cycle 3, 4-6 weeks after Cycle 6 Day 1, and if the patient discontinues protocol therapy prior to completion of Cycle 6
PROCEDUREOral rinse
-Baseline
PROCEDUREBone marrow collection
-Bone marrow will be collected at baseline if the patient requires a marrow for staging purposes and at end of treatment if the patient requires a marrow for restaging.
Sponsors
Washington University School of Medicine
Acerta Pharma BV
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed mantle cell lymphoma with documented expression of Cyclin D1 by immune-histochemical stains and/or t(11;14) by cytogenetics or FISH. * Presence of evaluable disease by PET imaging per the Lugano classification. * Eligible for autologous stem cell transplantation. * Between 18 and 70 years of age, inclusive. * ECOG performance status ≤ 2 * Normal bone marrow and organ function as defined below: * Absolute neutrophil count ≥ 1,000/mcL unless, in the opinion of the treating physician, neutropenia is due to splenomegaly or bone marrow involvement * Platelets ≥ 100,000/mcL unless, in the opinion of the treating physician, thrombocytopenia is due to splenomegaly or bone marrow involvement * Total bilirubin ≤ 2.0 x IULN and AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN except when, in the opinion of the treating physician, elevation is due to direct involvement of lymphoma (e.g. hepatic infiltration or biliary obstruction due to lymphoma) or Gilbert's disease * Creatinine ≤ IULN OR creatinine clearance ≥ 40 mL/min for patients with creatinine levels above institutional normal * Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. * Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).
Exclusion criteria
* Any previous chemotherapy or radiation for mantle cell lymphoma. Short course of steroids for symptom relief prior to presentation is permissible. * Symptomatic meningeal or parenchymal brain lymphoma. * Prior exposure to a BTK inhibitor. * Currently receiving any other investigational agents. * A history of allergic reactions attributed to compounds of similar chemical or biologic composition to acalabrutinib, rituximab, cytarabine, bendamustine, or other agents used in the study. * Received a live virus vaccination within 28 days of first dose of study drug. * Uncontrolled active systemic fungal, bacterial, viral, or other infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment), or intravenous anti-infective treatment within 2 weeks before first dose of study drug. * Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or corrected QT interval (QTc) \> 480 msec at screening. Exception: subjects with controlled, asymptomatic atrial fibrillation during screening are allowed to enroll on study. * Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel that is likely to affect absorption, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass. * Active bleeding or history of bleeding diathesis (eg, hemophilia or von Willebrand disease). * Uncontrolled AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenic purpura). * Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening. * Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer. * Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 7 days of first dose of study drug. * Prothrombin time (PT)/INR or aPTT (in the absence of lupus anticoagulant) \>2x ULN. Exception: Subjects receiving warfarin are excluded; however, those receiving other anticoagulant therapy who have a higher INR/aPTT may be permitted to enroll to this study after discussion with the PI. * Requires treatment with proton pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment to this study. * History of significant cerebrovascular disease/event, including stroke or intracranial hemorrhage, within 6 months before the first dose of study drug. * Major surgical procedure within 28 days of first dose of study drug. Note: If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug. * Subjects with serologic status reflecting active viral hepatitis B or C infection. Subjects who are hepatitis B core antibody positive but surface antigen negative will need negative polymerase chain reaction (PCR) prior to enrollment. Hepatitis B surface antigen positive or PCR positive patients will be excluded. Subjects who are hepatitis C antibody positive will need negative PCR prior to enrollment. Subjects with positive hepatitis C PCR will be excluded. * Pregnant and/or breastfeeding. Women of childbearing potential must have a negative serum pregnancy test within 14 days of study entry. * Known HIV-positivity on combination antiretroviral therapy because of the potential for pharmacokinetic interactions with acalabrutinib. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Stem Cell Mobilization Success Rate With Cytarabine and Rituximab | Through 5 courses of apheresis (up to 5 days) | -Stem cell mobilization success is defined as a yield of \>2x10\^6 CD34+ stem cells/kg with a maximum of 5 courses of apheresis |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability of Regimen in Subjects With MCL as Measured by Treatment Related Non-hematologic Toxicity of Grade 3 or Higher | 30 days following completion of treatment (estimated to be 7 months) | -Toxicity is measured using NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 |
| Overall Response Rate (ORR = Complete Response (CR) + Partial Response (PR)) of Subjects | Through completion of treatment (estimated to be 6 months) | -For definitions of CR and PR please refer to the Recommendations for Initial Evaluation, Staging and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification |
| Pre-transplant Complete Response Rate | Through completion of treatment (estimated to be 6 months) | -For definitions of CR, please refer to the Recommendations for Initial Evaluation, Staging and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification |
| Median Progression-free Survival (PFS) | Up to approximately 5 years of follow-up | * Kaplan-Meier estimate of the median time of PFS from start of treatment to time of progression or death, whichever occurs first. * Progressive disease: * London Deauville score of 4 or 5 in individual target nodes/masses with an increase in intensity of uptake from the baseline and/or new FDG avid foci consistent with lymphoma at interim or end of treatment assessment. * New FDG avid foci of extranodal disease consistent with lymphoma. If there is concern regarding the etiology of the new lesions, biopsy or interval scan may be considered * New or recurrent FDG avid foci in the bone marrow |
| Overall Survival (OS) | Up to approximately 5 years of follow-up | — |
| Median Overall Survival (OS) | Up to approximately 5 years of follow-up | * Overall survival (OS) is defined as the time from study registration to date of death due to any cause. * Kaplan-Meier method will be used for analysis. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORBrad S Kahl, M.D.
Washington University School of Medicine
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bendamustine/Rituximab/Acalabrutinib/Cytarabine * Patients will receive (6) 28 day cycles
* Cycles 1-3 will consist of bendamustine on Days 1 and 2, rituximab on Day 1, and acalabrutinib twice per day (BID) on Days 1 through 28.
* Cycles 4-6 will consist of rituximab on Day 1, cytarabine every 12 hours on Days 1 and 2, acalabrutinib BID on Days 1 through 7 and 22 through 28 (one week on, two weeks off, one week on), and growth factors as per institutional standard
* After Cycle 6, patients will undergo leukapheresis | 13 |
| Total | 13 |
Baseline characteristics
| Characteristic | Bendamustine/Rituximab/Acalabrutinib/Cytarabine |
|---|---|
| Age, Continuous | 57 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 13 Participants |
| Region of Enrollment United States | 13 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 4 / 13 |
| other Total, other adverse events | 13 / 13 |
| serious Total, serious adverse events | 8 / 13 |
Outcome results
Primary
Stem Cell Mobilization Success Rate With Cytarabine and Rituximab
-Stem cell mobilization success is defined as a yield of \>2x10\^6 CD34+ stem cells/kg with a maximum of 5 courses of apheresis
Time frame: Through 5 courses of apheresis (up to 5 days)
Population: 9 participants are not evaluable because they did not receive stem cell transplant.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bendamustine/Rituximab/Acalabrutinib/Cytarabine | Stem Cell Mobilization Success Rate With Cytarabine and Rituximab | 4 Participants |
Secondary
Overall Response Rate (ORR = Complete Response (CR) + Partial Response (PR)) of Subjects
-For definitions of CR and PR please refer to the Recommendations for Initial Evaluation, Staging and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification
Time frame: Through completion of treatment (estimated to be 6 months)
Population: 1 participant did not complete 2 cycles and was not evaluable for response
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bendamustine/Rituximab/Acalabrutinib/Cytarabine | Overall Response Rate (ORR = Complete Response (CR) + Partial Response (PR)) of Subjects | 10 Participants |
Secondary
Overall Survival (OS)
-OS=time from study registration until death from any cause
Time frame: Through 5 years
Secondary
Pre-transplant Complete Response Rate
-For definitions of CR, please refer to the Recommendations for Initial Evaluation, Staging and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification
Time frame: Through completion of treatment (estimated to be 6 months)
Population: 1 participant did not complete 2 cycles and was not evaluable for response
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bendamustine/Rituximab/Acalabrutinib/Cytarabine | Pre-transplant Complete Response Rate | 9 Participants |
Secondary
Progression-free Survival (PFS)
* PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first * London Deauville score of 4 or 5 in individual target nodes/masses with an increase in intensity of uptake from the baseline and/or new FDG avid foci consistent with lymphoma at interim or end of treatment assessment; New FDG avid foci of extranodal disease consistent with lymphoma. If there is concern regarding the etiology of the new lesions, biopsy or interval scan may be considered; New or recurrent FDG avid foci in the bone marrow
Time frame: Through 5 years
Secondary
Safety and Tolerability of Regimen in Subjects With MCL as Measured by Treatment Related Non-hematologic Toxicity of Grade 3 or Higher
-Toxicity is measured using NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
Time frame: 30 days following completion of treatment (estimated to be 7 months)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Bendamustine/Rituximab/Acalabrutinib/Cytarabine | Safety and Tolerability of Regimen in Subjects With MCL as Measured by Treatment Related Non-hematologic Toxicity of Grade 3 or Higher | Diarrhea | 1 Participants |
| Bendamustine/Rituximab/Acalabrutinib/Cytarabine | Safety and Tolerability of Regimen in Subjects With MCL as Measured by Treatment Related Non-hematologic Toxicity of Grade 3 or Higher | Infusion related reaction | 1 Participants |
| Bendamustine/Rituximab/Acalabrutinib/Cytarabine | Safety and Tolerability of Regimen in Subjects With MCL as Measured by Treatment Related Non-hematologic Toxicity of Grade 3 or Higher | Upper respiratory infection | 1 Participants |
| Bendamustine/Rituximab/Acalabrutinib/Cytarabine | Safety and Tolerability of Regimen in Subjects With MCL as Measured by Treatment Related Non-hematologic Toxicity of Grade 3 or Higher | Skin infection | 1 Participants |
| Bendamustine/Rituximab/Acalabrutinib/Cytarabine | Safety and Tolerability of Regimen in Subjects With MCL as Measured by Treatment Related Non-hematologic Toxicity of Grade 3 or Higher | Perirectal abscess | 1 Participants |
| Bendamustine/Rituximab/Acalabrutinib/Cytarabine | Safety and Tolerability of Regimen in Subjects With MCL as Measured by Treatment Related Non-hematologic Toxicity of Grade 3 or Higher | Peritoneal infection | 1 Participants |
| Bendamustine/Rituximab/Acalabrutinib/Cytarabine | Safety and Tolerability of Regimen in Subjects With MCL as Measured by Treatment Related Non-hematologic Toxicity of Grade 3 or Higher | Blood bilirubin increased | 1 Participants |
| Bendamustine/Rituximab/Acalabrutinib/Cytarabine | Safety and Tolerability of Regimen in Subjects With MCL as Measured by Treatment Related Non-hematologic Toxicity of Grade 3 or Higher | Ejection fraction decreased | 1 Participants |
| Bendamustine/Rituximab/Acalabrutinib/Cytarabine | Safety and Tolerability of Regimen in Subjects With MCL as Measured by Treatment Related Non-hematologic Toxicity of Grade 3 or Higher | Alanine aminotransferase increased | 1 Participants |