Chronic Lymphocytic Leukemia, Diffuse Large B Cell Lymphoma, Marginal Zone Lymphoma, Small Lymphocytic Leukemia
Conditions
Keywords
Non-Germinal Center Diffuse Large B Cell Lymphoma
Brief summary
The purpose of this study is to test a combination treatment of acalabrutunib when given together with rituximab-ifosfamide-carboplatin-etoposide (R-ICE) to evaluate if it will be able to improve durable responses and cure some patients.
Interventions
DRUGAcalabrutinib
Acalabrutinib 100 mg capsules taken by mouth every 12 hours (PO BID), for a total of 2 daily doses on Days 1 to 21 of each cycle.
DRUGRituximab
Rituximab 375 mg/m2 administered intravenously (IV) on Day 1 of each cycle.
DRUGIfosfamide
Ifosfamide 5g/m2 administered intravenously (IV) over 24 hours on Day 2 of each cycle.
DRUGCarboplatin
Carboplatin Area Under the Concentration time Curve (AUC) 5 IV administered intravenously (IV) on Day 2 of each cycle.
DRUGEtoposide
Etoposide 100 mg/m2 administered intravenously (IV) on Days 1, 2 and 3 of each cycle.
Sponsors
AstraZeneca
University of Miami
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Men and women ≥ 18 years of age. 2. Patients must have histologic confirmation of relapsed or refractory lymphoma. 3. Baseline FDG-PET scans must demonstrate positive lesions compatible with CT defined anatomical tumor sites. a) CT scan showing at least: * i. 2 or more clearly demarcated lesions/nodes with a long axis \>1.5cm and short axis ≥ 1.0cm, or * ii. 1 clearly demarcated lesion/node with a long axis \>2.0cm and short axis ≥1.0cm. 4. Patient must have been previously treated for B cell non-Hodgkin lymphoma with any of the allowable below: 1. First-line treatment with rituximab and an anthracycline-based chemotherapy. 2. Monotherapy rituximab, dosed prior to first-line rituximab combined with anthracycline containing chemotherapy, or as maintenance therapy. 3. Radiotherapy as part of the first-line treatment plan including anthracycline and rituximab. 5. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. 6. Life expectancy of greater than 6 weeks. 7. Patients must have normal organ and marrow function as defined below, 1. absolute neutrophil count ≥ 1000/microliters (mcL) (unless due to lymphoma involvement of the bone marrow), 2. platelets ≥75,000/mcL (unless due to lymphoma involvement of the bone marrow), 3. total bilirubin \<1.5 x within normal institutional limits (unless due to lymphoma involvement of liver or a known history of Gilbert's disease), 4. Aspartate transaminase (AST) (SGOT)/Alanine transaminase (ALT) (SGPT) ≤ 2.5 × institutional upper limit of normal (unless due to lymphoma involvement of liver), 5. creatinine within normal institutional limits, or 6. creatinine clearance ≥40 mL/min/1.73 m2 for patients with creatinine levels above institutional normal. (unless due to lymphoma). 8. Major surgical procedure within 28 days of first dose of study drug. 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. 9. Women who are sexually active and can bear children must agree to use highly effective forms of contraception during the study and for 90 days after the last dose of acalabrutinib + R-ICE. 10. Men who are sexually active and can beget children must agree to use highly effective forms of contraception during the study and for 90 days after the last dose of acalabrutinib + R-ICE. 11. Men must agree to refrain from sperm donation during the study and for 90 days after the last dose of study drug. 12. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty. 13. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local subject privacy regulations).
Exclusion criteria
1. Germinal-center cell-of-origin DLBCL. 2. Patients who have had chemotherapy or radiotherapy \< 21 days prior to first administration of study treatment or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier. 3. Patients who are receiving any other investigational agents. 4. Patients with known central nervous system involvement of lymphoma. 5. History of allergic reactions attributed to compounds of similar chemical or biologic composition to acalabrutinib or R-ICE with the exception of first-infusion reaction to rituximab. 6. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Recent infections requiring systemic treatment need to have completed therapy \> 7 days before the first dose of study drug. 7. Pregnant women are excluded from this study because an acalabrutinib R-ICE is a chemotherapy program with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with acalabrutinib R-ICE, breastfeeding should be discontinued if the mother is treated with acalabrutinib R-ICE. 8. HIV-positive patients on combination antiretroviral therapy are eligible, unless the patient's CD4 count is below the institutional lower limit of normal, or the patient is taking prohibited CYP3A4/5 strong inhibitors or inducers. 9. Patients may not have received any anti-cancer therapy for their primary rel/ref DLBCL with the exception of palliative radiation therapy (RT). 10. Uncontrolled Autoimmune Hemolytic Anemia or immune thrombocytopenia purpura (ITP) resulting in (or as evidenced by) declining platelet or Hgb levels within the 4 weeks prior to first dose of study drug. 11. Presence of transfusion-dependent thrombocytopenia. 12. Prior exposure to a Bruton's tyrosine kinase (BTK) inhibitor. 13. History of prior malignancy, with the exception of the following: 1. Malignancy treated with curative intent felt to be at low risk for recurrence by treating physician, 2. Adequately treated non-melanomatous skin cancer or lentigo maligna melanoma without current evidence of disease, 3. Adequately treated cervical carcinoma in situ without current evidence of disease. 14. Currently active clinically significant cardiovascular disease such as uncontrolled arrhythmia, congestive heart failure, or Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification, or history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to first dose with study drug. 15. Unable to swallow capsules, or disease significantly affecting gastrointestinal function or, resection of the stomach or small bowel, or symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction. 16. Serologic status reflecting active hepatitis B or C infection. Patients that are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody will need a negative polymerase chain reaction (PCR) prior to enrollment. (PCR positive patients will be excluded.) Hepatitis C antibody positive patients are eligible if PCR is negative. Hepatitis B core antibody (+) patients without evidence of HBsAg or Hep B PCR (+) are eligible with appropriate Hepatitis B reactivation prophylaxis. 17. History of stroke or intracranial hemorrhage within 6 months prior to enrollment. 18. Current life-threatening illness, medical condition, or organ system dysfunction which, in the Investigator's opinion, could compromise the patient's safety, or put the study at risk. 19. Received anticoagulation therapy with Coumadin or equivalent vitamin K antagonists within the last 28 days. 20. Vaccinated with live, attenuated vaccines with 4 weeks of first does of study drug. 21. Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to Common Terminology Criteria for Adverse Event (CTCAE, version 5), grade ≤1, or to the levels dictated in the inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Complete Response (CR) | 9 weeks (End of Cycle 3) | The percentage of participants achieving complete response (CR) will be assessed using Response Evaluation Criteria in Lymphoma (RECIL 2017) criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Partial Response (PR) | 9 weeks | The percentage of participants achieving partial response (PR) will be assessed using Response Evaluation Criteria in Lymphoma (RECIL 2017) criteria. |
| Percentage of Participants Achieving Overall Response | 9 weeks | Overall response is defined as the percentage of participants who achieved complete response (CR) or partial response (PR) to acalabrutinib + R-ICE therapy. Response will be assessed using Response Evaluation Criteria in Lymphoma (RECIL 2017) criteria. |
| Percentage of Participants Achieving Mobilization Rate Greater Than or Equal to 2x10^6 CD34+ Cells/kg Body Weight | 9 weeks | Percentage of study participants achieving a mobilization rate of greater than or equal to 2x10\^6 CD34+ cells/kg body weight. Descriptive statistics will be used to summarize the mobilization rates. |
| Number of Treatment-Emergent Adverse Events | 13 weeks | The safety profile and tolerability of acalabrutinib + R-ICE will be reported as the number of treatment-emergent adverse events (AEs) or abnormalities of laboratory tests; serious adverse events (SAEs); dose-limiting toxicities (DLTs), or AEs leading to discontinuation of study treatment, or death. Severity and relationship will be assessed by the treating physician using the Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0. |
| Progression-Free Survival (PFS) | Up to 61 weeks | Duration of Progression-Free Survival (PFS) in study participants. PFS is defined as the time from first dose to documented disease progression, or death from any cause, whichever occurs first. Data for subjects who are still alive and free from progression at the time of data cutoff date, lost to follow-up, or have discontinued the study will be censored on last assessment (or, if no post-baseline tumor assessment, at the time of first dose plus 1 day). |
| Overall Survival (OS) | Up to 61 weeks | Duration of Overall Survival (OS) in study participants. OS is defined as the time from first dose to death from any cause. Data for subjects who are still alive at the time of data cutoff date, lost to follow-up, have discontinued the study (or, if no post-baseline assessment, at the time of first dose plus 1 day) will be censored. |
| Event-Free Survival (EFS) | Up to 61 weeks | Duration of Event-Free Survival (EFS) in study participants. EFS is defined as the time from first dose to documented disease progression, death from any cause, or study dropout, whichever occurs first. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Acalabrutinib + R-ICE Acalabrutinib in combination with rituximab, ifosfamide, carboplatin and etoposide (R-ICE). All participants will receive combination treatment for 3 cycles. Each cycle lasts 21 consecutive days. Combination treatment includes twice daily dose of Acalabrutinib, Rituximab on Day 1 of each cycle, Ifosfamide and Carboplatin on Day 2 of each cycle, and Etoposide on Days 1-3 of each cycle.
Acalabrutinib: Acalabrutinib 100 mg capsules taken by mouth every 12 hours (PO BID), for a total of 2 daily doses on Days 1 to 21 of each cycle.
Rituximab: Rituximab 375 mg/m2 administered intravenously (IV) on Day 1 of each cycle.
Ifosfamide: Ifosfamide 5g/m2 administered intravenously (IV) over 24 hours on Day 2 of each cycle.
Carboplatin: Carboplatin Area Under the Concentration time Curve (AUC) 5 IV administered intravenously (IV) on Day 2 of each cycle.
Etoposide: Etoposide 100 mg/m2 administered intravenously (IV) on Days 1, 2 and 3 of each cycle. | 2 |
| Total | 2 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Follow-up Period | Death | 1 |
| Follow-up Period | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Acalabrutinib + R-ICE |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 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 | 2 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 2 |
| other Total, other adverse events | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 |
Outcome results
Primary
Percentage of Participants Achieving Complete Response (CR)
The percentage of participants achieving complete response (CR) will be assessed using Response Evaluation Criteria in Lymphoma (RECIL 2017) criteria.
Time frame: 9 weeks (End of Cycle 3)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Acalabrutinib + R-ICE | Percentage of Participants Achieving Complete Response (CR) | NA percentage of participants |
Secondary
Event-Free Survival (EFS)
Duration of Event-Free Survival (EFS) in study participants. EFS is defined as the time from first dose to documented disease progression, death from any cause, or study dropout, whichever occurs first.
Time frame: Up to 61 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Acalabrutinib + R-ICE | Event-Free Survival (EFS) | NA weeks |
Secondary
Number of Treatment-Emergent Adverse Events
The safety profile and tolerability of acalabrutinib + R-ICE will be reported as the number of treatment-emergent adverse events (AEs) or abnormalities of laboratory tests; serious adverse events (SAEs); dose-limiting toxicities (DLTs), or AEs leading to discontinuation of study treatment, or death. Severity and relationship will be assessed by the treating physician using the Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0.
Time frame: 13 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Acalabrutinib + R-ICE | Number of Treatment-Emergent Adverse Events | NA Treatment-emergent adverse events |
Secondary
Overall Survival (OS)
Duration of Overall Survival (OS) in study participants. OS is defined as the time from first dose to death from any cause. Data for subjects who are still alive at the time of data cutoff date, lost to follow-up, have discontinued the study (or, if no post-baseline assessment, at the time of first dose plus 1 day) will be censored.
Time frame: Up to 61 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Acalabrutinib + R-ICE | Overall Survival (OS) | NA weeks |
Secondary
Percentage of Participants Achieving Mobilization Rate Greater Than or Equal to 2x10^6 CD34+ Cells/kg Body Weight
Percentage of study participants achieving a mobilization rate of greater than or equal to 2x10\^6 CD34+ cells/kg body weight. Descriptive statistics will be used to summarize the mobilization rates.
Time frame: 9 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Acalabrutinib + R-ICE | Percentage of Participants Achieving Mobilization Rate Greater Than or Equal to 2x10^6 CD34+ Cells/kg Body Weight | NA percentage of participants |
Secondary
Percentage of Participants Achieving Overall Response
Overall response is defined as the percentage of participants who achieved complete response (CR) or partial response (PR) to acalabrutinib + R-ICE therapy. Response will be assessed using Response Evaluation Criteria in Lymphoma (RECIL 2017) criteria.
Time frame: 9 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Acalabrutinib + R-ICE | Percentage of Participants Achieving Overall Response | NA percentage of participants |
Secondary
Percentage of Participants Achieving Partial Response (PR)
The percentage of participants achieving partial response (PR) will be assessed using Response Evaluation Criteria in Lymphoma (RECIL 2017) criteria.
Time frame: 9 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Acalabrutinib + R-ICE | Percentage of Participants Achieving Partial Response (PR) | NA percentage of participants |
Secondary
Progression-Free Survival (PFS)
Duration of Progression-Free Survival (PFS) in study participants. PFS is defined as the time from first dose to documented disease progression, or death from any cause, whichever occurs first. Data for subjects who are still alive and free from progression at the time of data cutoff date, lost to follow-up, or have discontinued the study will be censored on last assessment (or, if no post-baseline tumor assessment, at the time of first dose plus 1 day).
Time frame: Up to 61 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Acalabrutinib + R-ICE | Progression-Free Survival (PFS) | NA weeks |