Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma
Conditions
Keywords
Chronic lymphocytic leukemia, Small lymphocytic lymphoma, Relapsed or refractory chronic lymphocytic leukemia, Relapsed or refractory small lymphocytic lymphoma, Ibrutinib, PCI-32765, Bruton's tyrosine kinase inhibitor, Rituximab, Asia Pacific region participants
Brief summary
The purpose of this study is to evaluate the efficacy and safety of ibrutinib versus rituximab in adult Asia Pacific region patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
Detailed description
This is a randomized (individuals assigned to study treatment by chance), open-label (identity of assigned study drug will be known) study designed to evaluate the efficacy and safety of ibrutinib versus rituximab in adult Asia Pacific region patients with relapsed/refractory CLL or SLL with active disease requiring treatment who have failed at least 1 prior line of therapy and are not considered appropriate candidates for treatment or retreatment with purine analog-based therapy. Approximately 150 patients will be randomly assigned in a 1:2 ratio into 2 treatment arms to receive either intravenous rituximab (Treatment Arm A) for 6 cycles or oral ibrutinib (Treatment Arm B) until disease progression or unacceptable toxicity, whichever occurs first. The study will include screening, treatment, and follow-up phases. Treatment will extend from randomization until study drug discontinuation. Follow-up will consist of 2 phases: post-treatment (from the discontinuation of treatment for reasons other than disease progression until the patient has progressive disease) and post-disease progression (subsequent anticancer therapy and survival status will be recorded until death, lost to follow-up, consent withdrawal, or study closure). Patients in the rituximab arm with disease progression or who meet the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria for requiring subsequent anti-CLL therapy may be considered for cross over to receive ibrutinib 420 mg orally, daily until disease progression, unacceptable toxicity, withdrawal from study, or until study end whichever occurs earliest. Efficacy evaluations will assess for disease response and progression in accordance with International Workshop on Chronic Lymphocytic Leukemia 2008 criteria. Serial pharmacokinetic (study of what a drug does to the body) blood samples will be collected in the ibrutinib treatment group. Safety will be assessed throughout the study.
Interventions
DRUGRituximab
Up to 6 cycles (total of 8 doses administered by intravenous infusion): 375 mg/m2 on Day 1 of Cycle 1, 500 mg/m2 on Day 15 of Cycle 1 (Weeks 1-4); 500 mg/m2 on Day 1 and Day 15 of Cycle 2 (Weeks 5-8); and 500 mg/m2 on Day 1 of Cycles 3-6 (Weeks 9-24).
DRUGIbrutinib
420 mg capsules administered by mouth daily until disease progression or unacceptable toxicity, whichever occurs first.
Sponsors
Pharmacyclics LLC.
Janssen Research & Development, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Eastern Cooperative Oncology Group performance status of 0-1 * Diagnosis of chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL) that meets protocol-defined criteria * Laboratory values within protocol-defined parameters * Active disease meeting International Workshop on Chronic Lymphocytic Leukemia 2008 criteria * Received at least 1 prior therapy for CLL/SLL and not appropriate for treatment or retreatment with purine analog-based therapy * Measurable nodal disease by computed tomography * Female subjects of childbearing potential must have a negative serum or urine pregnancy test at Screening and agree to use highly effective methods of contraception during the study and for 90 days following the last dose with ibrutinib or 12 months following the last dose of rituximab
Exclusion criteria
* Central nervous system lymphoma or leukemia * Prolymphocytic leukemia or history of or currently suspected Richter's transformation * Refractory to prior rituximab-based therapy * Received any chemotherapy, external beam radiation therapy, anticancer antibodies, or investigational drug within 30 days prior to first dose of study drug * Corticosteroid use \>20 mg within 1 week prior to first dose of study drug * Radio- or toxin-conjugated antibody therapy within 10 weeks prior to first dose of study drug * Prior autologous transplant within 6 months prior to first dose of study drug * Prior allogeneic stem cell transplant * Major surgery within 4 weeks prior to first dose of study drug * History of prior malignancy according to protocol-defined criteria * Currently active clinically significant cardiovascular disease within 6 months prior to first dose with study drug * Uncontrolled active systemic fungal, bacterial, viral, or other ongoing anti-infective treatment administered intravenously * History of human immunodeficiency virus or active infection with hepatitis B or C * History of stroke or intracranial hemorrhage within 6 months prior to random assignment * Pregnant or lactating women * 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 * Requires or receiving anticoagulation with warfarin or equivalent Vitamin K antagonists * Requires treatment with a strong CYP3A4/5 inhibitor * Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura (ITP), defined as declining hemoglobin or platelet count secondary to autoimmune destruction within the screening period or requirement for high doses of steroids (greater than \[\>\]20 milligram \[mg\] daily of prednisone daily or equivalent)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | From the date of randomization to the date of disease progression or death, whichever was first reported (Up to 3.7 years) | Progression-free survival was defined as the interval between the date of randomization and the date of disease progression or death, whichever was first reported. International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria for progressive disease (PD): New enlarged nodes greater than (\>)1.5 centimeter (cm), new hepatomegaly or splenomegaly, or other organ infiltrates; greater than or equal to (\>=)50 percent (%) increase from nadir in existing lymph node or \>=50% increase from nadir in sum of product of diameters of multiple nodes; \>=50% increase from nadir in enlargement of liver or spleen; \>=50% increase from baseline in lymphocyte count (and to \>=5\*10\^9/L) unless considered treatment-related lymphocytosis; New cytopenia (Hemoglobin b \[Hgb\] or platelets) attributable to chronic lymphocytic leukemia (CLL) and transformation to a more aggressive histology. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | From the date of randomization to disease progression (Up to 3.7 years) | ORR defined as number of participants achieving a complete response (CR), complete response with incomplete marrow recovery (CRi), nodular partial response (nPR) or partial response (PR). IWCLL 2008 criteria: CR- No lymphadenopathy and hepatosplenomegaly, no constitutional symptoms, neutrophils \>1.5\*10\^9/liter (L), platelets \>100\*10\^9/L, Hgb \>11 gram per deciliter (g/dL) and absolute lymphocyte count \<4000/microliter (mcL); CRi- CR with incomplete recovery of bone marrow; nPR- participants meet criteria for CR, but the bone marrow biopsy shows B-lymphoid nodules, may represent a clonal infiltrate; PR- \>=50% drop in lymphocyte count from baseline or \<=4.0\*10\^9/L with following: \>=50% decrease in sum products of up to 6 lymph nodes, no new enlarged lymph nodes, When abnormal, \>=50% decrease in enlargement of spleen from baseline or normalization and a response in 1 of following: Neutrophils \>1.5\*10\^9/L, Platelets\>100000/mcL and Hgb\>11 g/dL or \>=50% improvement over baseline in all. |
| Overall Survival (OS) | From the date of randomization to the date of death (Up to 3.7 years) | Overall survival was defined as the interval between the date of randomization and the date of death from any cause. |
| Number of Participants With Sustained Hematologic Improvement | From the date of randomization to disease progression (Up to 3.7 years) | Sustained hematologic improvement was defined as hematological improvement that was sustained continuously for greater than or equal to (\>=) 56 days without blood transfusion or growth factors: 1) Platelet counts greater than (\>)100\* 109/liter (L) if baseline less than or equal to (\<=) 100\*109/L or increase \>= 50 percent (%) over baseline; 2) Hemoglobin \>11 gram per deciliters (g/dL) if baseline \<= 11 g/dL or increase \>= 2 g/dL over baseline. |
| Number of Participants With Clinically Relevant Shifts in Disease-Related Symptoms | From the date of randomization to disease progression (Up to 3.7 years) | The most common disease-related symptoms associated with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (fatigue, weight loss, fevers, night sweats, and abdominal discomfort/splenomegaly) were reported by grade. |
Countries
Australia, China, Malaysia, Taiwan
Participant flow
Recruitment details
A Randomized, Multicenter, Open-Label, Phase 3 Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor PCI-32765 (Ibrutinib) versus Rituximab in Subjects with Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Participants by arm
| Arm | Count |
|---|---|
| Ibrutinib Receive 420 mg ibrutinib (3 x 140-mg capsules) by mouth once daily continuous (without interruption) self-administered home treatment until disease progression or unacceptable toxicity, whichever occurs first. | 106 |
| Rituximab Receive rituximab IV infusion 375 mg/m2 on Day 1 of Cycle 1 and 500 mg/m2 on Day 15 of Cycle 1 (Weeks 1-4); 500 mg/m2 on Day 1 and Day 15 of Cycle 2 (Weeks 5-8); 500 mg/m2 on Day 1 of Cycles 3-6 (Weeks 9-24). | 54 |
| Total | 160 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 14 | 4 |
| Overall Study | Death | 4 | 3 |
| Overall Study | Progressive disease or relapse | 16 | 5 |
| Overall Study | Randomized, not treated | 2 | 2 |
| Overall Study | Study terminated by sponsor | 63 | 0 |
| Overall Study | Withdrawal by Subject | 7 | 4 |
Baseline characteristics
| Characteristic | Ibrutinib | Rituximab | Total |
|---|---|---|---|
| Age, Continuous | 63.6 years STANDARD_DEVIATION 10.36 | 63.6 years STANDARD_DEVIATION 13.04 | 63.6 years STANDARD_DEVIATION 11.3 |
| Region of Enrollment Australia | 15 Participants | 9 Participants | 24 Participants |
| Region of Enrollment China | 87 Participants | 44 Participants | 131 Participants |
| Region of Enrollment Malaysia | 1 Participants | 1 Participants | 2 Participants |
| Region of Enrollment Taiwan, Province Of China | 3 Participants | 0 Participants | 3 Participants |
| Sex: Female, Male Female | 29 Participants | 18 Participants | 47 Participants |
| Sex: Female, Male Male | 77 Participants | 36 Participants | 113 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 21 / 104 | 20 / 52 |
| other Total, other adverse events | 103 / 104 | 46 / 52 |
| serious Total, serious adverse events | 56 / 104 | 17 / 52 |
Outcome results
Primary
Progression-free Survival (PFS)
Progression-free survival was defined as the interval between the date of randomization and the date of disease progression or death, whichever was first reported. International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria for progressive disease (PD): New enlarged nodes greater than (\>)1.5 centimeter (cm), new hepatomegaly or splenomegaly, or other organ infiltrates; greater than or equal to (\>=)50 percent (%) increase from nadir in existing lymph node or \>=50% increase from nadir in sum of product of diameters of multiple nodes; \>=50% increase from nadir in enlargement of liver or spleen; \>=50% increase from baseline in lymphocyte count (and to \>=5\*10\^9/L) unless considered treatment-related lymphocytosis; New cytopenia (Hemoglobin b \[Hgb\] or platelets) attributable to chronic lymphocytic leukemia (CLL) and transformation to a more aggressive histology.
Time frame: From the date of randomization to the date of disease progression or death, whichever was first reported (Up to 3.7 years)
Population: Intent-to-Treat (ITT) analysis set is defined as all participants randomized into the study and analyzed according to assigned treatment group, regardless of the actual treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ibrutinib | Progression-free Survival (PFS) | NA months |
| Rituximab | Progression-free Survival (PFS) | 8.38 months |
p-value: <0.000195% CI: [0.109, 0.291]Log Rank
Secondary
Number of Participants With Clinically Relevant Shifts in Disease-Related Symptoms
The most common disease-related symptoms associated with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (fatigue, weight loss, fevers, night sweats, and abdominal discomfort/splenomegaly) were reported by grade.
Time frame: From the date of randomization to disease progression (Up to 3.7 years)
Population: Intent-to-Treat (ITT) analysis set is defined as all participants randomized into the study and analyzed according to assigned treatment group, regardless of the actual treatment received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibrutinib | Number of Participants With Clinically Relevant Shifts in Disease-Related Symptoms | 0 participants |
| Rituximab | Number of Participants With Clinically Relevant Shifts in Disease-Related Symptoms | 0 participants |
Secondary
Number of Participants With Sustained Hematologic Improvement
Sustained hematologic improvement was defined as hematological improvement that was sustained continuously for greater than or equal to (\>=) 56 days without blood transfusion or growth factors: 1) Platelet counts greater than (\>)100\* 109/liter (L) if baseline less than or equal to (\<=) 100\*109/L or increase \>= 50 percent (%) over baseline; 2) Hemoglobin \>11 gram per deciliters (g/dL) if baseline \<= 11 g/dL or increase \>= 2 g/dL over baseline.
Time frame: From the date of randomization to disease progression (Up to 3.7 years)
Population: Intent-to-Treat (ITT) analysis set is defined as all participants randomized into the study and analyzed according to assigned treatment group, regardless of the actual treatment received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ibrutinib | Number of Participants With Sustained Hematologic Improvement | Hemoglobin | 43 participants |
| Ibrutinib | Number of Participants With Sustained Hematologic Improvement | Platelets | 48 participants |
| Rituximab | Number of Participants With Sustained Hematologic Improvement | Hemoglobin | 14 participants |
| Rituximab | Number of Participants With Sustained Hematologic Improvement | Platelets | 12 participants |
Secondary
Overall Response Rate (ORR)
ORR defined as number of participants achieving a complete response (CR), complete response with incomplete marrow recovery (CRi), nodular partial response (nPR) or partial response (PR). IWCLL 2008 criteria: CR- No lymphadenopathy and hepatosplenomegaly, no constitutional symptoms, neutrophils \>1.5\*10\^9/liter (L), platelets \>100\*10\^9/L, Hgb \>11 gram per deciliter (g/dL) and absolute lymphocyte count \<4000/microliter (mcL); CRi- CR with incomplete recovery of bone marrow; nPR- participants meet criteria for CR, but the bone marrow biopsy shows B-lymphoid nodules, may represent a clonal infiltrate; PR- \>=50% drop in lymphocyte count from baseline or \<=4.0\*10\^9/L with following: \>=50% decrease in sum products of up to 6 lymph nodes, no new enlarged lymph nodes, When abnormal, \>=50% decrease in enlargement of spleen from baseline or normalization and a response in 1 of following: Neutrophils \>1.5\*10\^9/L, Platelets\>100000/mcL and Hgb\>11 g/dL or \>=50% improvement over baseline in all.
Time frame: From the date of randomization to disease progression (Up to 3.7 years)
Population: Intent-to-Treat (ITT) analysis set is defined as all participants randomized into the study and analyzed according to assigned treatment group, regardless of the actual treatment received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibrutinib | Overall Response Rate (ORR) | 66 participants |
| Rituximab | Overall Response Rate (ORR) | 4 participants |
Secondary
Overall Survival (OS)
Overall survival was defined as the interval between the date of randomization and the date of death from any cause.
Time frame: From the date of randomization to the date of death (Up to 3.7 years)
Population: Intent-to-Treat (ITT) analysis set is defined as all participants randomized into the study and analyzed according to assigned treatment group, regardless of the actual treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ibrutinib | Overall Survival (OS) | NA months |
| Rituximab | Overall Survival (OS) | NA months |