Mantle Cell Lymphoma
Conditions
Keywords
Pharmacyclics, Mantle, Mantle Cell, Lymphoma, Non-Hodgkins, Bortezomib, Velcade, Naive, PCYC
Brief summary
The primary objective of this study was to evaluate the efficacy of ibrutinib in participants with relapsed or refractory MCL. The secondary objective was to evaluate the safety of a fixed daily dosing regimen (560 mg daily) of PCI-32765 in this population.
Detailed description
This is a Phase 2, open-label, nonrandomized, multicenter, monotherapy study in subjects with histologically documented MCL who have relapsed after ≥ 1 (but not \> 5) prior treatment regimens. All subjects meeting eligibility criteria will receive PCI-32765 capsules at a dosage of 560 mg/day once daily for a 28-day cycle until disease progression, unacceptable toxicity, or enrollment in a long-term extension study, whichever occurs earlier.
Interventions
DRUGPCI-32765
560 mg daily
Sponsors
Janssen Pharmaceuticals
Pharmacyclics LLC.
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
* Men and women ≥ 18 years of age * ECOG performance status of ≤ 2 * Pathologically confirmed MCL, with documentation of either overexpression of cyclin D1 or t(11;14), and measurable disease on cross sectional imaging that is ≥ 2 cm in the longest diameter and measurable in 2 perpendicular dimensions * Documented failure to achieve at least partial response (PR) with, or documented disease progression disease after, the most recent treatment regimen * At least 1, but no more than 5, prior treatment regimens for MCL (Note: Subjects having received ≥2 cycles of prior treatment with bortezomib, either as a single agent or as part of a combination therapy regimen, will be considered to be bortezomib-exposed.) * Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty * 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) Major
Exclusion criteria
* Prior chemotherapy within 3 weeks, nitrosoureas within 6 weeks, therapeutic anticancer antibodies within 4 weeks, radio- or toxin-immunoconjugates within 10 weeks, radiation therapy within 3 weeks, or major surgery within 2 weeks of first dose of study drug * Any life-threatening illness, medical condition or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of PCI-32765 capsules, or put the study outcomes at undue risk * 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 * Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction * Any of the following laboratory abnormalities: 1. Absolute neutrophil count (ANC) \< 750 cells/mm3 (0.75 x 109/L) unless there is documented bone marrow involvement 2. Platelet count \< 50,000 cells/mm3 (50 x 109/L) independent of transfusion support unless there is documented bone marrow involvement 3. Serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) ≥ 3.0 x upper limit of normal (ULN) 4. Creatinine \> 2.0 x ULN
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Response | The median follow-up time on study for all treated participants is 15.3 (range 1.9 - 22.3) months | The primary endpoint of the study was overall response rate (ORR), defined as the proportion of participants who achieved a best overall response of complete response (CR) or partial response (PR), according to the revised International Working Group Criteria for non-Hodgkin's lymphoma (Cheson et al, 2007), as assessed by the investigator. CR is a complete disappearance of all disease, no new lesions, lymph nodes must have regressed and be PET negative, spleen and liver should not be palpable and without nodules, and bone marrow must be negative. PR is a \>/= 50% decrease in the sum of the product of diameters of the target lesions, and \>/= 50% decrease of splenic and hepatic nodules from baseline, no new lesions and no increase in the size of liver, spleen or non-target lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Emergent Adverse Events (AEs) | From first dose of PCI-32765 to within 30 days of last dose for each participant or until study closure | Number of participants who had experienced at least one treatment emergent AE |
| PCI-32765 and Its Metabolite (PCI-45227) AUC0-24h After Repeat Dosing of PCI-32765 | Performed During the First Month of Receiving PCI-32765 | Area under the plasma concentration-time curve using data collected at 0, 1, 2, 4, 6-8, and 24 hours post dose (AUC0-24h) |
| Mean Change From Baseline to Cycle 5 in EORTC QLQ-C30 Global Health Status Score | From Baseline to Cycle 5 (Week 20) | Mean change from baseline to Cycle 5 in the European Organisation for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-C30) Global Health Status Score according to EORTC QLQ-C30 Scoring Manual (3rd Edition, 2001). For global health status, positive changes indicated better health status or functioning, and negative changes indicated worsening of health status or functioning. Scale scores range from 0 to 100. A change in 5 to 10 points in either direction represents a small change; 10 to 20 points represents a moderate change and greater than 20 points represents a large change. |
Countries
Germany, Poland, United Kingdom, United States
Participant flow
Pre-assignment details
One hundred fifteen subjects were enrolled and 111 subjects received at least 1 dose of ibrutinib and constitute the all treated population and the safety analysis set.
Participants by arm
| Arm | Count |
|---|---|
| PCI-32765 PCI-32765: 560 mg daily | 111 |
| Total | 111 |
Baseline characteristics
| Characteristic | PCI-32765 |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 70 Participants |
| Age, Categorical Between 18 and 65 years | 41 Participants |
| Age, Continuous | 67.1 years STANDARD_DEVIATION 8.6 |
| Region of Enrollment Germany | 3 participants |
| Region of Enrollment Poland | 10 participants |
| Region of Enrollment United Kingdom | 20 participants |
| Region of Enrollment United States | 78 participants |
| Sex: Female, Male Female | 26 Participants |
| Sex: Female, Male Male | 85 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 111 / 111 |
| serious Total, serious adverse events | 62 / 111 |
Outcome results
Primary
Percentage of Participants Achieving Response
The primary endpoint of the study was overall response rate (ORR), defined as the proportion of participants who achieved a best overall response of complete response (CR) or partial response (PR), according to the revised International Working Group Criteria for non-Hodgkin's lymphoma (Cheson et al, 2007), as assessed by the investigator. CR is a complete disappearance of all disease, no new lesions, lymph nodes must have regressed and be PET negative, spleen and liver should not be palpable and without nodules, and bone marrow must be negative. PR is a \>/= 50% decrease in the sum of the product of diameters of the target lesions, and \>/= 50% decrease of splenic and hepatic nodules from baseline, no new lesions and no increase in the size of liver, spleen or non-target lesions.
Time frame: The median follow-up time on study for all treated participants is 15.3 (range 1.9 - 22.3) months
Population: Participants who received at least 1 dose of PCI-32765 and constitute the all treated population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PCI-32765 | Percentage of Participants Achieving Response | 67.6 percentage of participants with response |
Secondary
Mean Change From Baseline to Cycle 5 in EORTC QLQ-C30 Global Health Status Score
Mean change from baseline to Cycle 5 in the European Organisation for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-C30) Global Health Status Score according to EORTC QLQ-C30 Scoring Manual (3rd Edition, 2001). For global health status, positive changes indicated better health status or functioning, and negative changes indicated worsening of health status or functioning. Scale scores range from 0 to 100. A change in 5 to 10 points in either direction represents a small change; 10 to 20 points represents a moderate change and greater than 20 points represents a large change.
Time frame: From Baseline to Cycle 5 (Week 20)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PCI-32765 | Mean Change From Baseline to Cycle 5 in EORTC QLQ-C30 Global Health Status Score | 0.6 scores on a scale | Standard Deviation 22.4 |
Secondary
Number of Participants With Treatment Emergent Adverse Events (AEs)
Number of participants who had experienced at least one treatment emergent AE
Time frame: From first dose of PCI-32765 to within 30 days of last dose for each participant or until study closure
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PCI-32765 | Number of Participants With Treatment Emergent Adverse Events (AEs) | 111 participants |
Secondary
PCI-32765 and Its Metabolite (PCI-45227) AUC0-24h After Repeat Dosing of PCI-32765
Area under the plasma concentration-time curve using data collected at 0, 1, 2, 4, 6-8, and 24 hours post dose (AUC0-24h)
Time frame: Performed During the First Month of Receiving PCI-32765
Population: PK samples were collected in a subset of participants (n=48) in this trial (n=111). PK parameters reported here reflects those that were PK evaluable from the 48 participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PCI-32765 | PCI-32765 and Its Metabolite (PCI-45227) AUC0-24h After Repeat Dosing of PCI-32765 | 953 AUC0-24h (ng*h/mL) | Standard Deviation 705 |
| PCI-45227 (Metabolite)- Day 8 | PCI-32765 and Its Metabolite (PCI-45227) AUC0-24h After Repeat Dosing of PCI-32765 | 1263 AUC0-24h (ng*h/mL) | Standard Deviation 707 |