B-cell Lymphoma, Follicular Lymphoma, Non-Hodgkin's Lymphoma
Conditions
Keywords
Pharmacyclics (PCYC), PCYC, Lymphoma, Follicular Lymphoma, FL, Rituximab, Ibrutinib, Rituxan, Non-Hodgkin's Lymphoma (NHL), NHL, B-cell Lymphoma
Brief summary
This is an open-label, Phase 2 study designed to assess the efficacy and safety of ibrutinib combined with rituximab in previously untreated subjects with Follicular Lymphoma (FL).
Detailed description
This is an open-label, Phase 2 study designed to assess the efficacy and safety of ibrutinib combined with rituximab in previously untreated subjects with FL. There are two study treatment arms. Subjects enrolled into main study treatment arm will receive ibrutinib continuously until disease progression or unacceptable toxicity. In addition, subjects will receive rituximab once weekly for four doses for the first four weeks of study treatment. Subjects enrolled into the exploratory study treatment arm will receive ibrutinib continuously as a single agent for the first eight weeks, then ibrutinib concurrently with rituximab once weekly for four doses. After the rituximab treatment, subjects will receive ibrutinib continuously until disease progression or unacceptable toxicity.
Interventions
DRUGIbrutinib
All subjects will receive 560 mg of Ibrutinib orally.
DRUGrituximab
All subjects will receive rituximab 375 mg/m2 intravenously
Sponsors
Pharmacyclics LLC.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion criteria: 1. Histologically documented FL (Grade 1, 2 and 3A) 2. Not previously treated with prior anti-cancer therapy for FL 3. Stage II, III or IV disease 4. At least one measurable lesion ≥ 2 cm in longest diameter by CT and/or MRI scan 5. Men and women ≥ 18 years of age 6. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 Key
Exclusion criteria
1. Medically apparent central nervous system lymphoma or leptomeningeal disease 2. FL with evidence of large cell transformation 3. Any prior history of other hematologic malignancy besides FL or myelodysplasia 4. History of other malignancies, except 1. Malignancy treated with curative intent and with no known active disease present for ≥5 years before the first dose of study drug and felt to be at low risk for recurrence by treating physician. 2. Adequately treated non-melanoma skin cancer or lentigomaligna without evidence of disease. 3. Adequately treated carcinoma in situ without evidence of disease. 5. Currently active, clinically significant cardiovascular disease or myocardial infarction within 6 months of screening 6. Known anaphylaxis or Immunoglobulin E (IgE)-mediated hypersensitivity to murine proteins or to any component of rituximab (Rituxan®) 7. Requires anti-coagulation with warfarin or a vitamin K antagonist. 8. Requires treatment with strong cytochrome P450 (CYP) 3A inhibitors. 9. Known bleeding diathesis or hemophilia
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR): Proportion of Subjects Achieving the Best Overall Responses of Complete Response (CR) or Partial Response (PR) | Subjects in Arm 1 will have imaging assessments every 12 weeks for the first 8 assessments, then every 24 weeks. Subjects in Arm 2 will have imaging assessments starting at week 9, then every 12 weeks for 8 assessments, then every 24 weeks. | Number of subjects achieving the best overall responses of CR or PR prior to the initiation of the next line of antineoplastic therapy as assessed by investigator per the Cheson et al, 2007 criteria. Target lesions are measured by CT, unless MRI is used as the assessment modality for lesions in anatomical locations not amenable to CT. CR is defined as the disappearance of all evidence of disease. PR is defined as \>=50% decrease in the sum of the product of the diameters of up to 6 largest dominant masses. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DOR) | Up to 45 months | DOR is defined as the interval between the date of the first documented response (CR, PR) and the date of the first documented evidence of progressive disease (PD) or death. DOR will be analyzed for the subjects who achieve an overall response during the duration of study. |
| Progression Free Survival (PFS) | Up to 45 months | PFS is defined as the time interval between the date of the first dose and the date of the earliest occurrence of PD or death due to any cause, whichever occurs first. PD is characterized by any new lesion or increase by \>=50% of previously involved sites from nadir. |
| Overall Survival (OS) | Up to 45 months | Subjects will be followed for survival information up to three years after the last dose of study treatment, until new treatment or death, whichever occurs first. OS is defined as the duration of time from the date of the first dose to the date of death from any cause. |
| Number of Participants With Treatment-emergent Adverse Events | Up to 45 months | Frequency, severity, and relatedness of treatment-emergent adverse events (AEs) Frequency of treatment-emergent AEs requiring discontinuation of study drug or dose reductions |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Main Study Arm 1 Subjects enrolled into this arm will receive ibrutinib continuously until disease progression or unacceptable toxicity. In addition, subjects will receive rituximab once weekly for four doses for the first four weeks of study treatment.
Ibrutinib: All subjects will receive 560 mg of Ibrutinib orally.
rituximab: All subjects will receive rituximab 375 mg/m2 intravenously | 60 |
| Exploratory Study Arm 2 Subjects enrolled into this arm will receive ibrutinib continuously as a single agent for the first eight weeks, then ibrutinib concurrently with rituximab once weekly for four doses. After the rituximab treatment, subjects will receive ibrutinib continuously until disease progression or unacceptable toxicity.
Ibrutinib: All subjects will receive 560 mg of Ibrutinib orally.
rituximab: All subjects will receive rituximab 375 mg/m2 intravenously | 20 |
| Total | 80 |
Baseline characteristics
| Characteristic | Main Study Arm 1 | Exploratory Study Arm 2 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 18 Participants | 8 Participants | 26 Participants |
| Age, Categorical Between 18 and 65 years | 42 Participants | 12 Participants | 54 Participants |
| Age, Continuous | 58.0 years | 55.0 years | 58.0 years |
| Baseline B-Symptoms B-Symptoms absent | 56 Participants | 20 Participants | 76 Participants |
| Baseline B-Symptoms B-Symptoms present prior to first dose | 4 Participants | 0 Participants | 4 Participants |
| Baseline Eastern Cooperative Oncology Group (ECOG) Score Baseline ECOG Score = 0 | 47 Participants | 12 Participants | 59 Participants |
| Baseline Eastern Cooperative Oncology Group (ECOG) Score Baseline ECOG Score = 1 | 13 Participants | 8 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 3 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 57 Participants | 17 Participants | 74 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 56 Participants | 18 Participants | 74 Participants |
| Region of Enrollment United States | 60 participants | 20 participants | 80 participants |
| Sex: Female, Male Female | 32 Participants | 8 Participants | 40 Participants |
| Sex: Female, Male Male | 28 Participants | 12 Participants | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 60 | 0 / 20 |
| other Total, other adverse events | 60 / 60 | 20 / 20 |
| serious Total, serious adverse events | 14 / 60 | 6 / 20 |
Outcome results
Primary
Overall Response Rate (ORR): Proportion of Subjects Achieving the Best Overall Responses of Complete Response (CR) or Partial Response (PR)
Number of subjects achieving the best overall responses of CR or PR prior to the initiation of the next line of antineoplastic therapy as assessed by investigator per the Cheson et al, 2007 criteria. Target lesions are measured by CT, unless MRI is used as the assessment modality for lesions in anatomical locations not amenable to CT. CR is defined as the disappearance of all evidence of disease. PR is defined as \>=50% decrease in the sum of the product of the diameters of up to 6 largest dominant masses.
Time frame: Subjects in Arm 1 will have imaging assessments every 12 weeks for the first 8 assessments, then every 24 weeks. Subjects in Arm 2 will have imaging assessments starting at week 9, then every 12 weeks for 8 assessments, then every 24 weeks.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Main Study Arm 1 | Overall Response Rate (ORR): Proportion of Subjects Achieving the Best Overall Responses of Complete Response (CR) or Partial Response (PR) | 51 Participants |
| Exploratory Study Arm 2 | Overall Response Rate (ORR): Proportion of Subjects Achieving the Best Overall Responses of Complete Response (CR) or Partial Response (PR) | 15 Participants |
Secondary
Duration of Response (DOR)
DOR is defined as the interval between the date of the first documented response (CR, PR) and the date of the first documented evidence of progressive disease (PD) or death. DOR will be analyzed for the subjects who achieve an overall response during the duration of study.
Time frame: Up to 45 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Main Study Arm 1 | Duration of Response (DOR) | NA months |
| Exploratory Study Arm 2 | Duration of Response (DOR) | NA months |
Secondary
Number of Participants With Treatment-emergent Adverse Events
Frequency, severity, and relatedness of treatment-emergent adverse events (AEs) Frequency of treatment-emergent AEs requiring discontinuation of study drug or dose reductions
Time frame: Up to 45 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Main Study Arm 1 | Number of Participants With Treatment-emergent Adverse Events | Subjects with any treatment-emergent AE Grade >=3 | 39 Participants |
| Main Study Arm 1 | Number of Participants With Treatment-emergent Adverse Events | Subjects with any Ibrutinib-related AE Grade >=3 | 29 Participants |
| Main Study Arm 1 | Number of Participants With Treatment-emergent Adverse Events | Subjects with any Rituximab-related AE | 50 Participants |
| Main Study Arm 1 | Number of Participants With Treatment-emergent Adverse Events | Ibrutinib-related SAEs Grade >=3 | 6 Participants |
| Main Study Arm 1 | Number of Participants With Treatment-emergent Adverse Events | Rituximab-related SAEs | 2 Participants |
| Main Study Arm 1 | Number of Participants With Treatment-emergent Adverse Events | TEAE Grade >=3 leading to Ibrutinib dose reduction | 6 Participants |
| Main Study Arm 1 | Number of Participants With Treatment-emergent Adverse Events | TEAE leading to witholding Rituximab | 1 Participants |
| Main Study Arm 1 | Number of Participants With Treatment-emergent Adverse Events | TEAE Grade >=3 leading to witholding Rituximab | 1 Participants |
| Main Study Arm 1 | Number of Participants With Treatment-emergent Adverse Events | TEAE leading to discontinuation of Ibrutinib | 14 Participants |
| Main Study Arm 1 | Number of Participants With Treatment-emergent Adverse Events | TEAE Grade >=3 leading to discontinuation of Ibrut | 11 Participants |
| Main Study Arm 1 | Number of Participants With Treatment-emergent Adverse Events | TEAE leading to discontinuation of Rituximab | 0 Participants |
| Main Study Arm 1 | Number of Participants With Treatment-emergent Adverse Events | TEAE Grade >=3 leading to discontinuation of Ritux | 0 Participants |
| Main Study Arm 1 | Number of Participants With Treatment-emergent Adverse Events | Subjects with any TE Serious Adverse Event (SAE) | 14 Participants |
| Main Study Arm 1 | Number of Participants With Treatment-emergent Adverse Events | Subjects with any TE SAE Grade >=3 | 13 Participants |
| Main Study Arm 1 | Number of Participants With Treatment-emergent Adverse Events | Ibrutinib-related SAEs | 6 Participants |
| Main Study Arm 1 | Number of Participants With Treatment-emergent Adverse Events | Rituximab-related SAEs Grade >=3 | 2 Participants |
| Main Study Arm 1 | Number of Participants With Treatment-emergent Adverse Events | Subjects with any treatment-emergent AE | 60 Participants |
| Main Study Arm 1 | Number of Participants With Treatment-emergent Adverse Events | Subjects with any treatment-related AE | 59 Participants |
| Main Study Arm 1 | Number of Participants With Treatment-emergent Adverse Events | Subjects with any treatment-related AE Grade >=3 | 29 Participants |
| Main Study Arm 1 | Number of Participants With Treatment-emergent Adverse Events | Subjects with any Ibrutinib-related AE | 57 Participants |
| Main Study Arm 1 | Number of Participants With Treatment-emergent Adverse Events | Subjects with any Rituximab-related AE Grade >=3 | 11 Participants |
| Main Study Arm 1 | Number of Participants With Treatment-emergent Adverse Events | TEAE leading to ibrutinib dose reduction | 9 Participants |
| Exploratory Study Arm 2 | Number of Participants With Treatment-emergent Adverse Events | TEAE leading to discontinuation of Rituximab | 0 Participants |
| Exploratory Study Arm 2 | Number of Participants With Treatment-emergent Adverse Events | Subjects with any treatment-emergent AE | 20 Participants |
| Exploratory Study Arm 2 | Number of Participants With Treatment-emergent Adverse Events | Subjects with any treatment-related AE Grade >=3 | 14 Participants |
| Exploratory Study Arm 2 | Number of Participants With Treatment-emergent Adverse Events | Subjects with any Ibrutinib-related AE Grade >=3 | 14 Participants |
| Exploratory Study Arm 2 | Number of Participants With Treatment-emergent Adverse Events | TEAE Grade >=3 leading to discontinuation of Ritux | 0 Participants |
| Exploratory Study Arm 2 | Number of Participants With Treatment-emergent Adverse Events | Subjects with any Rituximab-related AE | 17 Participants |
| Exploratory Study Arm 2 | Number of Participants With Treatment-emergent Adverse Events | Ibrutinib-related SAEs | 4 Participants |
| Exploratory Study Arm 2 | Number of Participants With Treatment-emergent Adverse Events | Subjects with any treatment-emergent AE Grade >=3 | 14 Participants |
| Exploratory Study Arm 2 | Number of Participants With Treatment-emergent Adverse Events | Ibrutinib-related SAEs Grade >=3 | 4 Participants |
| Exploratory Study Arm 2 | Number of Participants With Treatment-emergent Adverse Events | Subjects with any TE Serious Adverse Event (SAE) | 6 Participants |
| Exploratory Study Arm 2 | Number of Participants With Treatment-emergent Adverse Events | TEAE leading to ibrutinib dose reduction | 5 Participants |
| Exploratory Study Arm 2 | Number of Participants With Treatment-emergent Adverse Events | Subjects with any Rituximab-related AE Grade >=3 | 7 Participants |
| Exploratory Study Arm 2 | Number of Participants With Treatment-emergent Adverse Events | TEAE Grade >=3 leading to Ibrutinib dose reduction | 4 Participants |
| Exploratory Study Arm 2 | Number of Participants With Treatment-emergent Adverse Events | Subjects with any TE SAE Grade >=3 | 5 Participants |
| Exploratory Study Arm 2 | Number of Participants With Treatment-emergent Adverse Events | TEAE leading to witholding Rituximab | 1 Participants |
| Exploratory Study Arm 2 | Number of Participants With Treatment-emergent Adverse Events | Subjects with any treatment-related AE | 20 Participants |
| Exploratory Study Arm 2 | Number of Participants With Treatment-emergent Adverse Events | TEAE Grade >=3 leading to witholding Rituximab | 1 Participants |
| Exploratory Study Arm 2 | Number of Participants With Treatment-emergent Adverse Events | Rituximab-related SAEs | 2 Participants |
| Exploratory Study Arm 2 | Number of Participants With Treatment-emergent Adverse Events | TEAE leading to discontinuation of Ibrutinib | 2 Participants |
| Exploratory Study Arm 2 | Number of Participants With Treatment-emergent Adverse Events | Subjects with any Ibrutinib-related AE | 20 Participants |
| Exploratory Study Arm 2 | Number of Participants With Treatment-emergent Adverse Events | TEAE Grade >=3 leading to discontinuation of Ibrut | 1 Participants |
| Exploratory Study Arm 2 | Number of Participants With Treatment-emergent Adverse Events | Rituximab-related SAEs Grade >=3 | 2 Participants |
Secondary
Overall Survival (OS)
Subjects will be followed for survival information up to three years after the last dose of study treatment, until new treatment or death, whichever occurs first. OS is defined as the duration of time from the date of the first dose to the date of death from any cause.
Time frame: Up to 45 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Main Study Arm 1 | Overall Survival (OS) | 41.922 months |
| Exploratory Study Arm 2 | Overall Survival (OS) | NA months |
Secondary
Progression Free Survival (PFS)
PFS is defined as the time interval between the date of the first dose and the date of the earliest occurrence of PD or death due to any cause, whichever occurs first. PD is characterized by any new lesion or increase by \>=50% of previously involved sites from nadir.
Time frame: Up to 45 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Main Study Arm 1 | Progression Free Survival (PFS) | 41.922 months |
| Exploratory Study Arm 2 | Progression Free Survival (PFS) | NA months |