Relapsed or Refractory EBV-and CD30-positive Lymphomas
Conditions
Keywords
Brentuximab vedotin, EBV, Lymphoma
Brief summary
This is an open-label, non-randomized, multi-center, phase II trial of brentuximab vedotin to evaluate ORR primarily in patients with EBV- and CD30-positive lymphomas.
Detailed description
This is an open-label, non-randomized, multi-center, phase II trial of brentuximab vedotin to evaluate ORR primarily in patients with EBV- and CD30-positive lymphomas. The ORR will be evaluated based on the revised Cheson's criteria or modified SWAT criteria in case of cutaneous EBV- and CD30-positive lymphomas.
Interventions
DRUGbrentuximab vedotin
Brentuximab vedotin administered by IV infusion given over approximately 30 minutes on Day 1 of each 21-day cycle. The dose of brentuximab vedotin is 1.8 mg/kg q 3 weeks.
Sponsors
Seoul National University Hospital
Seoul National University Bundang Hospital
SMG-SNU Boramae Medical Center
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. Patients with relapsed or refractory EBV- and CD30-positive lymphomas 2. Age ≥ 18 years 3. ECOG performance status 0-2 4. At least one measurable lesion based on revised Cheson's or modified SWAT criteria 5. Provision archival tumor tissues (4 μm thickness x 5 unstained slides) and blood samples 6. Voluntary written informed consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care. 7. Female patient is either post-menopausal for at least 1 year before the screening visit or surgically sterile or if of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 6 months after the last dose of study drug, or agrees to completely abstain from heterosexual intercourse. 8. Male patients, even if surgically sterilized, (i.e., status post vasectomy) agree to practice effective barrier contraception during the entire study period and through 6 months after the last dose of study drug, or agrees to completely abstain from heterosexual intercourse. 9. Adequate hematologic function: absolute neutrophil count (ANC) ≥1,500/µL, platelet count ≥ 75,000/µL, and hemoglobin ≥8.0 g/dL unless there is known hematologic tumor marrow involvement (ANC ≥ 1,000/µL and platelet count ≥ 50,000/µL if there is known bone marrow involvement) 10. Adequate liver function: total bilirubin \< 1.5 x the upper limit of the normal (ULN) unless the elevation is known to be due to Gilbert syndrome and ALT or AST \< 3 x ULN (AST and AST \< 5 x ULN if their elevation can be reasonably ascribed to the presence of hematologic tumor in liver) 11. Adequate renal function: serum creatinine \< 2.0 mg/dL and/or creatinine clearance or calculated creatinine clearance \> 40 mL/minute. 12. Expected survival \> 3 months
Exclusion criteria
1. Female patient who are both lactating and breast-feeding or have a positive serum pregnancy test 2. Any serious medical or psychiatric illness 3. Known cerebral or meningeal involvement (EBV- and CD30-positive lymphoma or any other etiology), including signs or symptoms of PML 4. Symptomatic neurologic disease compromising normal activities or requiring medication 5. Any sensory or motor peripheral neuropathy greater than or equal to Grade 2 6. Known history of myocardial infarction within 1 year, NYHA class III/IV heart failure, or uncontrolled cardiovascular conditions including cardiac arrhythmias, congestive heart failure (CHF), angina, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Recent evidence (within 6 months before first dose of study drug) of a left-ventricular ejection fraction \<50%. 7. Any active systemic viral, bacterial, or fungal infection within 2 weeks prior to first study drug dose 8. Any prior chemotherapy and/or other investigational agents within at least 5 half-lives of last dose 9. Prior stem cell transplantation within 100 days or radioimmunotherapy within 8 weeks 10. Prior exposure to CD30-targeted agents 11. Known hypersensitivity to recombinant proteins, murine proteins, or to any excipient contained in the drug formulation of brentuximab vedotin 12. Known human immunodeficiency virus (HIV) positive 13. Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection 14. Another malignancy within 3 years before the first dose or previously diagnosed with another malignancy and have evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To Evaluate the Overall Response Rate (ORR) of Brentuximab Vedotin in EBV- and CD30-positive Lymphomas | One-year | The primary endpoint was the ORR based on the revised criteria or modified Severity Weighted Assessment Tool (SWAT) criteria in the case of cutaneous lymphomas. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To Calculate Progression-free Survival (PFS) Time | One-year | PFS as defined as the time from the date of initiation until the date of first documented progression. Revised tumor response criteria for lymphoma(Revised Cheson) or revised SWAT and assessed by MRI except a pregnant patient whose response evaluation can be assessed by CT scan: Progression is defined using these criteria, as observation of a new lesion or an increase of 50% or more from the nadir in a previously involved site. |
| To Evaluate the Safety Profile | From the first dose of brentuximab vedotin to up to 30 days after the last dose, a total of up to approximately 366 days | AEs/SAEs occurring during the study period defined by CTCAE version 4.03 |
| To Calculate the Duration of Response | From the first dose Up to the time of data cut-off. | The duration of response was assessed in 12 patients who had objective responses. The response continued even after the completion of the planned 16 cycles of brentuximab vedotin administration in three of these 12 patients (25%) at the time of data cut-off. |
| To Calculate Overall Survival (OS) Time | From first dose to end of data collection | OS as defined as the time from the date of first dose until death due to any cause. The median overall survival was obtained, but the upper value of 95% Confidence Interval was not reached at the time of data cut-off. Therefore the longest OS was 30.4 months, the follow-up duration up to the date of data cut-off. |
Other
| Measure | Time frame | Description |
|---|---|---|
| The ORR in the Groups With High sCD30 (≥ 99.03 ng/mL) and Low sCD30 (<99.03 ng/mL). | Up to the date of data cut-off | The ORR in the groups with high sCD30 (≥ 99.03 ng/mL) and low sCD30 (\<99.03 ng/mL) were determined up to the date of data cut-off. |
| Exploratory. | On the date of screening visit. | The level of soluble CD30 (sCD30) was determined using an enzyme-linked immunosorbent assay. The specimen were collected on the date of screening visit. |
| The Number of Participants With a Tumor Response Stratified by CD30-positive Expression | One-year | Exploratory. The level of soluble CD30 (sCD30) was determined using an enzyme-linked immunosorbent assay. |
Countries
South Korea
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Brentuximab Vedotin This group was consisted of patients with EBV-positive and CD30- positive non-Hodgkin lymphomas with various levels of CD30 in the relapsed or refractory setting and designed to evaluate the activity of brentuximab vedotin in the patients.
Brentuximab vedotin: Brentuximab vedotin administered by IV infusion given over approximately 30 minutes on Day 1 of each 21-day cycle. The dose of brentuximab vedotin is 1.8 mg/kg q 3 weeks. | 25 |
| Total | 25 |
Baseline characteristics
| Characteristic | Brentuximab Vedotin |
|---|---|
| Age, Continuous | 67 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 25 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 | 0 Participants |
| Region of Enrollment South Korea | 25 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 25 |
| other Total, other adverse events | 24 / 25 |
| serious Total, serious adverse events | 9 / 25 |
Outcome results
Primary
To Evaluate the Overall Response Rate (ORR) of Brentuximab Vedotin in EBV- and CD30-positive Lymphomas
The primary endpoint was the ORR based on the revised criteria or modified Severity Weighted Assessment Tool (SWAT) criteria in the case of cutaneous lymphomas.
Time frame: One-year
Population: Revised tumor response criteria for lymphoma(Revised Cheson) or revised SWAT and assessed by MRI except a pregnant patient whose response evaluation can be assessed by CT scan: Complete Response (CR), Disappearance of all evidence of the disease; Partial Response (PR), Regression of measurable disease and no new lesions. The SPD of the largest 6 major nodules should decrease by ≥ 50%, and there should be no increase in the size of other nodules; Overall Response (OR) = CR + PR.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Brentuximab Vedotin | To Evaluate the Overall Response Rate (ORR) of Brentuximab Vedotin in EBV- and CD30-positive Lymphomas | 12 Participants |
Secondary
To Calculate Overall Survival (OS) Time
OS as defined as the time from the date of first dose until death due to any cause. The median overall survival was obtained, but the upper value of 95% Confidence Interval was not reached at the time of data cut-off. Therefore the longest OS was 30.4 months, the follow-up duration up to the date of data cut-off.
Time frame: From first dose to end of data collection
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Brentuximab Vedotin | To Calculate Overall Survival (OS) Time | 15.6 months |
Secondary
To Calculate Progression-free Survival (PFS) Time
PFS as defined as the time from the date of initiation until the date of first documented progression. Revised tumor response criteria for lymphoma(Revised Cheson) or revised SWAT and assessed by MRI except a pregnant patient whose response evaluation can be assessed by CT scan: Progression is defined using these criteria, as observation of a new lesion or an increase of 50% or more from the nadir in a previously involved site.
Time frame: One-year
Population: Clinical outcomes of brentuximab vedotin treatment according to lymphoma subtype and CD30 expression.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Brentuximab Vedotin | To Calculate Progression-free Survival (PFS) Time | All | 6.1 months |
| Brentuximab Vedotin | To Calculate Progression-free Survival (PFS) Time | CD 30 expression < 10% | 5.5 months |
| Brentuximab Vedotin | To Calculate Progression-free Survival (PFS) Time | Mature T/NK cell | 6.1 months |
| Brentuximab Vedotin | To Calculate Progression-free Survival (PFS) Time | Mature B cell | 3.0 months |
| Brentuximab Vedotin | To Calculate Progression-free Survival (PFS) Time | 10% <= CD 30 expression < 50% | 9.7 months |
| Brentuximab Vedotin | To Calculate Progression-free Survival (PFS) Time | 50% <= CD 30 expression | 6.1 months |
Secondary
To Calculate the Duration of Response
The duration of response was assessed in 12 patients who had objective responses. The response continued even after the completion of the planned 16 cycles of brentuximab vedotin administration in three of these 12 patients (25%) at the time of data cut-off.
Time frame: From the first dose Up to the time of data cut-off.
Population: The duration of response was assessed in 12 patients who had objective responses.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Brentuximab Vedotin | To Calculate the Duration of Response | 10 months |
Secondary
To Evaluate the Safety Profile
AEs/SAEs occurring during the study period defined by CTCAE version 4.03
Time frame: From the first dose of brentuximab vedotin to up to 30 days after the last dose, a total of up to approximately 366 days
Population: Among 25 patients, treatment-related serious adverse reactions were observed in 9 patients.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Brentuximab Vedotin | To Evaluate the Safety Profile | 9 Participants |
Other Pre-specified
Exploratory.
The level of soluble CD30 (sCD30) was determined using an enzyme-linked immunosorbent assay. The specimen were collected on the date of screening visit.
Time frame: On the date of screening visit.
Population: The median value of soluble CD30 (sCD30) was obtained.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Brentuximab Vedotin | Exploratory. | 99.03 ng/mL |
Other Pre-specified
The Number of Participants With a Tumor Response Stratified by CD30-positive Expression
Exploratory. The level of soluble CD30 (sCD30) was determined using an enzyme-linked immunosorbent assay.
Time frame: One-year
Population: The level of soluble CD30 (sCD30) was determined using an enzyme-linked immunosorbent assay.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Brentuximab Vedotin | The Number of Participants With a Tumor Response Stratified by CD30-positive Expression | CD30 expression < 10% | CR | 2 Participants |
| Brentuximab Vedotin | The Number of Participants With a Tumor Response Stratified by CD30-positive Expression | CD30 expression < 10% | PR | 4 Participants |
| Brentuximab Vedotin | The Number of Participants With a Tumor Response Stratified by CD30-positive Expression | CD30 expression < 10% | Non-CR and Non-PR | 7 Participants |
| Brentuximab Vedotin | The Number of Participants With a Tumor Response Stratified by CD30-positive Expression | 10% <= CD30 expression < 50% | CR | 3 Participants |
| Brentuximab Vedotin | The Number of Participants With a Tumor Response Stratified by CD30-positive Expression | 10% <= CD30 expression < 50% | PR | 0 Participants |
| Brentuximab Vedotin | The Number of Participants With a Tumor Response Stratified by CD30-positive Expression | 10% <= CD30 expression < 50% | Non-CR and Non-PR | 2 Participants |
| Brentuximab Vedotin | The Number of Participants With a Tumor Response Stratified by CD30-positive Expression | 50% <= CD30 expression | CR | 0 Participants |
| Brentuximab Vedotin | The Number of Participants With a Tumor Response Stratified by CD30-positive Expression | 50% <= CD30 expression | PR | 3 Participants |
| Brentuximab Vedotin | The Number of Participants With a Tumor Response Stratified by CD30-positive Expression | 50% <= CD30 expression | Non-CR and Non-PR | 4 Participants |
Other Pre-specified
The ORR in the Groups With High sCD30 (≥ 99.03 ng/mL) and Low sCD30 (<99.03 ng/mL).
The ORR in the groups with high sCD30 (≥ 99.03 ng/mL) and low sCD30 (\<99.03 ng/mL) were determined up to the date of data cut-off.
Time frame: Up to the date of data cut-off
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Brentuximab Vedotin | The ORR in the Groups With High sCD30 (≥ 99.03 ng/mL) and Low sCD30 (<99.03 ng/mL). | The ORR in the groups with high sCD30 (1-<10%) | 13 Participants |
| Brentuximab Vedotin | The ORR in the Groups With High sCD30 (≥ 99.03 ng/mL) and Low sCD30 (<99.03 ng/mL). | The ORR in the groups with intermediate sCD30 (10-<50%) | 5 Participants |
| Brentuximab Vedotin | The ORR in the Groups With High sCD30 (≥ 99.03 ng/mL) and Low sCD30 (<99.03 ng/mL). | The ORR in the groups with low sCD30 (>=50%) | 7 Participants |