Lymphoma, Follicular, Lymphoma, Large B-Cell, Diffuse, Lymphoma, Mantle-Cell
Conditions
Keywords
Lymphoma, Mantle-Cell, Lymphoma, Large B-Cell, Diffuse, Lymphoma, Follicular, Daratumumab
Brief summary
The purpose of this study is to assess overall response rate \[ORR, including complete response (CR) and partial response (PR)\], of daratumumab in participants with non-Hodgkin's lymphoma \[a cancer of the lymph nodes (or tissues)-NHL\] and to evaluate association between ORR and CD38 expression level in order to determine a threshold for CD38 expression level in each NHL subtype, above which daratumumab activity is enhanced in participants with relapsed or refractory mantle cell lymphoma, diffuse large B-cell lymphoma, and follicular lymphoma.
Detailed description
This is an open label (everyone knows the study intervention), Phase 2 study to evaluate efficacy and safety of daratumumab in relapsed or refractory mantle cell lymphoma, diffuse large B-cell lymphoma, and follicular lymphoma. The study will have three phases. Screening phase, treatment phase, follow-up phase. Participants will receive daratumumab (16 milligram per kilogram \[mg/kg\]) as intravenous infusion approximately 3.5 years. Participants will primarily be assessed for overall response rate. Safety will be monitored throughout the study.
Interventions
DRUGDaratumumab
Daratumumab 16 mg/kg will be administered as intravenous infusion to participants once every week for 8 weeks; then once every other week for 16 weeks; thereafter once every 4 weeks until documented progression, unacceptable toxicity, or study end.
Sponsors
Janssen Research & Development, 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
* Has diagnosis and prior treatment for each non-hodgkin's lymphoma (NHL) subtype as defined below: Mantle cell lymphoma (MCL): pathologically verified diagnosis of MCL based on local pathology report, relapsed or refractory disease after at least 2 prior lines of therapy, including at least 1 cycle of Bruton's tyrosine kinase (BTK) inhibitor therapy and documented progressive disease (PD) during or after BTK inhibitor treatment or participants who could not tolerate BTK inhibitor \[ie, discontinued BTK inhibitor due to adverse events (AEs)\], b) Diffuse large B cell lymphoma (DLBCL): pathologically confirmed diagnosis of non-transformed DLBCL, and relapsed or refractory disease; for those participants who have not received HDT/ASCT are not eligible for HDT/ASCT due to comorbidities, c) Follicular lymphoma (FL): pathologically confirmed diagnosis of FL of Grade 1, 2, or 3a according to World Health Organization (WHO) criteria without pathological evidence of transformation, and relapsed disease after at least two prior systemic therapies including one anti-CD20 containing combination regimen * At least 1 measurable site of disease * Participants must have available archival or fresh tumor tissue or both to submit to a central laboratory for CD38 assay. Expression of CD38 is measured by immunohistochemistry on fresh or archived tumor sample by central assessment using a CD38 investigational IHC assay under development: a) Stage 1: participants whose tumors are more than or equal to (\>=) 50 percent (%) positive for CD38, b) Stage 2: participant has less than (\<) 50% CD38+ or greater than (\>) 50% CD38+ depending on the distribution of CD 38 expression of enrolled participants during Stage 2. The sponsor will advise on which eligibility criterion is permitted during the enrollment period * Participant must have an ECOG performance status score of 0 or 1 * Women of childbearing potential must be practicing a highly effective method of birth control consistent with local regulations regarding the use of birth control methods for participants participating in clinical studies: example, established use of oral, injected or implanted hormonal methods of contraception; placement of an intrauterine device (IUD) or intrauterine system (IUS); barrier methods: condom with spermicidal foam/gel/film/cream/suppository or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository; male partner sterilization (the vasectomized partner should be the sole partner for that participant); true abstinence (when this is in line with the preferred and usual lifestyle of the participant) during and after the study (3 months after the last dose of any component of the treatment regimen) * A woman of childbearing potential must have a negative serum or urine pregnancy test within 14 days before commencing treatment. Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously * A man who is sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a barrier method of birth control example, either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository, and all men must also not donate sperm during the study and for 3 months after receiving the last dose of any component of the treatment regimen. The exception to this restriction is that if the participant's female partner is surgically sterile, a second method of birth control is not required
Exclusion criteria
* Known central nervous system lymphoma * Prior anti-tumor therapy including (all times measured prior to start of study drug): nitrosoureas within 6 weeks, chemotherapy within 3 weeks, therapeutic antibodies within 4 weeks, radio- or toxin-immunoconjugates within 10 weeks, radiation therapy within 2 weeks, investigational agents within 3 weeks, unless antibody this should be within 4 weeks * Daratumumab or other anti-CD38 therapies * Participant has a history of malignancy (other than NHL) within 3 years before the screening period (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, non-muscle invasive bladder cancer (papillary neoplasms of low malignant potential and primary non-invasive tumors), or malignancy that in the opinion of the investigator, with concurrence with the sponsor's medical monitor, is considered cured with minimal risk of recurrence within 2 years) * Participant has known chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) less than (\<) 50% predicted normal. Note that FEV1 testing is required for participants suspected of having COPD and participants must be excluded if FEV1 \<50% b) Participant has known moderate or severe persistent asthma within 2 years (see Attachment 4: NHLBI table of asthma severity), or currently has uncontrolled asthma of any classification. (Note that participants who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | After the first dose until disease progression, withdrawal of consent from study participation, or the end of study (approximately 1.9 years) | ORR was defined as the percentage of participants who achieved complete response (CR) or partial response (PR). As per Revised Response Criteria for Malignant Lymphoma, Lymph node measurements were taken from Computed Tomography (CT), CT portion of the Positron Emission Tomography/Computed Tomography (PET/CT), or Magnetic resonance imaging (MRI) scans where applicable. CR is defined as complete disappearance of all evidence of disease; PR as a greater than (\>) 50 percent (%) decrease in the sum of the products of the maximal perpendicular diameters of measured lesions (SPD) and no new sites. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response | Approximately 1.9 years | Duration of response was the duration from the date of the initial documentation of a response to the date of first documented evidence of progressive disease (PD). PD is defined as any new lesion \>1.5 centimeter (cm) in any axis or greater than or equal to (\>=) 50% increase in previously involved sites. |
| Progression Free Survival (PFS) | Approximately 1.9 years | PFS was defined as the duration from the date of the first daratumumab dose to the date of progression or death, whichever comes first. |
| Overall Survival (OS) | Approximately 1.9 years | Overall survival was defined as the duration from the date of the first daratumumab dose to the date of death. |
| Time to Response | Approximately 1.9 years | Time to response was defined as the duration from the date of the first dose of daratumumab to the earliest date that a response (CR/PR) is first documented. |
Countries
Australia, Belgium, France, Netherlands, South Korea, Turkey (Türkiye), United States
Participant flow
Pre-assignment details
In total 36 participants were treated (15 participants in the diffuse large B-cell lymphoma \[DLBCL\] cohort, 16 participants in the follicular lymphoma \[FL\] cohort, and 5 participants in the mantle cell lymphoma \[MCL\] cohort).
Participants by arm
| Arm | Count |
|---|---|
| Diffuse Large B-cell Lymphoma (DLBCL) Participants received daratumumab 16 milligram per kilogram (mg/kg) as intravenous infusion once every week for 8 weeks, then once every other week for 16 weeks, thereafter once every 4 weeks until documented progression, unacceptable toxicity or study end. | 15 |
| Follicular Lymphoma (FL) Participants received daratumumab 16 mg/kg as intravenous infusion once every week for 8 weeks, then once every other week for 16 weeks, thereafter once every 4 weeks until documented progression, unacceptable toxicity or study end. | 16 |
| Mantle Cell Lymphoma (MCL) Participants received daratumumab 16 mg/kg as intravenous infusion once every week for 8 weeks, then once every other week for 16 weeks, thereafter once every 4 weeks until documented progression, unacceptable toxicity or study end. | 5 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 11 | 3 | 4 |
| Overall Study | Study Terminated By Sponsor | 2 | 13 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | Diffuse Large B-cell Lymphoma (DLBCL) | Follicular Lymphoma (FL) | Mantle Cell Lymphoma (MCL) | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 10 Participants | 7 Participants | 1 Participants | 18 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 9 Participants | 4 Participants | 18 Participants |
| Age, Continuous | 66.7 years STANDARD_DEVIATION 11.88 | 62.3 years STANDARD_DEVIATION 9.77 | 59.8 years STANDARD_DEVIATION 6.69 | 63.8 years STANDARD_DEVIATION 10.45 |
| CD38 expression value | 76.3 Percentage of CD38 expression STANDARD_DEVIATION 18.07 | 70.3 Percentage of CD38 expression STANDARD_DEVIATION 16.78 | 64 Percentage of CD38 expression STANDARD_DEVIATION 8.22 | 71.9 Percentage of CD38 expression STANDARD_DEVIATION 16.66 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 15 Participants | 2 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 0 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized Asian | 4 Participants | 2 Participants | 0 Participants | 6 Participants |
| Race/Ethnicity, Customized Not Reported | 3 Participants | 1 Participants | 1 Participants | 5 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Unknown | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 7 Participants | 13 Participants | 2 Participants | 22 Participants |
| Region of Enrollment Australia | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Region of Enrollment Belgium | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Region of Enrollment France | 4 Participants | 2 Participants | 0 Participants | 6 Participants |
| Region of Enrollment Netherlands | 2 Participants | 3 Participants | 2 Participants | 7 Participants |
| Region of Enrollment Republic of Korea | 4 Participants | 2 Participants | 0 Participants | 6 Participants |
| Region of Enrollment Turkey | 2 Participants | 2 Participants | 1 Participants | 5 Participants |
| Region of Enrollment United States | 1 Participants | 5 Participants | 2 Participants | 8 Participants |
| Sex: Female, Male Female | 6 Participants | 5 Participants | 0 Participants | 11 Participants |
| Sex: Female, Male Male | 9 Participants | 11 Participants | 5 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 11 / 15 | 3 / 16 | 4 / 5 |
| other Total, other adverse events | 15 / 15 | 16 / 16 | 5 / 5 |
| serious Total, serious adverse events | 6 / 15 | 6 / 16 | 3 / 5 |
Outcome results
Primary
Overall Response Rate (ORR)
ORR was defined as the percentage of participants who achieved complete response (CR) or partial response (PR). As per Revised Response Criteria for Malignant Lymphoma, Lymph node measurements were taken from Computed Tomography (CT), CT portion of the Positron Emission Tomography/Computed Tomography (PET/CT), or Magnetic resonance imaging (MRI) scans where applicable. CR is defined as complete disappearance of all evidence of disease; PR as a greater than (\>) 50 percent (%) decrease in the sum of the products of the maximal perpendicular diameters of measured lesions (SPD) and no new sites.
Time frame: After the first dose until disease progression, withdrawal of consent from study participation, or the end of study (approximately 1.9 years)
Population: The analysis population was all participants that were treated with daratumumab.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Diffuse Large B-cell Lymphoma (DLBCL) | Overall Response Rate (ORR) | 6.7 Percentage of participants |
| Follicular Lymphoma (FL) | Overall Response Rate (ORR) | 12.5 Percentage of participants |
| Mantle Cell Lymphoma (MCL) | Overall Response Rate (ORR) | 0 Percentage of participants |
Secondary
Duration of Response
Duration of response was the duration from the date of the initial documentation of a response to the date of first documented evidence of progressive disease (PD). PD is defined as any new lesion \>1.5 centimeter (cm) in any axis or greater than or equal to (\>=) 50% increase in previously involved sites.
Time frame: Approximately 1.9 years
Population: The analysis population was all participants that were treated with daratumumab and who achieved overall response There was insufficient data to perform Kaplan Meier analysis, therefore individual data for each evaluable participant was reported.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Diffuse Large B-cell Lymphoma (DLBCL) | Duration of Response | Participant 1 | 1.6 Months |
| Diffuse Large B-cell Lymphoma (DLBCL) | Duration of Response | Participant 2 | NA Months |
| Follicular Lymphoma (FL) | Duration of Response | Participant 1 | 0.7 Months |
| Follicular Lymphoma (FL) | Duration of Response | Participant 2 | 7.4 Months |
Secondary
Overall Survival (OS)
Overall survival was defined as the duration from the date of the first daratumumab dose to the date of death.
Time frame: Approximately 1.9 years
Population: The analysis population was all participants that were treated with daratumumab.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Diffuse Large B-cell Lymphoma (DLBCL) | Overall Survival (OS) | 4.9 Months |
| Follicular Lymphoma (FL) | Overall Survival (OS) | 17.2 Months |
| Mantle Cell Lymphoma (MCL) | Overall Survival (OS) | 4.8 Months |
Secondary
Progression Free Survival (PFS)
PFS was defined as the duration from the date of the first daratumumab dose to the date of progression or death, whichever comes first.
Time frame: Approximately 1.9 years
Population: The analysis population was all participants that were treated with daratumumab.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Diffuse Large B-cell Lymphoma (DLBCL) | Progression Free Survival (PFS) | 1.2 Months |
| Follicular Lymphoma (FL) | Progression Free Survival (PFS) | 3.3 Months |
| Mantle Cell Lymphoma (MCL) | Progression Free Survival (PFS) | 1.3 Months |
Secondary
Time to Response
Time to response was defined as the duration from the date of the first dose of daratumumab to the earliest date that a response (CR/PR) is first documented.
Time frame: Approximately 1.9 years
Population: The analysis population was all participants that were treated with daratumumab and who achieved overall response There was insufficient data to perform Kaplan Meier analysis, therefore individual data for each evaluable participant was reported.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Diffuse Large B-cell Lymphoma (DLBCL) | Time to Response | Participant 1 | 1.9 Months |
| Diffuse Large B-cell Lymphoma (DLBCL) | Time to Response | Participant 2 | NA Months |
| Follicular Lymphoma (FL) | Time to Response | Participant 1 | 2.3 Months |
| Follicular Lymphoma (FL) | Time to Response | Participant 2 | 1.9 Months |