Diffuse Large B Cell Lymphoma
Conditions
Keywords
monoclonal antibody, CD19, tafasitamab
Brief summary
This is an open-label, multicentre study too Evaluate the Safety and Pharmacokinetics of a Modified Tafasitamab IV Dosing Regimen Combined with Lenalidomide (LEN) in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma (R/R DLBCL) who have had at least one, but no more than three prior systemic regimens and who are not eligible for high dose chemotherapy (HDC) with autologous stem-cell transplantation (ASCT) at the time of study entry.
Interventions
DRUGTafasitamab
tafasitamab will be administered intravenously at protocol defined timepoints
DRUGLenalidomide
lenalidomide will be administered orally at protocol defined timepoints
Sponsors
Incyte Corporation
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
Major Inclusion Criteria: 1. Capable of giving signed informed consent 2. Age 18 years or older 3. Histologically confirmed diagnosis of DLBCL 4. Tumor tissue for retrospective central pathology review must be provided as an adjunct to participation in this study. 5. Patients must have: * relapsed and/or refractory disease * at least one bidimensionally measurable, PET positive disease site (transverse diameter of ≥1.5 cm and perpendicular diameter of ≥1.0 cm at baseline) * received at least one, but no more than three previous systemic regimens for the treatment of DLBCL and one therapy line must have included a CD20-targeted therapy * Eastern Cooperative Oncology Group 0 to 2 6. Patients not considered in the opinion of the investigator eligible to undergo intensive salvage therapy including ASCT 7. Patients must meet the following laboratory criteria at screening: * absolute neutrophil count ≥1.5 × 10\^9/L * platelet count ≥90 × 10\^9/L * total serum bilirubin ≤2.5 × ULN or ≤5 × ULN in cases of Glibert's Syndrome or liver involvement by lymphoma * alanine transaminase, aspartate aminotransferase and alkaline phosphatase ≤3 × ULN or \<5 × ULN in cases of liver involvement * serum creatinine clearance ≥ 60 mL/minute 8. Patients who received previous CD19 targeted therapy (other than tafasitamab) must have CD19 positive lymphoma confirmed on a biopsy taken since completing the prior CD19 targeted therapy 9. Patients with primary refractory disease who received at least one, but no more than three previous systemic regimens (including a CD20 targeted therapy) Major
Exclusion criteria
1. Patients who are legally institutionalized or concurrent enrollment in another interventional clinical study 2. Patients who have: * other histological type of lymphoma * a history of double/triple hit genetics 3. Patients who have, within 14 days prior to Day 1 dosing: * not discontinued CD20-targeted therapy, chemotherapy, radiotherapy, investigational anticancer therapy or other lymphoma specific therapy * undergone major surgery (with 4 weeks) or suffered from significant traumatic injury * received live vaccines (within 4 weeks). * required parenteral antimicrobial therapy for active, intercurrent infections 4. Patients who: * have not recovered sufficiently from the adverse toxic effects of prior therapies * were previously treated with IMiDs® (e.g. thalidomide, LEN) * have history of hyper sensitivity to compounds of similar biological or chemical composition to tafasitamab IMiDs® and/or the excipients contained in the study treatment formulations * have undergone ASCT within the period ≤ 3 months prior to signing the informed consent form. * have undergone previous allogenic stem cell transplantation * have a history of deep venous thrombosis/embolism and who are not willing/able to take venous thromboembolic event prophylaxis during the entire treatment period * concurrently use other anticancer or experimental treatments 5. History of other malignancy that could affect compliance with the protocol or interpretation of results. Exceptions * Patients with any malignancy appropriately treated with curative intent and the malignancy has been in remission without treatment for \>2 years prior to enrollment are eligible * Patients with low-grade, early-stage prostate cancer (Gleason score 6 or below, Stage 1 or 2) with no requirement for therapy at any time prior to study are eligible 6. Patients with: * positive hepatitis B and/or C serology. * known seropositivity for or history of active viral infection with human immunodeficiency virus (HIV) * CNS lymphoma involvement * history or evidence of clinically significant cardiovascular, CNS and/or other systemic disease that would in the investigator's opinion preclude participation in the study or compromise the patient's ability to give informed consent * history or evidence of rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption * gastrointestinal (GI) abnormalities (issue with absorption) including the inability to take oral medication * history or evidence of severe hepatic impairment (total serum bilirubin \> 3mg/dL), jaundice unless secondary to Gilbert's syndrome or documented liver involvement by lymphoma * history of hypersensitivity to any of the study treatments or its excipients or to drugs of similar chemical class * any other medical condition which, in the investigator's opinion, makes the patient unsuitable for the study 7. Female participants: Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods and refrain from breast feeding and donating eggs; agreement to ongoing pregnancy testing during the course of the study, and after study therapy has ended Male participants: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom and agreement to refrain from donating sperm
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | up to approximately 2 years | An adverse event (AE) was defined as any untoward medical occurrence in a participant temporally associated with the use of study treatment, whether or not considered related to the study treatment. Therefore, an AE could be any unfavorable or unintended sign (including an abnormal laboratory finding) or symptom temporally associated with the use of study treatment. A TEAE was defined as any AE that started or worsened after the first dose of study treatment until 90 days after the last dose of the study treatment. An AE that was present prior to study drug administration but increased in severity after treatment start was also included as a TEAE. |
| Number of Participants With Any ≥Grade 3 TEAE | up to approximately 2 years | The toxicity grade of TEAEs was graded using the National Cancer Institute-Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE v5.0) using the following definitions: Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2: moderate; minimal; local or non-invasive intervention indicated; limiting age-appropriate instrumental activities of daily living (refers to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc.). Grade 3: severe or medically significant but not immediately life threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. Grade 4: life-threatening consequences; urgent intervention indicated. Grade 5: death related to AE. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best Objective Response Rate (ORR) by Investigator Assessment up to Treatment Cycle 12 | up to 19.8 months | ORR was defined as the percentage of participants with complete response (CR: disappearance of all evidence disease) or partial response (PR: regression of measurable disease and no new sites) as the best response achieved at any time during the study. Only responses of CR or PR that were documented before the initiation of new antilymphoma therapy (NALT) were considered. Response assessments were based on revised International Working Group response criteria for malignant lymphoma. |
| Duration of Response (DoR) by Investigator Assessment | up to approximately 64 months (approximately 5 years) | — |
| Ctrough of Tafasitamab After 3 and 12 Treatment Cycles | predose on Cycle 3 Day 15; predose on Cycle 12 Day 28 (up to approximately 1 year [after twelve 28-day cycles]) | Ctrough was defined as the minimum concentration of tafasitamab. |
| Number of Participants Developing Anti-tafasitamab Antibodies up to Treatment Cycle 12 | up to approximately 1 year (after twelve 28-day cycles) | Anti-tafasitamab antibody samples were defined as negative if they were screened or confirmed negative. Anti-tafasitamab antibody samples were defined as positive if they were positive in both the screening and the confirmatory assays. |
| Progression-free Survival (PFS) by Investigator Assessment | up to approximately 64 months (approximately 5 years) | — |
| Cmax of Tafasitamab After 3 Treatment Cycles | 30 minutes after the end of tafasitamab infusion on Cycle 3 Day 15 (up to approximately 85 days [after three 28-day cycles]) | Cmax was defined as the maximum observed plasma concentration of tafasitamab. |
Countries
Austria, Czechia, France, Israel, Italy, Poland, South Korea, Spain, United States
Participant flow
Pre-assignment details
A total of 53 participants were enrolled at 26 study sites in Austria, Czech Republic, Israel, Italy, Poland, South Korea, Spain, and the United States through the data cutoff date of 17 July 2024.
Participants by arm
| Arm | Count |
|---|---|
| Tafasitamab Dose Level 1 + 25 mg Lenalidomide Tafasitamab was administered as an intravenous (IV) infusion in 28-day cycles until disease progression, unacceptable toxicity, or other criteria for treatment discontinuation were met. Lenalidomide 25 mg was administered once daily (QD) orally on Days 1 to 21 of each 28-day cycle for up to 12 cycles or until criteria for treatment discontinuation were met. Following discontinuation of lenalidomide, participants continued with tafasitamab monotherapy at the assigned treatment regimen. | 6 |
| Tafasitamab Dose Level 2 + 25 mg Lenalidomide Tafasitamab was administered as an IV infusion in 28-day cycles until disease progression, unacceptable toxicity, or other criteria for treatment discontinuation were met. Lenalidomide 25 mg was administered QD orally on Days 1 to 21 of each 28-day cycle for up to 12 cycles or until criteria for treatment discontinuation were met. Following discontinuation of lenalidomide, participants continued with tafasitamab monotherapy at the assigned treatment regimen. | 47 |
| Total | 53 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Death | 0 | 6 |
| Overall Study | Ongoing | 2 | 18 |
| Overall Study | Withdrawal by Subject | 0 | 11 |
Baseline characteristics
| Characteristic | Tafasitamab Dose Level 2 + 25 mg Lenalidomide | Total | Tafasitamab Dose Level 1 + 25 mg Lenalidomide |
|---|---|---|---|
| Age, Continuous | 71.9 years STANDARD_DEVIATION 9.97 | 71.7 years STANDARD_DEVIATION 9.94 | 70.0 years STANDARD_DEVIATION 10.49 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 44 Participants | 49 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 18 Participants | 18 Participants | 0 Participants |
| Race/Ethnicity, Customized Unknown | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 27 Participants | 33 Participants | 6 Participants |
| Sex: Female, Male Female | 14 Participants | 16 Participants | 2 Participants |
| Sex: Female, Male Male | 33 Participants | 37 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 6 | 8 / 47 | 9 / 53 |
| other Total, other adverse events | 6 / 6 | 40 / 47 | 46 / 53 |
| serious Total, serious adverse events | 2 / 6 | 20 / 47 | 22 / 53 |
Outcome results
Primary
Number of Participants With Any ≥Grade 3 TEAE
The toxicity grade of TEAEs was graded using the National Cancer Institute-Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE v5.0) using the following definitions: Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2: moderate; minimal; local or non-invasive intervention indicated; limiting age-appropriate instrumental activities of daily living (refers to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc.). Grade 3: severe or medically significant but not immediately life threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. Grade 4: life-threatening consequences; urgent intervention indicated. Grade 5: death related to AE.
Time frame: up to approximately 2 years
Population: Safety Analysis Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tafasitamab Dose Level 1 + 25 mg Lenalidomide | Number of Participants With Any ≥Grade 3 TEAE | 5 Participants |
| Tafasitamab Dose Level 2 + 25 mg Lenalidomide | Number of Participants With Any ≥Grade 3 TEAE | 38 Participants |
Primary
Number of Participants With Any Treatment-emergent Adverse Event (TEAE)
An adverse event (AE) was defined as any untoward medical occurrence in a participant temporally associated with the use of study treatment, whether or not considered related to the study treatment. Therefore, an AE could be any unfavorable or unintended sign (including an abnormal laboratory finding) or symptom temporally associated with the use of study treatment. A TEAE was defined as any AE that started or worsened after the first dose of study treatment until 90 days after the last dose of the study treatment. An AE that was present prior to study drug administration but increased in severity after treatment start was also included as a TEAE.
Time frame: up to approximately 2 years
Population: Safety Analysis Set: all participants who received at least 1 dose of study drug and had at least 1 postbaseline safety assessment. A valid safety assessment included death. Treatment groups were determined according to the actual treatment the participant received regardless of assigned study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tafasitamab Dose Level 1 + 25 mg Lenalidomide | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | 6 Participants |
| Tafasitamab Dose Level 2 + 25 mg Lenalidomide | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | 45 Participants |
Secondary
Best Objective Response Rate (ORR) by Investigator Assessment up to Treatment Cycle 12
ORR was defined as the percentage of participants with complete response (CR: disappearance of all evidence disease) or partial response (PR: regression of measurable disease and no new sites) as the best response achieved at any time during the study. Only responses of CR or PR that were documented before the initiation of new antilymphoma therapy (NALT) were considered. Response assessments were based on revised International Working Group response criteria for malignant lymphoma.
Time frame: up to 19.8 months
Population: Full Analysis Set: all participants who received at least 1 dose of study treatment. Participants were analyzed according to the dose group to which they were initially assigned. Confidence intervals were calculated based on the Clopper-Pearson exact method for binomial distributions.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tafasitamab Dose Level 1 + 25 mg Lenalidomide | Best Objective Response Rate (ORR) by Investigator Assessment up to Treatment Cycle 12 | 50.0 percentage of participants |
| Tafasitamab Dose Level 2 + 25 mg Lenalidomide | Best Objective Response Rate (ORR) by Investigator Assessment up to Treatment Cycle 12 | 48.9 percentage of participants |
Secondary
Cmax of Tafasitamab After 3 Treatment Cycles
Cmax was defined as the maximum observed plasma concentration of tafasitamab.
Time frame: 30 minutes after the end of tafasitamab infusion on Cycle 3 Day 15 (up to approximately 85 days [after three 28-day cycles])
Population: Pharmacokinetic Analysis Set. Only participants with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tafasitamab Dose Level 1 + 25 mg Lenalidomide | Cmax of Tafasitamab After 3 Treatment Cycles | 792 micrograms per milliliter (μg/mL) | Standard Deviation 420 |
| Tafasitamab Dose Level 2 + 25 mg Lenalidomide | Cmax of Tafasitamab After 3 Treatment Cycles | 797 micrograms per milliliter (μg/mL) | Standard Deviation 273 |
Secondary
Ctrough of Tafasitamab After 3 and 12 Treatment Cycles
Ctrough was defined as the minimum concentration of tafasitamab.
Time frame: predose on Cycle 3 Day 15; predose on Cycle 12 Day 28 (up to approximately 1 year [after twelve 28-day cycles])
Population: Pharmacokinetic Analysis Set: all participants who received at least 1 dose of tafasitamab and had at least 1 quantifiable serum tafasitamab concentration. Only participants with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tafasitamab Dose Level 1 + 25 mg Lenalidomide | Ctrough of Tafasitamab After 3 and 12 Treatment Cycles | Cycle 3 Day 15 | 170 micrograms per milliliter (μg/mL) | Standard Deviation 117 |
| Tafasitamab Dose Level 1 + 25 mg Lenalidomide | Ctrough of Tafasitamab After 3 and 12 Treatment Cycles | Cycle 12 Day 28 | 87 micrograms per milliliter (μg/mL) | Standard Deviation 26 |
| Tafasitamab Dose Level 2 + 25 mg Lenalidomide | Ctrough of Tafasitamab After 3 and 12 Treatment Cycles | Cycle 3 Day 15 | 228 micrograms per milliliter (μg/mL) | Standard Deviation 102 |
| Tafasitamab Dose Level 2 + 25 mg Lenalidomide | Ctrough of Tafasitamab After 3 and 12 Treatment Cycles | Cycle 12 Day 28 | 149 micrograms per milliliter (μg/mL) | Standard Deviation 69 |
Secondary
Duration of Response (DoR) by Investigator Assessment
Time frame: up to approximately 64 months (approximately 5 years)
Secondary
Number of Participants Developing Anti-tafasitamab Antibodies up to Treatment Cycle 12
Anti-tafasitamab antibody samples were defined as negative if they were screened or confirmed negative. Anti-tafasitamab antibody samples were defined as positive if they were positive in both the screening and the confirmatory assays.
Time frame: up to approximately 1 year (after twelve 28-day cycles)
Population: Immunogenicity Analysis Set: all participants who received at least 1 dose of tafasitamab and had at least 1 valid anti-tafasitamab antibody assessment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tafasitamab Dose Level 1 + 25 mg Lenalidomide | Number of Participants Developing Anti-tafasitamab Antibodies up to Treatment Cycle 12 | 0 Participants |
| Tafasitamab Dose Level 2 + 25 mg Lenalidomide | Number of Participants Developing Anti-tafasitamab Antibodies up to Treatment Cycle 12 | 0 Participants |
Secondary
Progression-free Survival (PFS) by Investigator Assessment
Time frame: up to approximately 64 months (approximately 5 years)