Lymphoma, Follicular
Conditions
Brief summary
The primary objective of the study is to assess the pharmacokinetic (PK) similarity of Boehringer Ingelheim (BI) 695500 vs. rituximab (MabThera®) in previously untreated patients with low tumor burden follicular lymphoma (LTBFL). The secondary objective of the study is to evaluate the pharmacodynamics (PD), safety, and anti-tumor activity of BI 695500 vs. rituximab (MabThera®), as well as the presence of anti-drug antibodies (ADAs).
Interventions
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Must give written informed consent and be willing to follow this Clinical Trial Protocol. * Male or female patients, at least 18 years of age at Screening. * Histologically-confirmed, stage II - IV Non-Hodgkin's lymphoma (CD20+ FL of Grades 1, 2, or 3a). * Low tumor burden according to the Groupe d'Etudes des Lymphomes Folliculaires (GELF) criteria - no nodal or extranodal involvement of more than 7 cm, no more than 3 nodal sites with a diameter \>3 cm, no B symptoms (i.e., fever \>38°C, weight loss - unexplained loss of \>10 % body weight over the past 6 months, and sweats - the presence of drenching night sweats), no significant splenomegaly, no significant serious effusion, no complications such as organ compression, and less than 5x10\^9/L circulating tumor cells. * Availability of archived tumor sample prior to screening. * Patients not previously treated for their FL. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. * Have at least 1 measurable lesion as per the International Working Group (IWG) criteria 2007 at Screening (lesion clearly measurable in at least 2 perpendicular dimensions; see Appendix 10.1 for further details). * Adequate hematological function (unless abnormalities are related to lymphoma infiltration of the bone marrow) within 28 days prior to randomization, including: * \- hemoglobin =9.0 g/dL (=5.6 mmol/L). * \- absolute neutrophil count =1.5 × 10\^9/L. * \- platelet count =100 × 10\^9/L. * Adequate renal and liver function: * \- serum creatinine \<2.0 mg/dL (\<176.8 micromol/L). * \- total bilirubin \<2.0 mg/dL (\<34 mcmol/L) except for patient with Gilbert's Syndrome or Hemolysis. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \<3 x upper limit of normal (ULN) (\<5 x ULN is acceptable if abnormalities are thought to be related to hepatic infiltration by FL). * For participants of reproductive potential (males and females), use of a medically acceptable method of contraception during the trial, i.e., a combination of 2 forms of effective contraception (defined as hormonal contraception, intrauterine device, condom with spermicide, etc.). Females of childbearing potential (includes tubal ligation) and males with female partners of childbearing potential must also agree to use an acceptable method of contraception (see above) for 12 months following completion or discontinuation from the trial medication.
Exclusion criteria
* Transformation to high-grade lymphoma (secondary to low-grade lymphoma). * Presence or history of central nervous system lymphoma. * Patients receiving current treatment with corticosteroids must not be receiving a dose exceeding 20 mg/day prednisone or equivalent. * Patients with prior or concomitant malignancies within 5 years prior to screening except non-melanoma skin cancer, adequately treated carcinoma in situ of the cervix, adequately treated breast cancer in situ, localized prostate cancer stage T1c - provided that the patient underwent curative treatment, and remains relapse free. * Major surgery (excluding lymph node biopsy) within 28 days prior to randomization. * Active, chronic or persistent infection that might worsen with immunosuppressive treatment (e.g., Human Immunodeficiency Virus \[HIV\], Hepatitis C Virus \[HCV\], Herpes Zoster); positive for HIV or tuberculosis at Screening. * Patients with serological evidence of Hepatitis B virus (HBV) infection. Patients seropositive because of HBV vaccine are eligible. HBV positive patients may participate following consultation with a hepatitis expert regarding monitoring and use of HBV antiviral therapy, and provided they agree to receive treatment as indicated. * Serious underlying medical conditions, which, per the investigator's discretion, could impair the ability of the patient to participate in the trial (including but not limited to ongoing active infection, severe immunosuppression, uncontrolled diabetes mellitus, gastric ulcers, active autoimmune disease); patients who have significant cardiac disease, including but not limited to congestive heart failure of Class III or IV of the NYHA classification; uncontrolled angina or arrhythmia; any uncontrolled or severe cardiovascular or cerebrovascular disease. * Known hypersensitivity or allergy to murine products. * History of a severe allergic reaction or anaphylactic reaction to a biological agent or history of hypersensitivity to any component of the trial drug. * Receipt of a live/attenuated vaccine within 12 weeks prior to the Screening Visit. * Prior treatment with BI 695500 and/or rituximab. * Patients who received any prior therapy using monoclonal antibodies will be excluded; this does not apply to other biological drugs such as growth factors or anticoagulants. * Treatment within a clinical trial within 4 weeks prior to initiation of trial treatment. Patients who have received treatment with a drug that has not received regulatory approval for any indication within 4 weeks or a minimum of 5 half-lives, whichever is longer, of the initial dose of trial medication. * Any other co-existing medical or psychological condition(s) that will preclude participation in the trial or compromise ability to give informed consent and/or comply with study procedures. * Pregnancy or breast feeding. For women of childbearing potential, a positive serum pregnancy test at the Screening Visit. * Patients who have significant cardiac disease, including but not limited to congestive heart failure of Class III or IV of the New York Heart Association (NYHA) classification; uncontrolled angina or arrhythmia; any uncontrolled or severe cardiovascular or cerebrovascular disease; or uncontrolled hypertension.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration (AUC) Time Curve of BI 695500 and Rituximab (MabThera®) Over the First Dosing Interval (Pre-infusion on Day 1 to Pre-infusion on Day 8) | Blood samplings were done at pre-infusion and at end of infusion at 1, 2, and 4 hours from end of infusion 1, and at 24, 48, 72, 96 and 168 hours from start of infusion 1. | This outcome measure presents area under the concentration time curve of BI 695500 and Rituximab (MabThera®) over the first dosing interval (pre-infusion on Day 1 to pre-infusion on Day 8) (AUCDay 1-Day 8) for assessment of PK (Pharmacokinetics) similarity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Measured Concentration of BI 695500 and Rituximab (MabThera®) in Plasma (Cmax) Following Dose 1 | Blood samplings were done at pre-infusion and at end of infusion at 1, 2, and 4 hours from end of infusion 1, and at 24, 48, 72, 96 and 168 hours from start of infusion 1. | This outcome measure presents maximum measured concentration of BI 695500 and Rituximab (MabThera®) in plasma (Cmax) following Dose 1 |
| Maximum Measured Concentration of Rituximab (MabThera®) and BI 695500 in Plasma (Cmax) Following Dose 4 | Blood samplings were done at pre-infusion and at end of infusion at 1, 2, and 4 hours from end of infusion 4, and at 24, 48, 72, 96, 168, 336, 672, 1344, 2016 and 2880 hours from start of infusion 4. | This outcome measure presents maximum measured concentration of Rituximab (MabThera®) and BI 695500 in plasma (Cmax) following Dose 4. |
| Area Under the Depletion-time Curve of the Cluster of Differentiation (CD)19+ B-cell Count (% Change From Baseline (CFB)) in Peripheral Blood From Pre-infusion on Day 1 Until Last Measurement on Day 8 (Pre-infusion) | Blood samplings were done at pre-infusion and at end of infusion at 1, 2, and 4 hours from end of infusion, and at 24, 48, 72, 96 and 168 hours from start of infusion. | This outcome measure presents area under the depletion-time curve of the CD19+ B-cell count (% change from baseline) in peripheral blood from pre-infusion on Day 1 until last measurement on Day 8 (pre-infusion) (AUC Day 1-Day 8, CD19+). |
| AUC of BI 695500 and Rituximab (MabThera®) Over the Fourth Dosing Interval (Pre-infusion on Day 22 to Day 29) (AUC Day 22-Day 29) | Blood samplings were done at pre-infusion and at end of infusion at 1, 2, and 4 hours from end of infusion 4, and at 24, 48, 72, 96 and 168 hours from start of infusion 4. | This outcome measure presents area under the concentration of BI 695500 and Rituximab (MabThera®) over the fourth dosing interval (pre-infusion on Day 22 to Day 29). |
| Overall Response Rate (ORR) (Complete Response (CR) Plus Partial Response (PR)) Evaluated Approximately One Month After Last Dose of BI 695500 or Rituximab (MabThera®) | at Day 50. | Overall Response Rate (ORR) comprised Complete Response (CR) plus Partial Response (PR) evaluated approximately one month after last dose of BI 695500 or Rituximab \[MabThera®\]. Overall Response as defined by the revised International Working Group (IWG) Criteria 2007, using the Investigator's assessment. |
| Percentage of Patients With Treatment Emergent Adverse Events (TEAEs) Selected for Comparability Assessment of BI 695500 and Rituximab (MabThera®) | Adverse Events (AEs) that started or worsened on or after the first dose of study medication and prior to the last date of study medication + 4 months (120 days) inclusive. | This outcome measure presents percentage of patients with Treatment Emergent Adverse Events (TEAEs) selected for comparability assessment of BI 695500 and Rituximab (MabThera®). |
| Change From Baseline (%) of CD19+ B-cells in Peripheral Blood Measured After Seven Days on Day 8 (Day 8 Pre-infusion Time Point) | Blood sampling was done at 168 hours from start of infusion. | This outcome measure presents percent change from baseline of CD19+ B-cells in peripheral blood, measured after 7 days (i.e., Day 8 pre-infusion time point) (PCFBpre,2 CD19+). |
Countries
Australia, Austria, Belgium, Croatia, Czechia, France, Germany, Greece, Hungary, New Zealand, Poland, Russia, Spain
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| BI 695500 The subjects received BI 695500/100 mg/10 mL concentrate for solution for infusion at 375 mg/m2 once a week for 4 weeks (for a total of 4 dosages administered on Days 1, 8, 15, and 22) by intravenous (IV) infusion. | 49 |
| Rituximab (MabThera®) The subjects received Rituximab (MabThera®)/100 mg/10 mL and 500 mg/50 mL concentrate for solution for infusion at 375 mg/m2 once a week for 4 weeks (for a total of 4 dosages administered on Days 1, 8, 15, and 22) by IV infusion. | 46 |
| Total | 95 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Other not defined above | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | BI 695500 | Rituximab (MabThera®) | Total |
|---|---|---|---|
| Age, Continuous | 59.6 Years STANDARD_DEVIATION 12.44 | 58.4 Years STANDARD_DEVIATION 11.48 | 59.0 Years STANDARD_DEVIATION 11.93 |
| Sex: Female, Male Female | 23 Participants | 27 Participants | 50 Participants |
| Sex: Female, Male Male | 26 Participants | 19 Participants | 45 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 25 / 49 | 28 / 46 |
| serious Total, serious adverse events | 4 / 49 | 3 / 46 |
Outcome results
Primary
Area Under the Concentration (AUC) Time Curve of BI 695500 and Rituximab (MabThera®) Over the First Dosing Interval (Pre-infusion on Day 1 to Pre-infusion on Day 8)
This outcome measure presents area under the concentration time curve of BI 695500 and Rituximab (MabThera®) over the first dosing interval (pre-infusion on Day 1 to pre-infusion on Day 8) (AUCDay 1-Day 8) for assessment of PK (Pharmacokinetics) similarity.
Time frame: Blood samplings were done at pre-infusion and at end of infusion at 1, 2, and 4 hours from end of infusion 1, and at 24, 48, 72, 96 and 168 hours from start of infusion 1.
Population: The PK analysis Set Inferential (PKSI) used for inferential analysis of PK parameters, consisted of all randomized subjects who received at least one dose of trial medication and had an estimable primary PK parameter value and were without important protocol deviations that would significantly affect the PK of BI 695500 or Rituximab (MabThera®).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BI 695500 | Area Under the Concentration (AUC) Time Curve of BI 695500 and Rituximab (MabThera®) Over the First Dosing Interval (Pre-infusion on Day 1 to Pre-infusion on Day 8) | 15700 microgram*hour/millilitre (µg*h/mL) | Geometric Coefficient of Variation 69.8 |
| Rituximab (MabThera®) | Area Under the Concentration (AUC) Time Curve of BI 695500 and Rituximab (MabThera®) Over the First Dosing Interval (Pre-infusion on Day 1 to Pre-infusion on Day 8) | 17600 microgram*hour/millilitre (µg*h/mL) | Geometric Coefficient of Variation 27.9 |
90% CI: [75.42, 106.29]
Secondary
Area Under the Depletion-time Curve of the Cluster of Differentiation (CD)19+ B-cell Count (% Change From Baseline (CFB)) in Peripheral Blood From Pre-infusion on Day 1 Until Last Measurement on Day 8 (Pre-infusion)
This outcome measure presents area under the depletion-time curve of the CD19+ B-cell count (% change from baseline) in peripheral blood from pre-infusion on Day 1 until last measurement on Day 8 (pre-infusion) (AUC Day 1-Day 8, CD19+).
Time frame: Blood samplings were done at pre-infusion and at end of infusion at 1, 2, and 4 hours from end of infusion, and at 24, 48, 72, 96 and 168 hours from start of infusion.
Population: The PK analysis Set Descriptive (PKSD) consisted of all randomized subjects who received at least one dose of trial medication BI 695500 or Rituximab \[MabThera®\], had at least one post-treatment PK concentration value and were without important protocol deviations that would significantly affect the PK of BI 695500 or Rituximab (MabThera®).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BI 695500 | Area Under the Depletion-time Curve of the Cluster of Differentiation (CD)19+ B-cell Count (% Change From Baseline (CFB)) in Peripheral Blood From Pre-infusion on Day 1 Until Last Measurement on Day 8 (Pre-infusion) | -16895.2 Percentage CFB of CD19+ B-cells*hour | Standard Deviation 1016.9 |
| Rituximab (MabThera®) | Area Under the Depletion-time Curve of the Cluster of Differentiation (CD)19+ B-cell Count (% Change From Baseline (CFB)) in Peripheral Blood From Pre-infusion on Day 1 Until Last Measurement on Day 8 (Pre-infusion) | -17064.4 Percentage CFB of CD19+ B-cells*hour | Standard Deviation 1403.2 |
90% CI: [-210.6, 709]
Secondary
AUC of BI 695500 and Rituximab (MabThera®) Over the Fourth Dosing Interval (Pre-infusion on Day 22 to Day 29) (AUC Day 22-Day 29)
This outcome measure presents area under the concentration of BI 695500 and Rituximab (MabThera®) over the fourth dosing interval (pre-infusion on Day 22 to Day 29).
Time frame: Blood samplings were done at pre-infusion and at end of infusion at 1, 2, and 4 hours from end of infusion 4, and at 24, 48, 72, 96 and 168 hours from start of infusion 4.
Population: The PK analysis Set Inferential (PKSI) used for inferential analysis of PK parameters, consisted of all randomized subjects who received at least one dose of trial medication and had estimable primary PK parameter value and were without important protocol deviations that would significantly affect the PK of BI 695500 or Rituximab (MabThera®).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BI 695500 | AUC of BI 695500 and Rituximab (MabThera®) Over the Fourth Dosing Interval (Pre-infusion on Day 22 to Day 29) (AUC Day 22-Day 29) | 41700 microgram*hour/millilitre (µg*h/mL) | Geometric Coefficient of Variation 32.3 |
| Rituximab (MabThera®) | AUC of BI 695500 and Rituximab (MabThera®) Over the Fourth Dosing Interval (Pre-infusion on Day 22 to Day 29) (AUC Day 22-Day 29) | 44300 microgram*hour/millilitre (µg*h/mL) | Geometric Coefficient of Variation 24.8 |
90% CI: [85.04, 105.23]
Secondary
Change From Baseline (%) of CD19+ B-cells in Peripheral Blood Measured After Seven Days on Day 8 (Day 8 Pre-infusion Time Point)
This outcome measure presents percent change from baseline of CD19+ B-cells in peripheral blood, measured after 7 days (i.e., Day 8 pre-infusion time point) (PCFBpre,2 CD19+).
Time frame: Blood sampling was done at 168 hours from start of infusion.
Population: The PK analysis Set Descriptive (PKSD) consisted of all randomized subjects who received at least one dose of trial medication BI 695500 or Rituximab \[MabThera®\], had at least one post-treatment PK concentration value and were without important protocol deviations that would significantly affect the PK of BI 695500 or Rituximab (MabThera®).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BI 695500 | Change From Baseline (%) of CD19+ B-cells in Peripheral Blood Measured After Seven Days on Day 8 (Day 8 Pre-infusion Time Point) | -99.2 Percentage (%) CFB of CD19+ B-cells | Standard Deviation 1.7 |
| Rituximab (MabThera®) | Change From Baseline (%) of CD19+ B-cells in Peripheral Blood Measured After Seven Days on Day 8 (Day 8 Pre-infusion Time Point) | -98.8 Percentage (%) CFB of CD19+ B-cells | Standard Deviation 4.2 |
Secondary
Maximum Measured Concentration of BI 695500 and Rituximab (MabThera®) in Plasma (Cmax) Following Dose 1
This outcome measure presents maximum measured concentration of BI 695500 and Rituximab (MabThera®) in plasma (Cmax) following Dose 1
Time frame: Blood samplings were done at pre-infusion and at end of infusion at 1, 2, and 4 hours from end of infusion 1, and at 24, 48, 72, 96 and 168 hours from start of infusion 1.
Population: The PK analysis Set Inferential (PKSI) used for inferential analysis of PK parameters, consisted of all randomized subjects who received at least one dose of trial medication and had estimable primary PK parameter value and were without important protocol deviations that would significantly affect the PK of BI 695500 or Rituximab (MabThera®).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BI 695500 | Maximum Measured Concentration of BI 695500 and Rituximab (MabThera®) in Plasma (Cmax) Following Dose 1 | 207.882 microgram/millilitre (µg/mL) | Geometric Coefficient of Variation 58.5 |
| Rituximab (MabThera®) | Maximum Measured Concentration of BI 695500 and Rituximab (MabThera®) in Plasma (Cmax) Following Dose 1 | 228.802 microgram/millilitre (µg/mL) | Geometric Coefficient of Variation 25 |
90% CI: [77.62, 104.23]
Secondary
Maximum Measured Concentration of Rituximab (MabThera®) and BI 695500 in Plasma (Cmax) Following Dose 4
This outcome measure presents maximum measured concentration of Rituximab (MabThera®) and BI 695500 in plasma (Cmax) following Dose 4.
Time frame: Blood samplings were done at pre-infusion and at end of infusion at 1, 2, and 4 hours from end of infusion 4, and at 24, 48, 72, 96, 168, 336, 672, 1344, 2016 and 2880 hours from start of infusion 4.
Population: The PK analysis Set Inferential (PKSI) used for inferential analysis of PK parameters, consisted of all randomized subjects who received at least one dose of trial medication and had estimable primary PK parameter value and were without important protocol deviations that would significantly affect the PK of BI 695500 or Rituximab (MabThera®).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BI 695500 | Maximum Measured Concentration of Rituximab (MabThera®) and BI 695500 in Plasma (Cmax) Following Dose 4 | 397.080 microgram/millilitre (µg/mL) | Geometric Coefficient of Variation 23.1 |
| Rituximab (MabThera®) | Maximum Measured Concentration of Rituximab (MabThera®) and BI 695500 in Plasma (Cmax) Following Dose 4 | 412.190 microgram/millilitre (µg/mL) | Geometric Coefficient of Variation 18.1 |
90% CI: [90.45, 105.42]
Secondary
Overall Response Rate (ORR) (Complete Response (CR) Plus Partial Response (PR)) Evaluated Approximately One Month After Last Dose of BI 695500 or Rituximab (MabThera®)
Overall Response Rate (ORR) comprised Complete Response (CR) plus Partial Response (PR) evaluated approximately one month after last dose of BI 695500 or Rituximab \[MabThera®\]. Overall Response as defined by the revised International Working Group (IWG) Criteria 2007, using the Investigator's assessment.
Time frame: at Day 50.
Population: Safety Analysis Set (SAS): The patients who received at least one dose of trial medication and classified as per treatment received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BI 695500 | Overall Response Rate (ORR) (Complete Response (CR) Plus Partial Response (PR)) Evaluated Approximately One Month After Last Dose of BI 695500 or Rituximab (MabThera®) | 44.9 Percentage of subjects |
| Rituximab (MabThera®) | Overall Response Rate (ORR) (Complete Response (CR) Plus Partial Response (PR)) Evaluated Approximately One Month After Last Dose of BI 695500 or Rituximab (MabThera®) | 54.3 Percentage of subjects |
95% CI: [-29.4, 11.1]
Secondary
Percentage of Patients With Treatment Emergent Adverse Events (TEAEs) Selected for Comparability Assessment of BI 695500 and Rituximab (MabThera®)
This outcome measure presents percentage of patients with Treatment Emergent Adverse Events (TEAEs) selected for comparability assessment of BI 695500 and Rituximab (MabThera®).
Time frame: Adverse Events (AEs) that started or worsened on or after the first dose of study medication and prior to the last date of study medication + 4 months (120 days) inclusive.
Population: Safety Analysis Set (SAS): The patients who received at least one dose of trial medication and classified as per treatment received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BI 695500 | Percentage of Patients With Treatment Emergent Adverse Events (TEAEs) Selected for Comparability Assessment of BI 695500 and Rituximab (MabThera®) | 36.7 Percentage of patients |
| Rituximab (MabThera®) | Percentage of Patients With Treatment Emergent Adverse Events (TEAEs) Selected for Comparability Assessment of BI 695500 and Rituximab (MabThera®) | 34.8 Percentage of patients |
95% CI: [-18, 22.1]