Diffuse Large B-cell Lymphoma(DLBCL), Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL)
Conditions
Brief summary
Evaluate the safety and tolerability of AMG 562 in adult subjects with DLBCL, MCL, or FL. Estimate the maximum tolerated dose (MTD) and/or a biologically active dose (e.g., recommended phase 2 dose \[RP2D\])
Interventions
DRUGAMG 562
AMG 562 is a BiTE® antibody construct that targets CD19 and is intended for the treatment of patients with B-cell malignancies.
Sponsors
Amgen
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
* Subject has provided informed consent prior to initiation of any study-specific activities/procedures * Age ≥ 18 at the time of informed consent. * Biopsy proven B-NHL including: * DLBCL, which also includes DLBCL that represents transformation of indolent NHL (including follicular, marginal zone, and lymphoplasmacytic lymphoma excluding chronic lymphocytic leukemia or Hodgkin Lymphoma) and DLBCL with alterations of MYC and BCL2 and/or BCL6 also described as double-hit and triple-hit lymphomas. * FL * MCL Presentations of these histologies with substantial occurrence of malignant cells into the bloodstream (lymphocyte count ≥ 7 x 10\^9/L) including all leukemic presentations are excluded. The following histologies are not eligible: Lymphoblastic lymphoma Burkitt lymphoma Any histologies not specifically mentioned must be discussed with the Medical Monitor * Subjects with transformation of indolent lymphoma must have received therapy after a diagnosis of transformation that is appropriate for aggressive histology. \- Subjects who received prior CD19-targeting treatment are allowed (CAR-T cell therapy is excluded). A biopsy following CD19-targeting treatment is required unless no lesions are accessible or the risk of the biopsy is deemed too high by the investigator For Part 2 (Expansion in patients with DLBCL): only biopsy proven DLBCL (biopsy proven at least at primary diagnosis), including DLBCL that represents transformation of indolent NHL (including follicular, marginal zone, and lymphoplasmacytic lymphoma excluding chronic lymphocytic leukemia or Hodgkin Lymphoma) are eligible. Other histologies are not eligible. * Presentations of these histologies with substantial occurrence of malignant cells into the bloodstream (lymphocyte count ≥ 7 x 10\^9/L) including all leukemic presentations are excluded. * Subjects with transformation of indolent lymphoma must have received therapy after a diagnosis of transformation that is appropriate for aggressive histology as described in inclusion criterial. * Subjects who received prior CD19-targeting treatment are allowed (CAR-T cell therapy is excluded) A biopsy following CD19-targeting treatment is required unless no lesions are accessible or the risk of the biopsy is deemed too high by the investigator - For DLBCL: Refractory (no prior CR/CMR) to first or later line of treatment or relapsed (prior CR/CMR) after two or more prior treatments, with at least one treatment consisting of standard multiagent chemotherapy containing an anthracycline AND an approved anti-CD20 agent. Examples of appropriate therapy include but are not limited to R-CHOP (14 or 21), R-CHOEP, and DA-R-EOCH. For FL: Refractory (no prior CR/CMR) to first or later line of treatment or relapsed (prior CR/CMR) after three or more prior treatments, with at least one treatment consisting of a standard chemotherapy containing an approved anti-CD20 agent. Examples of appropriate therapy include but are not limited to R-CHOP, R-CVP, and BR. For MCL: Refractory (no prior CR/CMR) to first or later line of treatment or relapsed (prior CR/CMR) after three or more prior treatments, with at least one treatment consisting of a standard chemotherapy containing an approved anti-CD20 agent. Examples of appropriate therapy include but are not limited to R-CHOP, BR and hyper-CVAD alternating with R-MTX/Ara-C. For subjects with refractory B-NHL and who have received radiotherapy, PET positivity should be demonstrated no less than 6 weeks after the last dose of radiotherapy * Minimum life expectancy of 12 weeks * Radiographically measurable disease with a clearly demarcated nodal lesion at least 1.5 cm in its largest dimension or a target extranodal lesion at least 1.0 cm in its largest dimension. In the dose exploration phase in case disease is not radiographically measurable PET positivity (ie, Deauville ≥4) instead is acceptable. * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 * Laboratory parameters (completed within 14 days prior to enrollment): Hematology: * Absolute neutrophil count (ANC) ≥ 1.0 x 10\^9/L * Platelets ≥ 75 x 10\^9/L Chemistry: * Creatinine clearance ≥ 60 mL/min (calculated using Cockcroft Gault equation) * Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) \< 3X upper limit of normal (ULN) * Total bilirubin (TBL) \< 2x ULN (unless Gilbert's disease or if liver involvementwith lymphoma)
Exclusion criteria
* Treatment within 30 days prior to enrollment with another investigational device or drug (interventional clinical study / studies). Other investigational procedures while participating in this study are excluded (observational studies are permitted). * Prior anti-cancer therapy as specified below: * At least 6 weeks must have elapsed since any prior systemic inhibitory/stimulatory immune checkpoint molecule therapy (eg, ipilimumab, nivolumab, pembrolizumab, atezolizumab, OX40 agonists, 4-1BB agonists, etc) before the first dose of AMG 562. * Other targeted anti-cancer therapy (chemotherapy, molecular targeted therapy, steroids) within 14 days or 5 half lives (which ever is longer) prior to first dose of AMG 562. Patients requiring continued treatment due to aggressive disease may only be included if there is agreement by both the investigator and the Amgen Medical Monitor. * Radiation therapy completed within 28 days prior to first dose of AMG 562. * Autologous HSCT within six weeks prior to start of AMG 562 treatment. * At least 4 weeks must have elapsed since any prior treatment with antibody therapy (exception immune checkpoint inhibitors) before the first dose of AMG 562. * Prior CD19-directed CAR-T cell therapies * Prior allogeneic HSCT. * For Part 2 (Expansion in patients with DLBCL): fluorodeoxyglucose non-avid patients. * Baseline electrocardiogram (ECG) QTc \> 470 msec. * Autoimmune disorders requiring chronic systemic steroid therapy or any other form of immunosuppressive therapy. Patient may be included if the treatment is discontinued more than 3 months prior to the first dose of AMG 562 at a low likelihood of relapse AND if there is agreement by both the investigator and the Amgen Medical Monitor. * Unresolved toxicity from prior anti-tumor therapy, defined as not having resolved to CTCAE version 4.0 grade 1, or to levels dictated in the eligibility criteria with the exception of alopecia or toxicities from prior anti-tumor therapy that are considered irreversible (defined as having been present and stable for \> 28 days) which may be allowed if they are not otherwise described in the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) | Day 1 to Day 28 | — |
| Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Up to 2 years | An adverse event (AE) was defined as any untoward medical occurrence in a clinical trial participant. TEAEs were any AE that occurred after receiving at least 1 dose of treatment. Treatment-related TEAEs were those considered related to study treatment by the investigator. Disease-Related TEAEs were events (serious or non-serious) anticipated to occur in the study population due to the underlying disease. Any clinically significant changes in vital signs, physical examinations, electrocardiograms (ECG)s and clinical laboratory tests were recorded as TEAEs. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Timepoint (AUClast) of AMG 562 | Day 1 | — |
| Half-life (t1/2) of AMG 562 | Day 22 | — |
| Objective Response Rate (ORR) Per Lugano Classification | Day 1 up to 2 years | ORR was defined as the percentage of participants with a confirmed complete metabolic response (CMR) or partial metabolic response (PMR) as defined by Lugano Classification. Per the Lugano Classification, positron emission tomography-computed tomography (PET-CT) were defined on the 5-point scale as scores 1, 2, or 3 (where 1 = no uptake above background; 2 = uptake \</= mediastinum; and 3 = uptake \> mediastinum but \</= liver) and PET-positive scans, as scores of 4 or 5 (where 4 = uptake moderately higher than liver; 5 = uptake markedly higher than liver and/or new lesions). CMR: score of 1, 2 or 3 in nodal or extranodal sites with or without a residual mass. PMR: score of 4 or 5 with reduced uptake compared with baseline and residual mass(es) of any size. |
| Maximum Observed Concentration (Cmax) of AMG 562 | Day 1 | — |
| Duration of Response (DOR) | Day 1 up to 2 years | DOR was defined as the time from the date of an initial objective response per Lugano classification to the earlier of progression or death. Participants who had not ended their response at the time of analysis had DOR censored at their last disease assessment date. |
| Progression Free Survival (PFS) | Day 1 up to 2 years | PFS was defined as the interval from Day 1 to the earlier of a lymphoma progression or death from any cause; otherwise, PFS was censored at the last radiographic assessment date. If a participant had no post baseline radiographic assessment and a vital status of alive or unknown, PFS was censored at Day 1. |
| Overall Survival (OS) | Day 1 up to 2 years | OS was defined as the time from the date of Day 1 until death due to any cause. Any participant not known to have died at the time of analysis was censored based on the last recorded date on which the participant was alive. |
| Best Overall Response Per Lugano Classification | Day 1 up to 2 years | Per the Lugano Classification, positron emission tomography-computed tomography (PET-CT) were defined on the 5-point scale as scores 1, 2, or 3 (where 1 = no uptake above background; 2 = uptake \</= mediastinum; and 3 = uptake \> mediastinum but \</= liver) and PET-positive scans, as scores of 4 or 5 (where 4 = uptake moderately higher than liver; 5 = uptake markedly higher than liver and/or new lesions). CMR: score of 1, 2 or 3 in nodal or extranodal sites with or without a residual mass. PMR: score of 4 or 5 with reduced uptake compared with baseline and residual mass(es) of any size. No metabolic response (NMR): score of 4 or 5 with no obvious change in fluorodeoxyglucose (FDG) uptake. Progressive metabolic disease (PMD): score 4 or 5 in any lesion with an increase in intensity of FDG uptake from baseline (and/or new FDG-avid foci consistent with lymphoma). |
| Time of Maximum Concentration (Tmax) of AMG 562 | Day 1 | — |
Countries
Belgium, Canada, Germany, United States
Participant flow
Recruitment details
This study was conducted at 13 centers in United States, Canada, South Korea, Germany, and Japan from October 2018 to January 2022.
Pre-assignment details
The study planned to consist of 2 parts. Part 1 included a dose exploration and Part 2 a dose-expansion group. However, no participants were enrolled into Part 2.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: AMG 562 0.1 μg Participants with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), or follicular lymphoma (FL) received AMG 562 0.1 μg administered as once weekly intravenous (IV) infusions for up to approximately 8 months. | 8 |
| Cohort 2: AMG 562 0.3 μg Participants with relapsed/refractory DLBCL, MCL, or FL received AMG 562 0.3 μg administered as once weekly IV infusions for up to approximately 8 months. | 1 |
| Total | 9 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 2 | 0 |
| Overall Study | Decision by sponsor | 5 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Cohort 1: AMG 562 0.1 μg | Total | Cohort 2: AMG 562 0.3 μg |
|---|---|---|---|
| Age, Continuous | 63.3 Years STANDARD_DEVIATION 6.8 | 63.6 Years STANDARD_DEVIATION 6.4 | 66.0 Years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 9 Participants | 1 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 | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 7 Participants | 1 Participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 0 Participants |
| Sex: Female, Male Male | 5 Participants | 6 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 9 | 0 / 1 |
| other Total, other adverse events | 8 / 8 | 1 / 1 |
| serious Total, serious adverse events | 3 / 8 | 1 / 1 |
Outcome results
Primary
Number of Participants Who Experienced a Dose Limiting Toxicity (DLT)
Time frame: Day 1 to Day 28
Population: DLT Analysis Set: all participants who either experienced DLTs or completed 28 days of DLT observational period and did not experience DLTs.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: AMG 562 0.1 μg | Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) | 1 Participants |
| Cohort 2: AMG 562 0.3 μg | Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) | 0 Participants |
Primary
Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE)
An adverse event (AE) was defined as any untoward medical occurrence in a clinical trial participant. TEAEs were any AE that occurred after receiving at least 1 dose of treatment. Treatment-related TEAEs were those considered related to study treatment by the investigator. Disease-Related TEAEs were events (serious or non-serious) anticipated to occur in the study population due to the underlying disease. Any clinically significant changes in vital signs, physical examinations, electrocardiograms (ECG)s and clinical laboratory tests were recorded as TEAEs.
Time frame: Up to 2 years
Population: Safety Analysis Set: All participants who received at least one dose of investigational product.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1: AMG 562 0.1 μg | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | TEAEs | 8 Participants |
| Cohort 1: AMG 562 0.1 μg | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Treatment-related TEAEs | 4 Participants |
| Cohort 1: AMG 562 0.1 μg | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Disease-related TEAEs | 1 Participants |
| Cohort 2: AMG 562 0.3 μg | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | TEAEs | 1 Participants |
| Cohort 2: AMG 562 0.3 μg | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Treatment-related TEAEs | 0 Participants |
| Cohort 2: AMG 562 0.3 μg | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Disease-related TEAEs | 0 Participants |
Secondary
Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Timepoint (AUClast) of AMG 562
Time frame: Day 1
Population: Pharmacokinetic (PK) Analysis Set: all participants who have received at least 1 dose of AMG 562 and have at least 1 PK sample collected.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: AMG 562 0.1 μg | Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Timepoint (AUClast) of AMG 562 | 0.658 hr*ng/mL | Standard Deviation 0.426 |
Secondary
Best Overall Response Per Lugano Classification
Per the Lugano Classification, positron emission tomography-computed tomography (PET-CT) were defined on the 5-point scale as scores 1, 2, or 3 (where 1 = no uptake above background; 2 = uptake \</= mediastinum; and 3 = uptake \> mediastinum but \</= liver) and PET-positive scans, as scores of 4 or 5 (where 4 = uptake moderately higher than liver; 5 = uptake markedly higher than liver and/or new lesions). CMR: score of 1, 2 or 3 in nodal or extranodal sites with or without a residual mass. PMR: score of 4 or 5 with reduced uptake compared with baseline and residual mass(es) of any size. No metabolic response (NMR): score of 4 or 5 with no obvious change in fluorodeoxyglucose (FDG) uptake. Progressive metabolic disease (PMD): score 4 or 5 in any lesion with an increase in intensity of FDG uptake from baseline (and/or new FDG-avid foci consistent with lymphoma).
Time frame: Day 1 up to 2 years
Population: Safety Analysis Set: All participants who received at least one dose of investigational product.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1: AMG 562 0.1 μg | Best Overall Response Per Lugano Classification | PMR | 0.0 Percentage of participants |
| Cohort 1: AMG 562 0.1 μg | Best Overall Response Per Lugano Classification | PMD | 50.0 Percentage of participants |
| Cohort 1: AMG 562 0.1 μg | Best Overall Response Per Lugano Classification | NMR | 0.0 Percentage of participants |
| Cohort 1: AMG 562 0.1 μg | Best Overall Response Per Lugano Classification | Unable to Evaluate or Not Available | 37.5 Percentage of participants |
| Cohort 1: AMG 562 0.1 μg | Best Overall Response Per Lugano Classification | CMR | 12.5 Percentage of participants |
| Cohort 2: AMG 562 0.3 μg | Best Overall Response Per Lugano Classification | Unable to Evaluate or Not Available | 0.0 Percentage of participants |
| Cohort 2: AMG 562 0.3 μg | Best Overall Response Per Lugano Classification | CMR | 0.0 Percentage of participants |
| Cohort 2: AMG 562 0.3 μg | Best Overall Response Per Lugano Classification | PMR | 0.0 Percentage of participants |
| Cohort 2: AMG 562 0.3 μg | Best Overall Response Per Lugano Classification | NMR | 0.0 Percentage of participants |
| Cohort 2: AMG 562 0.3 μg | Best Overall Response Per Lugano Classification | PMD | 100.0 Percentage of participants |
Secondary
Duration of Response (DOR)
DOR was defined as the time from the date of an initial objective response per Lugano classification to the earlier of progression or death. Participants who had not ended their response at the time of analysis had DOR censored at their last disease assessment date.
Time frame: Day 1 up to 2 years
Population: Safety Analysis Set - Objective Responders: All participants who received at least one dose of investigational product and had a CMR or PMR.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cohort 1: AMG 562 0.1 μg | Duration of Response (DOR) | NA Days |
Secondary
Half-life (t1/2) of AMG 562
Time frame: Day 22
Population: Pharmacokinetic (PK) Analysis Set: all participants who have received at least 1 dose of AMG 562 and have at least 1 PK sample collected.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: AMG 562 0.1 μg | Half-life (t1/2) of AMG 562 | 61.2 hours |
Secondary
Maximum Observed Concentration (Cmax) of AMG 562
Time frame: Day 1
Population: Pharmacokinetic (PK) Analysis Set: all participants who have received at least 1 dose of AMG 562 and have at least 1 PK sample collected.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: AMG 562 0.1 μg | Maximum Observed Concentration (Cmax) of AMG 562 | 0.0460 ng/mL | Standard Deviation 0.0173 |
Secondary
Objective Response Rate (ORR) Per Lugano Classification
ORR was defined as the percentage of participants with a confirmed complete metabolic response (CMR) or partial metabolic response (PMR) as defined by Lugano Classification. Per the Lugano Classification, positron emission tomography-computed tomography (PET-CT) were defined on the 5-point scale as scores 1, 2, or 3 (where 1 = no uptake above background; 2 = uptake \</= mediastinum; and 3 = uptake \> mediastinum but \</= liver) and PET-positive scans, as scores of 4 or 5 (where 4 = uptake moderately higher than liver; 5 = uptake markedly higher than liver and/or new lesions). CMR: score of 1, 2 or 3 in nodal or extranodal sites with or without a residual mass. PMR: score of 4 or 5 with reduced uptake compared with baseline and residual mass(es) of any size.
Time frame: Day 1 up to 2 years
Population: Safety Analysis Set: All participants who received at least one dose of investigational product.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1: AMG 562 0.1 μg | Objective Response Rate (ORR) Per Lugano Classification | CMR | 12.5 Percentage of participants |
| Cohort 1: AMG 562 0.1 μg | Objective Response Rate (ORR) Per Lugano Classification | PMR | 0.0 Percentage of participants |
| Cohort 2: AMG 562 0.3 μg | Objective Response Rate (ORR) Per Lugano Classification | CMR | 0.0 Percentage of participants |
| Cohort 2: AMG 562 0.3 μg | Objective Response Rate (ORR) Per Lugano Classification | PMR | 0.0 Percentage of participants |
Secondary
Overall Survival (OS)
OS was defined as the time from the date of Day 1 until death due to any cause. Any participant not known to have died at the time of analysis was censored based on the last recorded date on which the participant was alive.
Time frame: Day 1 up to 2 years
Population: Safety Analysis Set: All participants who received at least one dose of investigational product.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: AMG 562 0.1 μg | Overall Survival (OS) | NA Months |
| Cohort 2: AMG 562 0.3 μg | Overall Survival (OS) | NA Months |
Secondary
Progression Free Survival (PFS)
PFS was defined as the interval from Day 1 to the earlier of a lymphoma progression or death from any cause; otherwise, PFS was censored at the last radiographic assessment date. If a participant had no post baseline radiographic assessment and a vital status of alive or unknown, PFS was censored at Day 1.
Time frame: Day 1 up to 2 years
Population: Safety Analysis Set: All participants who received at least one dose of investigational product.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: AMG 562 0.1 μg | Progression Free Survival (PFS) | 0.9 Months |
| Cohort 2: AMG 562 0.3 μg | Progression Free Survival (PFS) | 1.0 Months |
Secondary
Time of Maximum Concentration (Tmax) of AMG 562
Time frame: Day 1
Population: Pharmacokinetic (PK) Analysis Set: all participants who have received at least 1 dose of AMG 562 and have at least 1 PK sample collected.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: AMG 562 0.1 μg | Time of Maximum Concentration (Tmax) of AMG 562 | 1.2 hours |