Lymphoma, Metastatic Cancer, Solid Tumor
Conditions
Keywords
Locally advanced/unresectable, Metastatic solid tumor, Lymphoma, Anti-LAG-3, LAG-3, LAG3
Brief summary
This is the first study to test Sym022 in humans. The primary purpose of this study is to see if Sym022 is safe and tolerable for patients with locally advanced/unresectable or metastatic solid tumor malignancies or lymphomas that are refractory to available therapy or for which no standard therapy is available.
Detailed description
This study will evaluate the preliminary safety, tolerability, and dose-limiting toxicities (DLTs) of Sym022, an anti-lymphocyte activation gene 3 (anti-LAG-3) monoclonal antibody (mAb). The goal is to establish the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of sequential escalating doses of Sym022 when administered once every 2 weeks (Q2W) by intravenous (IV) infusion to patient cohorts with locally advanced/ unresectable or metastatic solid tumor malignancies or lymphomas that are refractory to available therapy or for which no standard therapy is available. If an MTD is not identified, a maximum administered dose (MAD) will be determined. Sym022 will be given to patients in escalating dose cohorts; each patient will be given one fixed dose level.
Interventions
DRUGSym022
Sym022 is a recombinant, fully human antibody that binds LAG-3 and blocks the LAG-3/major histocompatibility complex class II (MHC-II) interaction, thus allowing for increased T-cell proliferation and cytokine production.
Sponsors
Symphogen A/S
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
* Male or female patients, ≥ 18 years of age at the time of obtaining informed consent. * Documented (histologically- or cytologically-proven) solid tumor malignancy that is locally advanced or metastatic; patients with documented lymphomas. * Malignancy (solid tumor or lymphoma) that is currently not amenable to surgical intervention due to either medical contraindications or nonresectability of the tumor. * Refractory to or intolerant of existing therapy(ies) known to provide clinical benefit. * Measurable or non-measurable disease according to RECIST v1.1 or RECIL 2017. * Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. * Not of childbearing potential or who agree to use a highly effective method of contraception during the study beginning within 2 weeks prior to the first dose and continuing until 6 months after the last dose of study drug.
Exclusion criteria
* Women who are pregnant or lactating, or intending to become pregnant before, during, or within 6 months after the last dose of study drug. Women of childbearing potential (WOCBP) and fertile men with WOCBP partner(s), not using and not willing to use a highly effective method of contraception. * Known, untreated central nervous system (CNS) or leptomeningeal metastases, or spinal cord compression, patients with any of the above not controlled by prior surgery or radiotherapy, or patients with symptoms suggesting CNS involvement for which treatment is required. * Hematologic malignancies other than lymphomas. * Active thrombosis, or a history of deep vein thrombosis (DVT) or pulmonary embolism (PE) within 4 weeks prior to Cycle 1/Day 1 (C1/D1) unless adequately treated and considered stable * Active uncontrolled bleeding or a known bleeding diathesis * Clinically significant cardiovascular disease or condition * Significant pulmonary disease or condition * Current or recent (within 6 months) significant gastrointestinal (GI) disease or condition. * An active, known, or suspected autoimmune disease, or a documented history of autoimmune disease or syndrome, requiring systemic steroids or other immunosuppressive medications. * History of organ transplantation (e.g. stem cell or solid organ transplant) * History of significant toxicities associated with previous administration of immune checkpoint inhibitors that necessitated permanent discontinuation of that therapy * Patients with unresolved \> Grade 1 toxicity associated with any prior antineoplastic therapy, with exceptions. * Inadequate recovery from any prior surgical procedure, or having undergone any major surgical procedure within 4 weeks prior to C1/D1. * Known history of human immunodeficiency virus (HIV) or known active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV). * Other Inhibitors of LAG-3 * Any antineoplastic agent for the primary malignancy (standard or investigational) without delayed toxicity within 4 weeks or 5 plasma half-lives, whichever is shortest, prior to first administration of study drug and during study * Any other investigational treatments within 4 weeks prior to and during study * Radiotherapy for target lesions within 4 weeks prior to first administration of study drug unless PD has been documented in the lesion following treatment, and during study. * Radiotherapy for non-target lesions within 1 week prior to first administration of study drug * Immunosuppressive or systemic hormonal therapy * Prophylactic use of hematopoietic growth factors within 1 week prior to first administration of study drug and during Cycle 1 of study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Assessment of Treatment Related Adverse Events (AEs). | 19 months | Assess the safety, tolerability and dose-limiting toxicities of Sym022 on a Q2W schedule to establish the MTD and/or RP2D. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Evaluation of Objective Response (OR) or Stable Disease (SD). | 13 months | Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1), Response Evaluation Criteria in Lymphomas 2017 (RECIL 2017), or Immunotherapeutics Response Evaluation Criteria in Solid Tumors (iRECIST), depending on tumor type. The numbers shown below correspond to the values related to RECIST v1.1. |
| Time to Progression (TTP) of Disease. | 13 months | Based on time of enrollment to first evidence of progression on imaging studies, as assessed by RECIST v1.1, RECIL 2017, or iRECIST, depending on tumor type. The numbers shown below correspond to the values related to RECIST v1.1. |
| Area Under the Concentration-time Curve in a Dosing Interval (AUC). | 19 months | Will be estimated using non-compartmental methods and actual timepoints. |
| Maximum Concentration (Cmax) | 0, 2, 4, 8, 24, 48, 168 hours and 336 hours as administered Q2W (every second week) | Will be derived from observed data. |
| Evaluation of the Immunogenicity of Sym022. | 19 months | Serum sampling and incidence (%) per dose level to assess the potential for anti-drug antibody (ADA) formation. Count of participants show the number of participants who were tested positive for anti-Sym022 ADA. |
| Trough Concentration (Ctrough) | 0, 2, 4, 8, 24, 48, 168 hours and 336 hours as administered Q2W (every second week) | Will be derived from observed data. |
| Terminal Elimination Half-life (T½) | 0, 2, 4, 8, 24, 48, 168 hours and 336 hours as administered Q2W (every second week) | Will be estimated using non-compartmental methods and actual timepoints. |
| Clearance (CL) | 0, 2, 4, 8, 24, 48, 168 hours and 336 hours as administered Q2W (every second week) | Will be estimated using non-compartmental methods and actual timepoints. |
| Time to Reach Maximum Concentration (Tmax) | 0, 2, 4, 8, 24, 48, 168 hours and 336 hours as administered Q2W (every second week) | Will be derived from observed data. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dose Level 1 0.3 mg/kg dosing of Sym022 every second week (Q2W) | 3 |
| Dose Level 2 1.0 mg/kg dosing of Sym022 every second week (Q2W) | 3 |
| Dose Level 3 3 mg/kg dosing of Sym022 every second week (Q2W) | 3 |
| Dose Level 4 10.0 mg/kg dosing of Sym022 every second week (Q2W) | 6 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Clinical Progression (Worsening of Clini | 0 | 1 | 0 | 0 |
| Overall Study | Documented Progressive Disease | 3 | 2 | 3 | 6 |
Baseline characteristics
| Characteristic | Dose Level 2 | Dose Level 3 | Dose Level 4 | Dose Level 1 | Total |
|---|---|---|---|---|---|
| Age, Continuous | 69 years STANDARD_DEVIATION 1.73 | 70.3 years STANDARD_DEVIATION 13.28 | 64.8 years STANDARD_DEVIATION 6.11 | 58 years STANDARD_DEVIATION 10.82 | 65.4 years STANDARD_DEVIATION 8.69 |
| ECOG PS 0 | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| ECOG PS 1 | 3 Participants | 2 Participants | 6 Participants | 3 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 2 Participants | 5 Participants | 3 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 3 Participants | 2 Participants | 4 Participants | 3 Participants | 12 Participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 4 Participants | 1 Participants | 7 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 | 1 / 3 | 5 / 6 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 6 / 6 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 | 1 / 3 | 2 / 6 |
Outcome results
Primary
Assessment of Treatment Related Adverse Events (AEs).
Assess the safety, tolerability and dose-limiting toxicities of Sym022 on a Q2W schedule to establish the MTD and/or RP2D.
Time frame: 19 months
Population: Patients evaluable for Maximum Tolerated Dose
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Level 1 | Assessment of Treatment Related Adverse Events (AEs). | 0 Patients with any DLT |
| Dose Level 2 | Assessment of Treatment Related Adverse Events (AEs). | 0 Patients with any DLT |
| Dose Level 3 | Assessment of Treatment Related Adverse Events (AEs). | 0 Patients with any DLT |
| Dose Level 4 | Assessment of Treatment Related Adverse Events (AEs). | 1 Patients with any DLT |
Secondary
Area Under the Concentration-time Curve in a Dosing Interval (AUC).
Will be estimated using non-compartmental methods and actual timepoints.
Time frame: 19 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Level 1 | Area Under the Concentration-time Curve in a Dosing Interval (AUC). | 926 hours*μg/mL | Standard Deviation 151 |
| Dose Level 2 | Area Under the Concentration-time Curve in a Dosing Interval (AUC). | 3860 hours*μg/mL | Standard Deviation 1010 |
| Dose Level 3 | Area Under the Concentration-time Curve in a Dosing Interval (AUC). | 10000 hours*μg/mL | Standard Deviation 1720 |
| Dose Level 4 | Area Under the Concentration-time Curve in a Dosing Interval (AUC). | 28300 hours*μg/mL | Standard Deviation 7110 |
Secondary
Clearance (CL)
Will be estimated using non-compartmental methods and actual timepoints.
Time frame: 0, 2, 4, 8, 24, 48, 168 hours and 336 hours as administered Q2W (every second week)
Population: Participants with an extrapolated AUC above 20% (for single dose administration) are not part of the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Level 1 | Clearance (CL) | 0.32 (mL/h)/kg | Standard Deviation 0.006 |
| Dose Level 2 | Clearance (CL) | 0.31 (mL/h)/kg | — |
| Dose Level 3 | Clearance (CL) | 0.24 (mL/h)/kg | Standard Deviation 0.06 |
Secondary
Evaluation of Objective Response (OR) or Stable Disease (SD).
Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1), Response Evaluation Criteria in Lymphomas 2017 (RECIL 2017), or Immunotherapeutics Response Evaluation Criteria in Solid Tumors (iRECIST), depending on tumor type. The numbers shown below correspond to the values related to RECIST v1.1.
Time frame: 13 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Level 1 | Evaluation of Objective Response (OR) or Stable Disease (SD). | 0 Participants |
| Dose Level 2 | Evaluation of Objective Response (OR) or Stable Disease (SD). | 0 Participants |
| Dose Level 3 | Evaluation of Objective Response (OR) or Stable Disease (SD). | 1 Participants |
| Dose Level 4 | Evaluation of Objective Response (OR) or Stable Disease (SD). | 0 Participants |
Secondary
Evaluation of the Immunogenicity of Sym022.
Serum sampling and incidence (%) per dose level to assess the potential for anti-drug antibody (ADA) formation. Count of participants show the number of participants who were tested positive for anti-Sym022 ADA.
Time frame: 19 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Level 1 | Evaluation of the Immunogenicity of Sym022. | 1 Participants |
| Dose Level 2 | Evaluation of the Immunogenicity of Sym022. | 0 Participants |
| Dose Level 3 | Evaluation of the Immunogenicity of Sym022. | 0 Participants |
| Dose Level 4 | Evaluation of the Immunogenicity of Sym022. | 0 Participants |
Secondary
Maximum Concentration (Cmax)
Will be derived from observed data.
Time frame: 0, 2, 4, 8, 24, 48, 168 hours and 336 hours as administered Q2W (every second week)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Level 1 | Maximum Concentration (Cmax) | 7.61 μg/mL | Standard Deviation 1.706 |
| Dose Level 2 | Maximum Concentration (Cmax) | 29.58 μg/mL | Standard Deviation 4.06 |
| Dose Level 3 | Maximum Concentration (Cmax) | 76.54 μg/mL | Standard Deviation 4.865 |
| Dose Level 4 | Maximum Concentration (Cmax) | 243.99 μg/mL | Standard Deviation 88.517 |
Secondary
Terminal Elimination Half-life (T½)
Will be estimated using non-compartmental methods and actual timepoints.
Time frame: 0, 2, 4, 8, 24, 48, 168 hours and 336 hours as administered Q2W (every second week)
Population: For some participants in Dose Level 4, the time span between the first and the last data point for the terminal rate constant did not cover at least 1.5 halflives, and these participants are therefore not part of the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Level 1 | Terminal Elimination Half-life (T½) | 119.48 hours | Standard Deviation 33.674 |
| Dose Level 2 | Terminal Elimination Half-life (T½) | 133.12 hours | Standard Deviation 35.491 |
| Dose Level 3 | Terminal Elimination Half-life (T½) | 152.94 hours | Standard Deviation 24.57 |
| Dose Level 4 | Terminal Elimination Half-life (T½) | 169.05 hours | Standard Deviation 18.83 |
Secondary
Time to Progression (TTP) of Disease.
Based on time of enrollment to first evidence of progression on imaging studies, as assessed by RECIST v1.1, RECIL 2017, or iRECIST, depending on tumor type. The numbers shown below correspond to the values related to RECIST v1.1.
Time frame: 13 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Level 1 | Time to Progression (TTP) of Disease. | 1.64 months |
| Dose Level 2 | Time to Progression (TTP) of Disease. | 5.59 months |
| Dose Level 3 | Time to Progression (TTP) of Disease. | 6.14 months |
| Dose Level 4 | Time to Progression (TTP) of Disease. | 1.58 months |
Secondary
Time to Reach Maximum Concentration (Tmax)
Will be derived from observed data.
Time frame: 0, 2, 4, 8, 24, 48, 168 hours and 336 hours as administered Q2W (every second week)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Level 1 | Time to Reach Maximum Concentration (Tmax) | 3.06 hours | Standard Deviation 2.018 |
| Dose Level 2 | Time to Reach Maximum Concentration (Tmax) | 4.52 hours | Standard Deviation 2.869 |
| Dose Level 3 | Time to Reach Maximum Concentration (Tmax) | 2.43 hours | Standard Deviation 2.271 |
| Dose Level 4 | Time to Reach Maximum Concentration (Tmax) | 1.98 hours | Standard Deviation 1.636 |
Secondary
Trough Concentration (Ctrough)
Will be derived from observed data.
Time frame: 0, 2, 4, 8, 24, 48, 168 hours and 336 hours as administered Q2W (every second week)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Level 1 | Trough Concentration (Ctrough) | 0.85 μg/mL | Standard Deviation 0.465 |
| Dose Level 2 | Trough Concentration (Ctrough) | 4.09 μg/mL | Standard Deviation 1.931 |
| Dose Level 3 | Trough Concentration (Ctrough) | 12.22 μg/mL | Standard Deviation 1.547 |
| Dose Level 4 | Trough Concentration (Ctrough) | 44.10 μg/mL | Standard Deviation 12.475 |