Lymphoma, Metastatic Cancer, Solid Tumor
Conditions
Keywords
Locally advanced/unresectable, Metastatic solid tumor, Lymphoma, Anti-TIM-3, TIM-3, TIM3
Brief summary
This was the first study to test Sym023 in humans. The primary purpose of this study was to see if Sym023 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 evaluated the preliminary safety, tolerability, and dose-limiting toxicities (DLTs) of Sym023, a recombinant, fully human, anti-T-cell immunoglobulin and mucin-domain containing-3 (anti-TIM-3) monoclonal antibody (mAb). The goal was to establish the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of sequential escalating doses of Sym023 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 was not identified, a maximum administered dose (MAD) was to be determined. Sym023 was given to patients in escalating dose cohorts; each patient was given one fixed dose level.
Interventions
DRUGSym023
Sym023 is a recombinant, fully human antibody that binds TIM-3 and induces activation of immune cells.
Sponsors
Symphogen A/S
Study design
Allocation
NON_RANDOMIZED
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 ocular disease or condition, including history of autoimmune or inflammatory disorder. * 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 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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Assessment of Treatment Emergent Adverse Events (AEs) Meeting Dose-limiting Toxicity (DLT) Criteria. | 28 days | Assess the safety and tolerability of Sym023 on a Q2W (once every 2 weeks) schedule to establish the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). Assessment based on the occurrence of AEs meeting DLT criteria measured during Cycle 1. The MTD was to be determined by those DLTs that occurred during C1 in either more than 1 patient in a 3 to 6 patient cohort or ≥33.3% of patients in the event of an expanded 7 to 12 patient cohort. One patient in the 10.0 mg/kg dose cohort was not evaluable for MTD as she did not complete C1 for a reason other than drug toxicity (i.e., discontinuation after 1 dose due to patient withdrawal of consent). However, this patient was included in the evaluation of other outcomes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Evaluation of Objective Response (OR) or Stable Disease (SD) by RECIST v1.1 | 24 months | OR or SD Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1). The number of patients with confirmed or unconfirmed OR (partial or complete response) is presented. Duration of SD for patients with best overall response = SD was defined as the time from the day of first study treatment to the start of radiologic disease progression or death. If the patient did not have a radiological disease progression or death, the duration of SD was defined as the time from the day of first study treatment to the date of the last SD assessment. |
| Evaluation of Objective Response (OR) or Stable Disease (SD) by iRECIST | 24 months | OR or SD Assessed by Immunotherapeutics Response Evaluation Criteria in Solid Tumors (iRECIST). The number of patients with confirmed or unconfirmed OR (partial or complete response) is presented. Duration of SD for patients with best overall response = SD was defined as the time from the day of first study treatment to the start of radiologic disease progression or death. If the patient did not have a radiological disease progression or death, the duration of SD was defined as the time from the day of first study treatment to the date of the last SD assessment. |
| Evaluation of Objective Response (OR) or Stable Disease (SD) by RECIL 2017. | 24 months | OR or SD Assessed by Response Evaluation Criteria in Lymphomas 2017 (RECIL 2017) |
| Time to Progression (TTP) of Disease. | 24 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). | From before the start of the infusion to 168 hours after the end of the infusion | The AUC after first dose was estimated using non-compartmental methods. Blood samples for PK analysis were taken at the following timepoints: before the start of the infusion, at the end of the infusion and at 2, 4, 8, 24, 48 and 168 hours after the end of the infusion. Actual timepoints were recorded. |
| Evaluation of the Immunogenicity of Sym023. | Baseline up to 6-months follow-up, approximately 1 year | Serum sampling to assess the potential for anti-drug antibody (ADA) formation. The number of patients with positive samples at indicated visits is presented. |
| Time to Reach Maximum Concentration (Tmax) | From before the start of the infusion to 168 hours after the end of the infusion | Outcome measure after first dose was derived from observed data. Blood samples for PK analysis were taken at the following timepoints: before the start of the infusion, at the end of the infusion and at 2, 4, 8, 24, 48 and 168 hours after the end of the infusion. Actual timepoints were recorded. |
| Trough Concentration (Ctrough) | From before the start of the infusion to 168 hours after the end of the infusion | Outcome measure after first dose was derived from observed data. Blood samples for PK analysis were taken at the following timepoints: before the start of the infusion, at the end of the infusion and at 2, 4, 8, 24, 48 and 168 hours after the end of the infusion. Actual timepoints were recorded. |
| Terminal Elimination Half-life (T½) | From before the start of the infusion to 168 hours after the end of the infusion | Outcome measure after first dose was estimated using non-compartmental methods. Blood samples for PK analysis were taken at the following timepoints: before the start of the infusion, at the end of the infusion and at 2, 4, 8, 24, 48 and 168 hours after the end of the infusion. Actual timepoints were recorded. |
| Clearance (CL) | From before the start of the infusion to 168 hours after the end of the infusion | Outcome measure after first dose was estimated using non-compartmental methods. Blood samples for PK analysis were taken at the following timepoints: before the start of the infusion, at the end of the infusion and at 2, 4, 8, 24, 48 and 168 hours after the end of the infusion. Actual timepoints were recorded. |
| Maximum Concentration (Cmax) | From before the start of the infusion to 168 hours after the end of the infusion | Outcome measure after first dose was derived from observed data. Blood samples for PK analysis were taken at the following timepoints: before the start of the infusion, at the end of the infusion and at 2, 4, 8, 24, 48 and 168 hours after the end of the infusion. Actual timepoints were recorded. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sym023 0.03 mg/kg Sym023 0.03 mg/kg intravenous infusion once every 2 weeks | 1 |
| Sym023 0.1 mg/kg Sym023 0.1 mg/kg intravenous infusion once every 2 weeks | 1 |
| Sym023 0.3 mg/kg Sym023 0.3 mg/kg intravenous infusion once every 2 weeks | 3 |
| Sym023 1.0 mg/kg Sym023 1.0 mg/kg intravenous infusion once every 2 weeks | 3 |
| Sym023 3.0 mg/kg Sym023 3.0 mg/kg intravenous infusion once every 2 weeks | 3 |
| Sym023 10.0 mg/kg Sym023 10.0 mg/kg intravenous infusion once every 2 weeks | 7 |
| Sym023 20.0 mg/kg Sym023 20.0 mg/kg intravenous infusion once every 2 weeks | 6 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Clinical progression | 0 | 0 | 0 | 1 | 0 | 0 | 1 |
| Overall Study | Documented progressive disease | 1 | 0 | 3 | 1 | 3 | 5 | 4 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | Sym023 0.03 mg/kg | Sym023 0.1 mg/kg | Sym023 0.3 mg/kg | Sym023 1.0 mg/kg | Sym023 3.0 mg/kg | Sym023 10.0 mg/kg | Sym023 20.0 mg/kg | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 2 Participants | 2 Participants | 1 Participants | 8 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 1 Participants | 2 Participants | 1 Participants | 1 Participants | 5 Participants | 5 Participants | 16 Participants |
| Age, Continuous | 64 years | 64 years | 62 years | 66 years | 71 years | 54 years | 61 years | 63 years |
| ECOG PS 0 | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants | 5 Participants |
| ECOG PS 1 | 1 Participants | 1 Participants | 2 Participants | 2 Participants | 3 Participants | 6 Participants | 4 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 1 Participants | 3 Participants | 3 Participants | 2 Participants | 7 Participants | 6 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 1 Participants | 1 Participants | 3 Participants | 3 Participants | 2 Participants | 2 Participants | 5 Participants | 17 Participants |
| Region of Enrollment Canada | 0 participants | 0 participants | 0 participants | 1 participants | 1 participants | 2 participants | 1 participants | 5 participants |
| Region of Enrollment United States | 1 participants | 1 participants | 3 participants | 2 participants | 2 participants | 5 participants | 5 participants | 19 participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 2 Participants | 2 Participants | 3 Participants | 4 Participants | 4 Participants | 16 Participants |
| Sex: Female, Male Male | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 3 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 | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 1 | 3 / 3 | 0 / 3 | 2 / 3 | 1 / 7 | 1 / 6 |
| other Total, other adverse events | 1 / 1 | 1 / 1 | 3 / 3 | 3 / 3 | 3 / 3 | 7 / 7 | 5 / 6 |
| serious Total, serious adverse events | 0 / 1 | 1 / 1 | 0 / 3 | 0 / 3 | 0 / 3 | 2 / 7 | 1 / 6 |
Outcome results
Primary
Assessment of Treatment Emergent Adverse Events (AEs) Meeting Dose-limiting Toxicity (DLT) Criteria.
Assess the safety and tolerability of Sym023 on a Q2W (once every 2 weeks) schedule to establish the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). Assessment based on the occurrence of AEs meeting DLT criteria measured during Cycle 1. The MTD was to be determined by those DLTs that occurred during C1 in either more than 1 patient in a 3 to 6 patient cohort or ≥33.3% of patients in the event of an expanded 7 to 12 patient cohort. One patient in the 10.0 mg/kg dose cohort was not evaluable for MTD as she did not complete C1 for a reason other than drug toxicity (i.e., discontinuation after 1 dose due to patient withdrawal of consent). However, this patient was included in the evaluation of other outcomes.
Time frame: 28 days
Population: DLT analysis set of patients who completed treatment dosing in a 4-week (28 day) period that was Cycle 1. One patient out of 7 patients in Group 10mg/kg did not complete Cycle 1 and are not included in the participants analyzed
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sym023 0.03 mg/kg | Assessment of Treatment Emergent Adverse Events (AEs) Meeting Dose-limiting Toxicity (DLT) Criteria. | 0 Number of DLTs |
| Sym023 0.1 mg/kg | Assessment of Treatment Emergent Adverse Events (AEs) Meeting Dose-limiting Toxicity (DLT) Criteria. | 0 Number of DLTs |
| Sym023 0.3 mg/kg | Assessment of Treatment Emergent Adverse Events (AEs) Meeting Dose-limiting Toxicity (DLT) Criteria. | 0 Number of DLTs |
| Sym023 1.0 mg/kg | Assessment of Treatment Emergent Adverse Events (AEs) Meeting Dose-limiting Toxicity (DLT) Criteria. | 0 Number of DLTs |
| Sym023 3.0 mg/kg | Assessment of Treatment Emergent Adverse Events (AEs) Meeting Dose-limiting Toxicity (DLT) Criteria. | 0 Number of DLTs |
| Sym023 10.0 mg/kg | Assessment of Treatment Emergent Adverse Events (AEs) Meeting Dose-limiting Toxicity (DLT) Criteria. | 0 Number of DLTs |
| Sym023 20.0 mg/kg | Assessment of Treatment Emergent Adverse Events (AEs) Meeting Dose-limiting Toxicity (DLT) Criteria. | 0 Number of DLTs |
Secondary
Area Under the Concentration-time Curve in a Dosing Interval (AUC).
The AUC after first dose was estimated using non-compartmental methods. Blood samples for PK analysis were taken at the following timepoints: before the start of the infusion, at the end of the infusion and at 2, 4, 8, 24, 48 and 168 hours after the end of the infusion. Actual timepoints were recorded.
Time frame: From before the start of the infusion to 168 hours after the end of the infusion
Population: Pharmacokinetic analysis set (same as the full analysis set) of all randomised and treated patients
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Sym023 0.03 mg/kg | Area Under the Concentration-time Curve in a Dosing Interval (AUC). | 70 h*μg/mL |
| Sym023 0.1 mg/kg | Area Under the Concentration-time Curve in a Dosing Interval (AUC). | 176 h*μg/mL |
| Sym023 0.3 mg/kg | Area Under the Concentration-time Curve in a Dosing Interval (AUC). | 878 h*μg/mL |
| Sym023 1.0 mg/kg | Area Under the Concentration-time Curve in a Dosing Interval (AUC). | 3193 h*μg/mL |
| Sym023 3.0 mg/kg | Area Under the Concentration-time Curve in a Dosing Interval (AUC). | 8062 h*μg/mL |
| Sym023 10.0 mg/kg | Area Under the Concentration-time Curve in a Dosing Interval (AUC). | 30581 h*μg/mL |
| Sym023 20.0 mg/kg | Area Under the Concentration-time Curve in a Dosing Interval (AUC). | 77262 h*μg/mL |
Secondary
Clearance (CL)
Outcome measure after first dose was estimated using non-compartmental methods. Blood samples for PK analysis were taken at the following timepoints: before the start of the infusion, at the end of the infusion and at 2, 4, 8, 24, 48 and 168 hours after the end of the infusion. Actual timepoints were recorded.
Time frame: From before the start of the infusion to 168 hours after the end of the infusion
Population: Pharmacokinetic analysis set (same as the full analysis set) of all randomized and treated patients. Data for cohort 0.03mg/kg: Clearence could not be accurately calculated since too few datapoint within the elimination period
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Sym023 0.1 mg/kg | Clearance (CL) | 0.501 mL/h)/kg |
| Sym023 0.3 mg/kg | Clearance (CL) | 0.364 mL/h)/kg |
| Sym023 3.0 mg/kg | Clearance (CL) | 0.582 mL/h)/kg |
Secondary
Evaluation of Objective Response (OR) or Stable Disease (SD) by iRECIST
OR or SD Assessed by Immunotherapeutics Response Evaluation Criteria in Solid Tumors (iRECIST). The number of patients with confirmed or unconfirmed OR (partial or complete response) is presented. Duration of SD for patients with best overall response = SD was defined as the time from the day of first study treatment to the start of radiologic disease progression or death. If the patient did not have a radiological disease progression or death, the duration of SD was defined as the time from the day of first study treatment to the date of the last SD assessment.
Time frame: 24 months
Population: Full analysis set of randomised and treated patients who were evaluable for response. One patient out of 7 in group 10mg/kg was not evaluable for response
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sym023 0.03 mg/kg | Evaluation of Objective Response (OR) or Stable Disease (SD) by iRECIST | iSD ≤16 weeks | 0 Participants |
| Sym023 0.03 mg/kg | Evaluation of Objective Response (OR) or Stable Disease (SD) by iRECIST | iSD >16 weeks | 0 Participants |
| Sym023 0.03 mg/kg | Evaluation of Objective Response (OR) or Stable Disease (SD) by iRECIST | OR rate | 0 Participants |
| Sym023 0.1 mg/kg | Evaluation of Objective Response (OR) or Stable Disease (SD) by iRECIST | iSD >16 weeks | 1 Participants |
| Sym023 0.1 mg/kg | Evaluation of Objective Response (OR) or Stable Disease (SD) by iRECIST | OR rate | 0 Participants |
| Sym023 0.1 mg/kg | Evaluation of Objective Response (OR) or Stable Disease (SD) by iRECIST | iSD ≤16 weeks | 0 Participants |
| Sym023 0.3 mg/kg | Evaluation of Objective Response (OR) or Stable Disease (SD) by iRECIST | iSD ≤16 weeks | 0 Participants |
| Sym023 0.3 mg/kg | Evaluation of Objective Response (OR) or Stable Disease (SD) by iRECIST | OR rate | 0 Participants |
| Sym023 0.3 mg/kg | Evaluation of Objective Response (OR) or Stable Disease (SD) by iRECIST | iSD >16 weeks | 0 Participants |
| Sym023 1.0 mg/kg | Evaluation of Objective Response (OR) or Stable Disease (SD) by iRECIST | iSD >16 weeks | 1 Participants |
| Sym023 1.0 mg/kg | Evaluation of Objective Response (OR) or Stable Disease (SD) by iRECIST | OR rate | 0 Participants |
| Sym023 1.0 mg/kg | Evaluation of Objective Response (OR) or Stable Disease (SD) by iRECIST | iSD ≤16 weeks | 2 Participants |
| Sym023 3.0 mg/kg | Evaluation of Objective Response (OR) or Stable Disease (SD) by iRECIST | iSD >16 weeks | 1 Participants |
| Sym023 3.0 mg/kg | Evaluation of Objective Response (OR) or Stable Disease (SD) by iRECIST | OR rate | 0 Participants |
| Sym023 3.0 mg/kg | Evaluation of Objective Response (OR) or Stable Disease (SD) by iRECIST | iSD ≤16 weeks | 1 Participants |
| Sym023 10.0 mg/kg | Evaluation of Objective Response (OR) or Stable Disease (SD) by iRECIST | OR rate | 0 Participants |
| Sym023 10.0 mg/kg | Evaluation of Objective Response (OR) or Stable Disease (SD) by iRECIST | iSD ≤16 weeks | 0 Participants |
| Sym023 10.0 mg/kg | Evaluation of Objective Response (OR) or Stable Disease (SD) by iRECIST | iSD >16 weeks | 0 Participants |
| Sym023 20.0 mg/kg | Evaluation of Objective Response (OR) or Stable Disease (SD) by iRECIST | iSD ≤16 weeks | 4 Participants |
| Sym023 20.0 mg/kg | Evaluation of Objective Response (OR) or Stable Disease (SD) by iRECIST | iSD >16 weeks | 1 Participants |
| Sym023 20.0 mg/kg | Evaluation of Objective Response (OR) or Stable Disease (SD) by iRECIST | OR rate | 0 Participants |
Secondary
Evaluation of Objective Response (OR) or Stable Disease (SD) by RECIL 2017.
OR or SD Assessed by Response Evaluation Criteria in Lymphomas 2017 (RECIL 2017)
Time frame: 24 months
Population: No lymphomas were recorded in this trial, therefore it was not possible to do the RECIL evaluation.
Secondary
Evaluation of Objective Response (OR) or Stable Disease (SD) by RECIST v1.1
OR or SD Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1). The number of patients with confirmed or unconfirmed OR (partial or complete response) is presented. Duration of SD for patients with best overall response = SD was defined as the time from the day of first study treatment to the start of radiologic disease progression or death. If the patient did not have a radiological disease progression or death, the duration of SD was defined as the time from the day of first study treatment to the date of the last SD assessment.
Time frame: 24 months
Population: Full analysis set of randomised and treated patients who was evaluable for response. One patient out of 7 in group 10mg/kg was not evaluable for response
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sym023 0.03 mg/kg | Evaluation of Objective Response (OR) or Stable Disease (SD) by RECIST v1.1 | SD ≤16 weeks | 0 Participants |
| Sym023 0.03 mg/kg | Evaluation of Objective Response (OR) or Stable Disease (SD) by RECIST v1.1 | SD >16 weeks | 0 Participants |
| Sym023 0.03 mg/kg | Evaluation of Objective Response (OR) or Stable Disease (SD) by RECIST v1.1 | OR rate | 0 Participants |
| Sym023 0.1 mg/kg | Evaluation of Objective Response (OR) or Stable Disease (SD) by RECIST v1.1 | SD >16 weeks | 1 Participants |
| Sym023 0.1 mg/kg | Evaluation of Objective Response (OR) or Stable Disease (SD) by RECIST v1.1 | OR rate | 0 Participants |
| Sym023 0.1 mg/kg | Evaluation of Objective Response (OR) or Stable Disease (SD) by RECIST v1.1 | SD ≤16 weeks | 0 Participants |
| Sym023 0.3 mg/kg | Evaluation of Objective Response (OR) or Stable Disease (SD) by RECIST v1.1 | SD ≤16 weeks | 0 Participants |
| Sym023 0.3 mg/kg | Evaluation of Objective Response (OR) or Stable Disease (SD) by RECIST v1.1 | OR rate | 0 Participants |
| Sym023 0.3 mg/kg | Evaluation of Objective Response (OR) or Stable Disease (SD) by RECIST v1.1 | SD >16 weeks | 0 Participants |
| Sym023 1.0 mg/kg | Evaluation of Objective Response (OR) or Stable Disease (SD) by RECIST v1.1 | SD >16 weeks | 0 Participants |
| Sym023 1.0 mg/kg | Evaluation of Objective Response (OR) or Stable Disease (SD) by RECIST v1.1 | OR rate | 0 Participants |
| Sym023 1.0 mg/kg | Evaluation of Objective Response (OR) or Stable Disease (SD) by RECIST v1.1 | SD ≤16 weeks | 2 Participants |
| Sym023 3.0 mg/kg | Evaluation of Objective Response (OR) or Stable Disease (SD) by RECIST v1.1 | SD >16 weeks | 0 Participants |
| Sym023 3.0 mg/kg | Evaluation of Objective Response (OR) or Stable Disease (SD) by RECIST v1.1 | OR rate | 0 Participants |
| Sym023 3.0 mg/kg | Evaluation of Objective Response (OR) or Stable Disease (SD) by RECIST v1.1 | SD ≤16 weeks | 2 Participants |
| Sym023 10.0 mg/kg | Evaluation of Objective Response (OR) or Stable Disease (SD) by RECIST v1.1 | OR rate | 0 Participants |
| Sym023 10.0 mg/kg | Evaluation of Objective Response (OR) or Stable Disease (SD) by RECIST v1.1 | SD ≤16 weeks | 0 Participants |
| Sym023 10.0 mg/kg | Evaluation of Objective Response (OR) or Stable Disease (SD) by RECIST v1.1 | SD >16 weeks | 0 Participants |
| Sym023 20.0 mg/kg | Evaluation of Objective Response (OR) or Stable Disease (SD) by RECIST v1.1 | SD ≤16 weeks | 3 Participants |
| Sym023 20.0 mg/kg | Evaluation of Objective Response (OR) or Stable Disease (SD) by RECIST v1.1 | SD >16 weeks | 2 Participants |
| Sym023 20.0 mg/kg | Evaluation of Objective Response (OR) or Stable Disease (SD) by RECIST v1.1 | OR rate | 0 Participants |
Secondary
Evaluation of the Immunogenicity of Sym023.
Serum sampling to assess the potential for anti-drug antibody (ADA) formation. The number of patients with positive samples at indicated visits is presented.
Time frame: Baseline up to 6-months follow-up, approximately 1 year
Population: Full analysis set of all randomised and treated patients
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sym023 0.03 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 4 days 1 and 15 | 0 Participants |
| Sym023 0.03 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 2 day 1 | 0 Participants |
| Sym023 0.03 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 5 day 1 | 0 Participants |
| Sym023 0.03 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 7 day 1 | 0 Participants |
| Sym023 0.03 mg/kg | Evaluation of the Immunogenicity of Sym023. | End of treatment | 0 Participants |
| Sym023 0.03 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 1 days 1 and 15 | 0 Participants |
| Sym023 0.03 mg/kg | Evaluation of the Immunogenicity of Sym023. | 3-month follow up | 0 Participants |
| Sym023 0.03 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 6 day 1 | 0 Participants |
| Sym023 0.03 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 3 days 1 and 15 | 0 Participants |
| Sym023 0.03 mg/kg | Evaluation of the Immunogenicity of Sym023. | 1-month follow up | 0 Participants |
| Sym023 0.1 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 3 days 1 and 15 | 0 Participants |
| Sym023 0.1 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 6 day 1 | 0 Participants |
| Sym023 0.1 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 4 days 1 and 15 | 0 Participants |
| Sym023 0.1 mg/kg | Evaluation of the Immunogenicity of Sym023. | End of treatment | 1 Participants |
| Sym023 0.1 mg/kg | Evaluation of the Immunogenicity of Sym023. | 1-month follow up | 1 Participants |
| Sym023 0.1 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 1 days 1 and 15 | 0 Participants |
| Sym023 0.1 mg/kg | Evaluation of the Immunogenicity of Sym023. | 3-month follow up | 0 Participants |
| Sym023 0.1 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 2 day 1 | 0 Participants |
| Sym023 0.1 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 5 day 1 | 1 Participants |
| Sym023 0.1 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 7 day 1 | 1 Participants |
| Sym023 0.3 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 6 day 1 | 0 Participants |
| Sym023 0.3 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 7 day 1 | 0 Participants |
| Sym023 0.3 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 1 days 1 and 15 | 0 Participants |
| Sym023 0.3 mg/kg | Evaluation of the Immunogenicity of Sym023. | 3-month follow up | 0 Participants |
| Sym023 0.3 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 2 day 1 | 0 Participants |
| Sym023 0.3 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 3 days 1 and 15 | 0 Participants |
| Sym023 0.3 mg/kg | Evaluation of the Immunogenicity of Sym023. | 1-month follow up | 1 Participants |
| Sym023 0.3 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 4 days 1 and 15 | 0 Participants |
| Sym023 0.3 mg/kg | Evaluation of the Immunogenicity of Sym023. | End of treatment | 1 Participants |
| Sym023 0.3 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 5 day 1 | 0 Participants |
| Sym023 1.0 mg/kg | Evaluation of the Immunogenicity of Sym023. | End of treatment | 1 Participants |
| Sym023 1.0 mg/kg | Evaluation of the Immunogenicity of Sym023. | 1-month follow up | 1 Participants |
| Sym023 1.0 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 6 day 1 | 0 Participants |
| Sym023 1.0 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 5 day 1 | 1 Participants |
| Sym023 1.0 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 3 days 1 and 15 | 0 Participants |
| Sym023 1.0 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 2 day 1 | 0 Participants |
| Sym023 1.0 mg/kg | Evaluation of the Immunogenicity of Sym023. | 3-month follow up | 1 Participants |
| Sym023 1.0 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 1 days 1 and 15 | 0 Participants |
| Sym023 1.0 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 7 day 1 | 0 Participants |
| Sym023 1.0 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 4 days 1 and 15 | 0 Participants |
| Sym023 3.0 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 1 days 1 and 15 | 0 Participants |
| Sym023 3.0 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 3 days 1 and 15 | 0 Participants |
| Sym023 3.0 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 2 day 1 | 0 Participants |
| Sym023 3.0 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 4 days 1 and 15 | 0 Participants |
| Sym023 3.0 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 5 day 1 | 0 Participants |
| Sym023 3.0 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 6 day 1 | 0 Participants |
| Sym023 3.0 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 7 day 1 | 0 Participants |
| Sym023 3.0 mg/kg | Evaluation of the Immunogenicity of Sym023. | End of treatment | 0 Participants |
| Sym023 3.0 mg/kg | Evaluation of the Immunogenicity of Sym023. | 1-month follow up | 0 Participants |
| Sym023 3.0 mg/kg | Evaluation of the Immunogenicity of Sym023. | 3-month follow up | 0 Participants |
| Sym023 10.0 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 7 day 1 | 0 Participants |
| Sym023 10.0 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 5 day 1 | 0 Participants |
| Sym023 10.0 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 4 days 1 and 15 | 0 Participants |
| Sym023 10.0 mg/kg | Evaluation of the Immunogenicity of Sym023. | End of treatment | 0 Participants |
| Sym023 10.0 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 3 days 1 and 15 | 0 Participants |
| Sym023 10.0 mg/kg | Evaluation of the Immunogenicity of Sym023. | 3-month follow up | 0 Participants |
| Sym023 10.0 mg/kg | Evaluation of the Immunogenicity of Sym023. | 1-month follow up | 0 Participants |
| Sym023 10.0 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 2 day 1 | 0 Participants |
| Sym023 10.0 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 6 day 1 | 0 Participants |
| Sym023 10.0 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 1 days 1 and 15 | 0 Participants |
| Sym023 20.0 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 2 day 1 | 0 Participants |
| Sym023 20.0 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 7 day 1 | 0 Participants |
| Sym023 20.0 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 1 days 1 and 15 | 0 Participants |
| Sym023 20.0 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 4 days 1 and 15 | 0 Participants |
| Sym023 20.0 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 6 day 1 | 0 Participants |
| Sym023 20.0 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 3 days 1 and 15 | 0 Participants |
| Sym023 20.0 mg/kg | Evaluation of the Immunogenicity of Sym023. | 3-month follow up | 0 Participants |
| Sym023 20.0 mg/kg | Evaluation of the Immunogenicity of Sym023. | 1-month follow up | 0 Participants |
| Sym023 20.0 mg/kg | Evaluation of the Immunogenicity of Sym023. | End of treatment | 0 Participants |
| Sym023 20.0 mg/kg | Evaluation of the Immunogenicity of Sym023. | Cycle 5 day 1 | 0 Participants |
Secondary
Maximum Concentration (Cmax)
Outcome measure after first dose was derived from observed data. Blood samples for PK analysis were taken at the following timepoints: before the start of the infusion, at the end of the infusion and at 2, 4, 8, 24, 48 and 168 hours after the end of the infusion. Actual timepoints were recorded.
Time frame: From before the start of the infusion to 168 hours after the end of the infusion
Population: Pharmacokinetic analysis set (same as the full analysis set) of all randomised and treated patients
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Sym023 0.03 mg/kg | Maximum Concentration (Cmax) | 0.85 μg/mL |
| Sym023 0.1 mg/kg | Maximum Concentration (Cmax) | 1.98 μg/mL |
| Sym023 0.3 mg/kg | Maximum Concentration (Cmax) | 7.94 μg/mL |
| Sym023 1.0 mg/kg | Maximum Concentration (Cmax) | 23.71 μg/mL |
| Sym023 3.0 mg/kg | Maximum Concentration (Cmax) | 68.03 μg/mL |
| Sym023 10.0 mg/kg | Maximum Concentration (Cmax) | 232.11 μg/mL |
| Sym023 20.0 mg/kg | Maximum Concentration (Cmax) | 470.24 μg/mL |
Secondary
Terminal Elimination Half-life (T½)
Outcome measure after first dose was estimated using non-compartmental methods. Blood samples for PK analysis were taken at the following timepoints: before the start of the infusion, at the end of the infusion and at 2, 4, 8, 24, 48 and 168 hours after the end of the infusion. Actual timepoints were recorded.
Time frame: From before the start of the infusion to 168 hours after the end of the infusion
Population: Pharmacokinetic analysis set (same as the full analysis set) of all randomised and treated patients. Data for cohort 0.03mg/kg: T½ could not be accurately calculated due to few datapoint within the elimination period
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Sym023 0.03 mg/kg | Terminal Elimination Half-life (T½) | NA hours |
| Sym023 0.1 mg/kg | Terminal Elimination Half-life (T½) | 105.10 hours |
| Sym023 0.3 mg/kg | Terminal Elimination Half-life (T½) | 153.49 hours |
| Sym023 3.0 mg/kg | Terminal Elimination Half-life (T½) | 140.60 hours |
| Sym023 10.0 mg/kg | Terminal Elimination Half-life (T½) | 185.22 hours |
| Sym023 20.0 mg/kg | Terminal Elimination Half-life (T½) | 203.07 hours |
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: 24 months
Population: The full analysis set of randomized and treated patients who were evaluable for response. One patient out of 7 in group 10mg/kg was not evaluable for response or time to progression (TTP) as the patient left trial due to Adverse Event
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sym023 0.03 mg/kg | Time to Progression (TTP) of Disease. | 1.81 months |
| Sym023 0.1 mg/kg | Time to Progression (TTP) of Disease. | 7.89 months |
| Sym023 0.3 mg/kg | Time to Progression (TTP) of Disease. | 1.18 months |
| Sym023 1.0 mg/kg | Time to Progression (TTP) of Disease. | 3.48 months |
| Sym023 3.0 mg/kg | Time to Progression (TTP) of Disease. | 1.28 months |
| Sym023 10.0 mg/kg | Time to Progression (TTP) of Disease. | 1.68 months |
| Sym023 20.0 mg/kg | Time to Progression (TTP) of Disease. | 5.36 months |
Secondary
Time to Reach Maximum Concentration (Tmax)
Outcome measure after first dose was derived from observed data. Blood samples for PK analysis were taken at the following timepoints: before the start of the infusion, at the end of the infusion and at 2, 4, 8, 24, 48 and 168 hours after the end of the infusion. Actual timepoints were recorded.
Time frame: From before the start of the infusion to 168 hours after the end of the infusion
Population: Pharmacokinetic analysis set (same as the full analysis set) of all randomised and treated patients
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Sym023 0.03 mg/kg | Time to Reach Maximum Concentration (Tmax) | 4.5 hours |
| Sym023 0.1 mg/kg | Time to Reach Maximum Concentration (Tmax) | 0.6 hours |
| Sym023 0.3 mg/kg | Time to Reach Maximum Concentration (Tmax) | 1.2 hours |
| Sym023 1.0 mg/kg | Time to Reach Maximum Concentration (Tmax) | 4.5 hours |
| Sym023 3.0 mg/kg | Time to Reach Maximum Concentration (Tmax) | 1.8 hours |
| Sym023 10.0 mg/kg | Time to Reach Maximum Concentration (Tmax) | 3.4 hours |
| Sym023 20.0 mg/kg | Time to Reach Maximum Concentration (Tmax) | 7.3 hours |
Secondary
Trough Concentration (Ctrough)
Outcome measure after first dose was derived from observed data. Blood samples for PK analysis were taken at the following timepoints: before the start of the infusion, at the end of the infusion and at 2, 4, 8, 24, 48 and 168 hours after the end of the infusion. Actual timepoints were recorded.
Time frame: From before the start of the infusion to 168 hours after the end of the infusion
Population: Pharmacokinetic analysis set (same as the full analysis set) of all randomized and treated patients. Data for cohort 0.03mg/kg: Ctrough at 168 hours were below the limit of quantification, hence no reported data
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Sym023 0.03 mg/kg | Trough Concentration (Ctrough) | NA μg/mL |
| Sym023 0.1 mg/kg | Trough Concentration (Ctrough) | 0.16 μg/mL |
| Sym023 0.3 mg/kg | Trough Concentration (Ctrough) | 1.26 μg/mL |
| Sym023 1.0 mg/kg | Trough Concentration (Ctrough) | 6.39 μg/mL |
| Sym023 3.0 mg/kg | Trough Concentration (Ctrough) | 12.88 μg/mL |
| Sym023 10.0 mg/kg | Trough Concentration (Ctrough) | 74.33 μg/mL |
| Sym023 20.0 mg/kg | Trough Concentration (Ctrough) | 146.96 μg/mL |