Phase 1
N=51
Japanese Phase 1 Trial of Sym004 in Solid Tumors
Solid Tumors
Bottom Line
View on ClinicalTrials.gov: NCT01955473 ↗Enrolled (actual)
51
Serious AEs
21.6%
Results posted
Mar 2017
Primary outcome: Primary: Number of Subjects With Dose Limiting Toxicities (DLTs) Determined in Part-A — 0; 0; 0; 0 subjects
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 1
- Interventions
- Sym004 (Drug)
- Age
- Adult, Older Adult · 20+ yrs
- Sex
- All
- Sponsor
- Merck KGaA, Darmstadt, Germany
- Primary completion
- Oct 2015
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Number of Subjects With Dose Limiting Toxicities (DLTs) Determined in Part-A |
0; 0; 0; 0 | — |
| PRIMARY Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death |
3; 6; 6; 6; 30; 0 | — |
| SECONDARY Area Under Concentration-time Curve (AUC) From Start of First Infusion to 168 Hours (AUC0-168h) at Week 1: Single Dose |
3685.5; 5893.1; 8957.3; 12783; 7073.5; 4109.0 | — |
| SECONDARY Area Under Concentration-time Curve (AUC) From Start of First Infusion to 168 Hours (AUC0-168h) for the Weekly Regimen at Week 4: Multiple Dose |
NA; 7111.1; 15298; 13053; NA; 9738.5 | — |
| SECONDARY Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to 168 Hours (AUC0-168h) at Week 1: Single Dose |
22.50; 23.24; 25.79; 21.69; 22.70; 25.09 | — |
| SECONDARY Dose Nornamized Area Under Concentration-time Curve (AUC) From Start of First Infusion to 168 Hours (AUC0-168h) for the Weekly Regimen at Week 4: Multiple Dose |
NA; 43.90; 43.45; 42.38; NA; 59.12 | — |
| SECONDARY Area Under Concentration-time Curve (AUC) From Start of First Infusion to 336 Hours (AUC0-336hours) For the Biweekly Regimen at Week 1: Single Dose |
17318; 22458 | — |
| SECONDARY Area Under Concentration-time Curve (AUC) From Start of First Infusion to 336 Hours (AUC0-336hours) For the Biweekly Regimen at Week 5: Multiple Dose |
24755; 32336 | — |
| SECONDARY Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to 336 Hours (AUC0-336hours) For the Biweekly Regimen at Week 1: Single Dose |
29.39; 38.11 | — |
| SECONDARY Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to 336 Hours (AUC0-336hours) For the Biweekly Regimen at Week 5: Multiple Dose |
42.45; 55.46 | — |
| SECONDARY Area Under Concentration-time Curve (AUC) From Start of First Infusion to Infinity (AUC0-inf) For the Biweekly Regimen at Week 1: Single Dose |
19896; 27554 | — |
| SECONDARY Area Under Concentration-time Curve (AUC) From Start of First Infusion to Infinity (AUC0-inf) For the Biweekly Regimen at Week 5: Multiple Dose |
30127; 43308 | — |
| SECONDARY Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to Infinity (AUC0-inf) at Week 1: Single Dose |
27.30; 30.33; 34.471; 33.77; 31.05; 31.86 | — |
| SECONDARY Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to Infinity (AUC0-inf) for the Weekly Regimen at Week 4: Multiple Dose |
NA; 59.65; 77.86; 72.22; NA; 94.91 | — |
| SECONDARY Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to Infinity (AUC0-inf) For the Biweekly Regimen at Week 5: Multiple Dose |
51.67; 74.28 | — |
| SECONDARY Terminal Half-life (t1/2) of Sym004 at Week 1: Single Dose |
66.478; 79.041; 82.865; 111.69; 87.257; 74.075 | — |
| SECONDARY Terminal Half-life (t1/2) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose |
NA; 85.228; 135.98; 132.14; NA; 117.8 | — |
| SECONDARY Terminal Half-life (t1/2) of Sym004 For the Biweekly Regimen at Week 5: Multiple Dose |
130.39; 163.6 | — |
| SECONDARY Clearance (CL) of Sym004 at Week 1: Single Dose |
0.036626; 0.032967; 0.029012; 0.029615; 0.032202; 0.031385 | — |
| SECONDARY Clearance at Steady-state (CLss) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose |
NA; 0.022778; 0.023015; 0.023589; NA; 0.017 | — |
| SECONDARY Clearance at Steady-state (CLss) of Sym004 for the Biweekly Regimen at Week 5: Multiple Dose |
0.023552; 0.018 | — |
| SECONDARY Volume of Distribution at the Elimination Phase (Vz) of Sym004 at Week 1: Single Dose |
3.5130; 3.7593; 3.4688; 4.7726; 4.0536; 3.3543 | — |
| SECONDARY Volume of Distribution at Steady State (Vss) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose |
NA; 2.7931; 4.4777; 4.4383; NA; 2.85 | — |
| SECONDARY Volume of Distribution at Steady State (Vss) of Sym004 for the Biweekly Regimen at Week 5: Multiple Dose |
4.3988; 4.20 | — |
| SECONDARY Maximum Serum Concentration (Cmax) of Sym004 at Week 1: Single Dose |
50.131; 85.088; 120.37; 157.71; 88.589; 54.660 | — |
| SECONDARY Maximum Serum Concentration (Cmax) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose |
76.094; 86.763; 181.62; 143.79; 89.26; 91.70 | — |
| SECONDARY Maximum Serum Concentration (Cmax) of Sym004 for the Biweekly Regimen at Week 5: Multiple Dose |
187.40; 224.0 | — |
| SECONDARY Dose Normalized Maximum Serum Concentration (Cmax) of Sym004 at Week 1: Single Dose |
0.306; 0.336; 0.346; 0.268; 0.284; 0.334 | — |
| SECONDARY Dose Nornamized Maximum Serum Concentration (Cmax) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose |
0.486; 0.524; 0.516; 0.466; 0.570; 0.553 | — |
| SECONDARY Dose Normalized Maximum Serum Concentration (Cmax) of Sym004 for the Biweekly Regimen at Week 5: Multiple Dose |
0.318; 0.380 | — |
| SECONDARY Trough Concentrations (Ctrough) of Sym004 |
8.38333; 16.3617; 29.4483; 45.1117; 20.1517; 19.8700 | — |
| SECONDARY Time to Reach Maximum Concentration (Tmax) of Sym004 at Week 1: Single Dose |
2.07; 5.12; 5.73; 7.21; 6.30; 2.05 | — |
| SECONDARY Time to Reach Maximum Concentration (Tmax) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose |
10.1; 5.94; 9.13; 5.13; 2.07; 6.13 | — |
| SECONDARY Time to Reach Maximum Concentration (Tmax) of Sym004 for the Biweekly Regimen at Week 5: Multiple Dose |
7.03; 5.28 | — |
| SECONDARY Percentage of Subjects With Best Overall Response |
0; 0; 0; 0; 0; 0 | — |
| SECONDARY Duration of Overall Response |
25.85; 10.40 | — |
| SECONDARY Percentage of Subjects With Disease Control |
66.7; 66.7; 50.0; 16.7; 56.7 | — |
| SECONDARY Duration of Disease Control |
6.10; 5.35; 24.60; 6.10; 5.90 | — |
| SECONDARY Time to Progression |
2.37; 2.33 | — |
| SECONDARY Progression-free Survival Time |
2.12; 2.30 | — |
| SECONDARY Anti-drug Antibody Titers |
— | — |
| SECONDARY Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) |
0.0; 0.0; 0.0; 0.0; 7.7; 0.0 | — |
| SECONDARY Percentage of Participants With EGFR Amplification Using Fluorescent in Situ Hybridization (FISH) Method. |
0.0; 0.0; 0.0; 0.0; 0.0; 0.0 | — |
Summary
This trial is to assess the safety and tolerability of Sym004, administered weekly or biweekly as monotherapy in Japanese subjects with advanced solid tumors.This study consisted of two parts, a dose-escalation part ("Part-A") and a dose-expansion part ("Part-B"). In Part-A, Sym004 will be administered weekly or biweekly as monotherapy in Japanese subjects with advanced solid tumors. In Part-B, Sym004 will be administered weekly as monotherapy to Japanese subjects with advanced esophageal squamous cell carcinoma (ESCC) as dose-expansion. A subject will receive Sym004 administration weekly at a dose that will determined to be the MTD or a dose that will lower than the MTD and determined to be appropriate with recommendation by Safety monitoring committee (SMC). The dose going to used in Part-B will be determined after safety confirmation of weekly regimens in Part-A of this trial.
Eligibility Criteria
Inclusion Criteria
- Japanese male or female subjects aged greater than or equal to 20 years at the time of informed consent signature
- Histologically or cytologically confirmed cancer
- Refractory or recurrent advanced late stage solid tumors without available therapeutic options which are likely to provide patient benefit (failure and/or intolerance to standard anti-cancer therapy)
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Life expectancy of at least 3 months
- Written informed consent given before any trial-related activities are carried out
- Other protocol defined inclusion criteria could apply
Exclusion Criteria
- Subjects with symptomatic brain metastases
- Subjects who received total resection or irradiation of the target lesion
- Received any of the following medications within 4 weeks before the first administration of Sym004 at Week 1: cytotoxic or cytostatic anti-cancer therapy, antibody therapy, tyrosine kinase inhibitors, and any investigational agent
- Received vaccine therapy as anticancer treatment within 12 weeks before the first administration of Sym004 at Week 1
- Diarrhea of greater than Grade 1 according to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 (v4.03)
- Skin manifestation of greater than Grade 1 according to NCI-CTCAE (v4.03)
- Magnesium of less than 0.9 milligram per deciliter (mg/dL)
- Abnormal organ or bone marrow function as defined in the protocol
- Received immunosuppressive agents (including systemic corticosteroids used at doses above 20 milligram per day (mg/day) of prednisolone or equivalent) within 4 weeks before the first administration of Sym004 at Week 1
- Active severe infection, any other concurrent disease or medical conditions that are deemed to interfere with the conduct of the trial as judged by the Investigator
- Known human immunodeficiency virus (HIV) positive, active Hepatitis B or C, or uncontrolled allergic conditions or allergy to Sym004 or its components
- Clinically significant cardiac disease or concurrent, uncontrolled medical condition
- Known previous Grade 3 to 4 infusion-related reactions, according to NCI-CTCAE (v4.03), with chimeric monoclonal antibodies
- Other protocol defined exclusion criteria could apply
Data sourced from ClinicalTrials.gov (NCT01955473). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.