Clinical trial NCT01955473: Japanese Phase 1 Trial of Sym004 in Solid Tumors
Official title: A Japanese Phase I Open-label Dose-escalation Trial of Sym004 Administered as Monotherapy in Japanese Subjects With Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Solid Tumors
Keywords: Solid tumors
Sym004
Phase 1
Lead sponsor: Merck KGaA, Darmstadt, Germany
Sponsor class: INDUSTRY
First posted: 2013-10-07
Enrollment: 51
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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

Primary outcomes:
measure: Number of Subjects With Dose Limiting Toxicities (DLTs) Determined in Part-A
timeFrame: Week 1 up to Week 4 (Part A)
measure: Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death
timeFrame: Baseline up to 4 weeks after the last Sym004 administration, up to a maximum of 41.1 weeks
Secondary outcomes:
measure: Area Under Concentration-time Curve (AUC) From Start of First Infusion to 168 Hours (AUC0-168h) at Week 1: Single Dose
timeFrame: Pre-infusion, end of infusion, 4, 8, 12, 24, 48 and 168 hours post-infusion at Week 1
measure: 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
timeFrame: Pre-infusion, end of infusion, 4, 8, 12, 24, and 168 hours post-infusion at Week 4
measure: Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to 168 Hours (AUC0-168h) at Week 1: Single Dose
timeFrame: Pre-infusion, end of infusion, 4, 8, 12, 24, 48 and 168 hours post-infusion at Week 1
measure: 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
timeFrame: Pre-infusion, end of infusion, 4, 8, 12, 24, and 168 hours post-infusion at Week 4
measure: 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
timeFrame: Pre-infusion, end of infusion, 4, 8, 12, 24, 48, 168, 336 hours post-infusion at Week 1
measure: 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
timeFrame: Pre-infusion, end of infusion, 4, 8, 12, 24, 168 and 336 hours post-infusion at Week 5
measure: 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
timeFrame: Pre-infusion, end of infusion, 4, 8, 12, 24, 48, 168, 336 hours post-infusion at Week 1
measure: 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
timeFrame: Pre-infusion, end of infusion, 4, 8, 12, 24, 168 and 336 hours post-infusion at Week 5
measure: Area Under Concentration-time Curve (AUC) From Start of First Infusion to Infinity (AUC0-inf) For the Biweekly Regimen at Week 1: Single Dose
timeFrame: Pre-infusion, end of infusion, 4, 8, 12, 24, and 48 hours post-infusion at Week 1
measure: Area Under Concentration-time Curve (AUC) From Start of First Infusion to Infinity (AUC0-inf) For the Biweekly Regimen at Week 5: Multiple Dose
timeFrame: Pre-infusion, end of infusion, 4, 8, 12 and 24 hours post-infusion at Week 5
measure: Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to Infinity (AUC0-inf) at Week 1: Single Dose
timeFrame: Pre-infusion, end of infusion, 4, 8, 12, 24, and 48 hours post-infusion at Week 1
measure: 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
timeFrame: Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 4
measure: 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
timeFrame: Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 5
measure: Terminal Half-life (t1/2) of Sym004 at Week 1: Single Dose
timeFrame: Pre-infusion, end of infusion, 4, 8, 12, 24, 48 hours post-infusion at Week 1
measure: Terminal Half-life (t1/2) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose
timeFrame: Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 4
measure: Terminal Half-life (t1/2) of Sym004 For the Biweekly Regimen at Week 5: Multiple Dose
timeFrame: Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 5
measure: Clearance (CL) of Sym004 at Week 1: Single Dose
timeFrame: Pre-infusion, end of infusion, 4, 8, 12, 24, 48 hours post-infusion at Week 1
measure: Clearance at Steady-state (CLss) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose
timeFrame: Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 4
measure: Clearance at Steady-state (CLss) of Sym004 for the Biweekly Regimen at Week 5: Multiple Dose
timeFrame: Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 5
measure: Volume of Distribution at the Elimination Phase (Vz) of Sym004 at Week 1: Single Dose
timeFrame: Pre-infusion, end of infusion, 4, 8, 12, 24, 48 hours post-infusion at Week 1
measure: Volume of Distribution at Steady State (Vss) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose
timeFrame: Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 4
measure: Volume of Distribution at Steady State (Vss) of Sym004 for the Biweekly Regimen at Week 5: Multiple Dose
timeFrame: Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 5
measure: Maximum Serum Concentration (Cmax) of Sym004 at Week 1: Single Dose
timeFrame: Pre-infusion, end of infusion, 4, 8, 12, 24, 48 hours post-infusion at Week 1
measure: Maximum Serum Concentration (Cmax) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose
timeFrame: Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 4
measure: Maximum Serum Concentration (Cmax) of Sym004 for the Biweekly Regimen at Week 5: Multiple Dose
timeFrame: Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 5
measure: Dose Normalized Maximum Serum Concentration (Cmax) of Sym004 at Week 1: Single Dose
timeFrame: Pre-infusion, end of infusion, 4, 8, 12, 24, 48 hours post-infusion at Week 1
measure: Dose Nornamized Maximum Serum Concentration (Cmax) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose
timeFrame: Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 4
measure: Dose Normalized Maximum Serum Concentration (Cmax) of Sym004 for the Biweekly Regimen at Week 5: Multiple Dose
timeFrame: Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 5
measure: Trough Concentrations (Ctrough) of Sym004
timeFrame: Pre-infusion at Week 2, 3, 5, 6, 7, 8, End of Trial (up to 41.1 weeks) and Follow up (up to 45.1 Weeks)
measure: Time to Reach Maximum Concentration (Tmax) of Sym004 at Week 1: Single Dose
timeFrame: Pre-infusion, end of infusion, 4, 8, 12, 24, 48 hours post-infusion at Week 1
measure: Time to Reach Maximum Concentration (Tmax) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose
timeFrame: Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 4
measure: Time to Reach Maximum Concentration (Tmax) of Sym004 for the Biweekly Regimen at Week 5: Multiple Dose
timeFrame: Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 5
measure: Percentage of Subjects With Best Overall Response
timeFrame: Week 7 and thereafter every 6 weeks, up to 4 weeks after last dose for Part A or up to 8 weeks after the last dose for Part B (up to 45.1 Weeks)
measure: Duration of Overall Response
timeFrame: Week 7 and thereafter every 6 weeks until the first date of objectively documented recurrent or progressive disease, up to 45.1 Weeks
measure: Percentage of Subjects With Disease Control
timeFrame: Week 7 and thereafter every 6 weeks, up to 4 weeks after last dose for Part A or up to 8 weeks after the last dose for Part B (up to 45.1 Weeks)
measure: Duration of Disease Control
timeFrame: Week 7 and thereafter every 6 weeks until the first date of objectively documented recurrent or progressive disease, up to 45.1 weeks
measure: Time to Progression
timeFrame: Time from enrollment until the date of objectively documented disease progression or death, up to 45.1 Weeks
measure: Progression-free Survival Time
timeFrame: Time from enrollment until the date of objectively documented disease progression or death, up to 45.1 Weeks
measure: Anti-drug Antibody Titers
timeFrame: Week 1 (pre-dose) up to Follow-up assessment (up to maximum 45.1 Weeks)
measure: Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC)
timeFrame: Week 1 (pre-dose), Week 4 and Week 5
measure: Percentage of Participants With EGFR Amplification Using Fluorescent in Situ Hybridization (FISH) Method.
timeFrame: Week 1 (pre-dose) and Week 4.
Other outcomes:
Locations:
city: Darmstadt
country: Germany
facility: Please contact the Merck KGaA Communication Center located in
Study officials:
affiliation: Merck Serono Co., Ltd. Japan, an business of Merck KGaA, Darmstadt, Germany
name: Medical Responsible
role: STUDY_DIRECTOR
References:
citation: Kojima T, Yamazaki K, Kato K, Muro K, Hara H, Chin K, Goddemeier T, Kuffel S, Watanabe M, Doi T. Phase I dose-escalation trial of Sym004, an anti-EGFR antibody mixture, in Japanese patients with advanced solid tumors. Cancer Sci. 2018 Oct;109(10):3253-3262. doi: 10.1111/cas.13767. Epub 2018 Sep 25.