Sym004 in SCCHN Patients Failing Anti-EGFR Based Therapy

Study Overview
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Brief Summary
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The trial is designed as a multi-center, open label Phase 2 trial that investigates the efficacy and safety of Sym004 in subjects with squamous cell cancer of the head and neck (SCCHN). Subjects included must have responded to previous anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody-based therapy and subsequently become resistant to that therapy. It is believed that Sym004 has the potential to induce tumor responses and provide a superior treatment option to subjects with advanced SCCHN. Symphogen was the sponsor for planning/conducting and reporting results for this trial.

Official Title
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An Open-label, Single Arm, Phase II Trial to Investigate the Safety and Efficacy of Sym004 in Patients With Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN) Who Have Failed Anti-EGFR Monoclonal Antibody-based Therapy

Conditions
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Carcinoma, Squamous Cell of Head and Neck

Intervention / Treatment
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* Drug: Sym004


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed diagnosis initially or at relapse of SCCHN of the oral cavity, oropharynx, hypopharynx or larynx Recurrent and/or metastatic SCCHN not amenable to curative treatment with surgery and/or (chemo)radiation Previous treatment with an anti-EGFR monoclonal antibody (mAb) in the palliative setting either as monotherapy or in combination with chemotherapy or radiotherapy and showing: Documented clinical benefit or response for at least 8 weeks (PR, CR or SD) on the anti-EGFR mAb-based therapy and Documented disease progression (verified by computed tomography [CT] scan or magnetic resonance imaging [MRI] according to RECIST (1.1) during or within 12 weeks following the last administration of anti-EGFR mAb Accessible tumor for biopsy and subject acceptance of repeat tumor biopsies Other protocol-defined inclusion criteria could apply Exclusion Criteria: More than 2 lines of prior chemotherapy in the palliative setting Expected survival <12 weeks Subjects with known brain metastases Chemotherapy or radiation therapy within 21 days prior to Visit 2 at the exception of palliative radiotherapy for bleeding or pain, which is allowed anytime, if not given on target lesions Anti-EGFR mAbs within 14 days prior to Visit 2 Major surgery within 4 weeks prior to Visit 2 and subjects must have recovered from effects of major surgery Other protocol-defined exclusion criteria could apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sym004<br> | Drug: Sym004<br>* Sym004 will be administered at the dose of 12 milligram per kilogram (mg/kg) as an intravenous infusion every week up to disease progression or withdrawal from treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) Time | The PFS time was defined as the time from first infusion of Sym004 until progressive disease (PD) according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. or death. PD was defined as at least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the smallest sum on trial. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeter (mm). The unequivocal progression of existing non-target lesions and the appearance of one or more lesions was also considered progression. Subjects who died without confirmed PD were considered as progressed. Subjects who died or showed PD more than 21 days after last treatment were censored (that is, were considered alive without progression on Day 21 after last treatment). Evaluation was done using Kaplan-Meier estimates. | Time from the first infusion of Sym004 until progressive disease or death, assessed up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Tumor Response and Derived Endpoints (Objective Response Rate and Disease Control Rate) | Best objective tumor response was defined as the occurrence of complete response (CR), partial response (PR), stable disease (SD), or PD according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. Objective response was defined as the occurrence of CR or PR according to RECIST Version 1.1. Disease control was defined as the occurrence of CR, PR or SD according to RECIST Version 1.1. CR: Disappearance of all lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<) 10 mm; PR: At least a 30% decrease in the sum of diameters of all - lesions, taking as reference the baseline sum diameters; SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on trial. | Time from first infusion of Sym004 until disease progression or death, assessed up to 18 months | 
| Duration of Overall Response | Duration of overall response was defined as the time from the first time point where measurement criteria are met for CR or PR until first date of recurrence or PD was objectively documented according to RECIST Version 1.1. Duration of overall response was censored at date of last imaging data of measured lesions if no confirmation of recurrence or PD was available. | Time from first infusion of Sym004 until disease progression or death, assessed up to 18 months | 
| Time to Progression (TTP) | The TTP was defined as the time from first infusion of Sym004 until disease progression according to RECIST Version 1.1 criteria. Disease progression was defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. The subjects who died without prior assessment of PD were censored for TTP. | Time from first infusion of Sym04 until disease progression, assessed up to 18 months | 
| Overall Survival Time | Overall survival time was defined as the time from first infusion of Sym004 until date of death. Subjects who withdraw the consent or lost to follow-up were censored. | Time from first infusion of Sym004 until death, assessed up to 18 months | 
| Number of Subjects With Detectable Biomarkers at Any Visit | The biomarkers human papilloma virus (HPV), mutated epidermal growth factor receptor (EGFRvIII), c-MET and human epidermal growth factor receptor (HER) 2, HER3 were analyzed only in tumor cells while EGFR, phosphorylated epidermal growth factor receptor (pEGFR), and Ki-67 were analyzed both in tumor and skin biopsy cells. | Weeks 0 and 4; and 4 weeks after last dose | 
| Area Under the Serum Concentration Curve From Time Zero to 168 Hours (AUC [0-168]) | The AUC (0-168h) was estimated by determining the total area under the curve of the concentration versus time curve. | Pre-treatment, 1, 2, 4, 8, 24, and 48 hours post-infusion at Week 0 and Week 3 | 
| Area Under the Serum Concentration Curve From Time Zero to Infinity (AUC [0-inf]) | The AUC (0-inf) was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. | Pre-treatment, 1, 2, 4, 8, 24, and 48 hours post-infusion at Week 0 and Week 3 | 
| Maximum Serum Concentration (Cmax) |  | Pre-treatment, 1, 2, 4, 8, 24, and 48 hours post-infusion at Week 0 and Week 3 | 
| Minimum Serum Concentration (Cmin) |  | Pre-treatment, 1, 2, 4, 8, 24, and 48 hours post-infusion at Week 0 and Week 3 | 
| Clearance (CL) | Clearance of a drug was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. | Pre-treatment, 1, 2, 4, 8, 24, and 48 hours post-infusion at Week 0 and Week 3 | 
| Terminal Half Life (T1/2) | The apparent terminal half-life was defined as the time required for the serum concentration of Sym004 to decrease 50% in the final stage of its elimination. | Pre-treatment, 1, 2, 4, 8, 24, and 48 hours post-infusion at Week 0 and Week 3 | 
| Time to Reach Maximum Serum Concentration (Tmax) |  | Pre-treatment, 1, 2, 4, 8, 24, and 48 hours post-infusion at Week 0 and Week 3 | 
| Time to Reach Minimum Serum Concentration (Tmin) |  | Pre-treatment, 1, 2, 4, 8, 24, and 48 hours post-infusion at Week 0 and Week 3 | 
| Volume of Distribution (Vz) | Volume of distribution was defined as the theoretical volume in which the total amount of drug needed to be uniformly distributed to produce the desired serum concentration of a drug. | Pre-treatment, 1, 2, 4, 8, 24, and 48 hours post-infusion at Week 0 and Week 3 | 
| Number of Subjects With Adverse Events (AEs), Serious AEs, AEs Leading to Death and AEs Leading to Discontinuation | An adverse event (AE) was defined as any new untoward medical occurrences/worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. | From the first dose of study drug administration up to 4 weeks after the last dose of study drug administration |