CetuGEX™: Phase 1 Study in Cancer Patients

Study Overview
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Brief Summary
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This was a prospective, open label, multicenter study evaluating the safety, tolerability and pharmacokinetics of CetuGEX™ after intravenous administration in patients with EGFR positive, locally advanced and/or metastatic solid cancers. The effect of CetuGEX™ on the development of anti-drug antibodies and on tumour response was also evaluated.

Detailed Description
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Male or female patients ≥18 years of age with a histologically confirmed locally advanced and/or metastatic solid organ tumor. Patients enrolled in Germany were required to have a positive EGFR overexpression status. Patients must have experienced a failure or non-availability of standard therapy (had received at least one line of chemotherapy and further standard therapy was not an option at study entry). Open-label, non-randomized, inter-patient dose-escalation, multi-center study. Patients were to receive CetuGEX until disease progression or until intolerable toxicities occurred.

Official Title
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Dose-escalation, PK- and Safety Study With Single Agent CetuGEX™ in Patients With EGFR Positive Locally Advanced and/or Metastatic Cancer

Conditions
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Solid Tumors

Intervention / Treatment
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* Drug: CetuGEX™


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female and age ≥ 18 yrs Histologically confirmed EGFR positive locally advanced and/or metastatic solid organ tumour Measurable or non-measurable tumour Failure of standard therapy or non-availability of standard therapy (Patients must have received at least 1 line of chemotherapy and further standard therapy is not an option at study entry) All anti-tumour therapies must be completed 4 weeks before start of study treatment; treatment with Cetuximab must be completed at least 6 weeks prior to study start ECOG Performance Status ≤1 and estimated life expectancy of ≥ 3 months Adequate organ function: Bone marrow function: hemoglobin ≥ 100 g/L; white blood cell count (WBC) ≥ 3.0 x 10^9/L; absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L; platelet count ≥ 100 x 10^9/L Hepatic: aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) ≤ 2.5 times upper limit of normal (ULN) (≤ 5 x ULN if hepatic metastases present); bilirubin ≤ 1.5 x ULN; alkaline phosphatase ≤ 5.0 x upper limit of normal (ULN) Renal: creatinine < 1.5 x ULN Patients of both genders with procreative potential must use effective contraception while enrolled in the study and for at least 4 weeks after the last study drug infusion Written informed consent must be obtained prior to conducting any study-specific procedures For Expansion Phase only: No prior treatment with Cetuximab allowed Exclusion Criteria: Chemotherapy, radiation, other anti-cancer therapies including any investigational agents at the study enrolment within 4 weeks prior to study enrolment Concurrent anti-tumour therapy or concurrent immunotherapy Concurrent systemic steroids except topical (inhaled, topical, nasal) or replacement therapy for the last 28 days. Major surgery within 4 weeks prior entering the study and/or incomplete recovery from surgery or planned major surgery Primary or secondary immune deficiency Clinically active infections > CTCAE grade 2 Prior allergic reaction to a monoclonal antibody (e.g. Trastuzumab, Cetuximab or Bevacizumab). Active hepatitis B assessed by serology, hepatitis C by histology; human immunodeficiency virus (HIV) seropositivity Any concurrent malignancy other than basal cell carcinoma or carcinoma in situ of the cervix. Patients with a previous malignancy but without evidence of disease for ≥ 3 years will be allowed to enter the study. Uncontrolled medical condition considered as high risk for the treatment with an investigational drug including unstable diabetes mellitus, vena-cava-syndrome, chronic symptomatic respiratory disease. Clinical signs of brain metastasis or leptomeningeal involvement Symptomatic congestive heart failure (New York Heart Association [NYHA] 3 or 4); unstable angina pectoris within 6 months prior to enrollment; significant cardiac arrhythmia, or history of stroke or transient ischemic attack within 1 year. Active drug abuse or chronic alcoholism Pregnancy or Breastfeeding

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CetuGEX™, weekly<br>application weekly | Drug: CetuGEX™<br> <br> * Other names: tomuzotuximab;|
| Experimental: CetuGEX™ 2-weekly<br>application biweekly | Drug: CetuGEX™<br> <br> * Other names: tomuzotuximab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events (TEAE) assessed with the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0 | TEAE were coded by use of Medical Dictionary for Regulatory Activities (MedDRA) version 13.1 | throughout the study until 28±2 days after last infusion | 
| Incidence of clinically relevant abnormal clinical laboratory parameters | graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0 | from first infusion until 28±2 days following the last infusion | 
| Dose-limiting toxicities (DLT) | DLTs were defined as drug-related: Hematological or non-hematological toxicity grade 3 (excl. rash) or 4 excluding inadequately treated nausea and vomiting; In case of skin reaction (rash) grade 4 | from first infusion until 28±2 days following the last infusion | 
| Changes of corrected QT interval (QTc) duration | by use of 12-lead electrocardiograms (ECG) | from first infusion until 28±2 days following the last infusion | 
| To define the recommended phase II dose and regimen | Defining a recommended dose for a Phase II study was possible based on the available PK data in combination with the safety and activity data for CetuGEX™ | from first infusion until 28±2 days following the last infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-Tumor Activity: Confirmed Best Overall Response Rates | Assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Tumors were measured by computed tomography (CT) scan or magnetic resonance imaging (MRI) | From date of randomization until the date of first documented progression, assessed up to 60 months | 
| Anti-Tumor Activity: Clinical Benefit Rates | Assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Tumors were measured by computed tomography (CT) scan or magnetic resonance imaging (MRI) | From date of randomization until the date of first documented progression, assessed up to 60 months | 
| Eastern Cooperative Oncology Group (ECOG) Performance Status | The ECOG Scale of Performance Status describes a patient's level of functioning in terms of their ability to care for themself, daily activity, and physical ability (walking, working, etc.). The scale comprises six grades: 0 Fully active, able to carry on all pre-disease performance without restriction Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours Completely disabled; cannot carry on any selfcare; totally confined to bed or chair Dead | From date of randomization until 28 days ± 2 days after the end of treatment | 
| Pharmacokinetics (PK): Area under the serum concentration-time curve (AUC) | PK of CetuGEX™ after single and multiple administration | Prior to 1st infusion, end of 1st infusion, 4 hours after end, 72 and 168 hours after start of 1st infusion, then before and after each infusion up to 10 weeks | 
| Pharmacokinetics (PK): Maximum serum concentration (Cmax) | PK of CetuGEX™ after single and multiple administration | Prior to 1st infusion, end of 1st infusion, 4 hours after end, 72 and 168 hours after start of 1st infusion, then before and after each infusion up to 10 weeks | 
| Pharmacokinetics (PK): Time to maximum serum concentration (tmax) | PK of CetuGEX™ after single and multiple administration | Prior to 1st infusion, end of 1st infusion, 4 hours after end, 72 and 168 hours after start of 1st infusion, then before and after each infusion up to 10 weeks | 
| Pharmacokinetics (PK): Minimal serum concentration (Cmin) | PK of CetuGEX™ after single and multiple administration | Prior to 1st infusion, end of 1st infusion, 4 hours after end, 72 and 168 hours after start of 1st infusion, then before and after each infusion up to 10 weeks | 
| Pharmacokinetics (PK): Terminal elimination half-life (t1/2) | PK of CetuGEX™ after single and multiple administration | Prior to 1st infusion, end of 1st infusion, 4 hours after end, 72 and 168 hours after start of 1st infusion, then before and after each infusion up to 10 weeks | 
| Pharmacokinetics (PK): Clearance rate (CL) | PK of CetuGEX™ after single and multiple administration | Prior to 1st infusion, end of 1st infusion, 4 hours after end, 72 and 168 hours after start of 1st infusion, then before and after each infusion up to 10 weeks | 
| Pharmacokinetics (PK): Volume of distribution (Vz) | PK of CetuGEX™ after single and multiple administration | Prior to 1st infusion, end of 1st infusion, 4 hours after end, 72 and 168 hours after start of 1st infusion, then before and after each infusion up to 10 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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advanced solid cancers, metastatic solid cancers