EMD 521873 Plus Radiotherapy in Non Small Cell Lung Cancer (NSCLC)

Study Overview
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Brief Summary
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Primary trial objective in this single arm trial is to assess the safety and tolerability of Selectikine (EMD 521873) given in combination with and local tumor irradiation and to determine whether the maximum tolerated dose (MTD) is reached with EMD 521873 doses of up to 0.45 mg/kg. Secondary objectives are to evaluate PK, immunogenicity, overall response, changes in tumor marker levels and circulating tumor cell numbers, progression-free survival and overall survival. Also, to evaluate biological/immune responses to EMD 521873. NSCLC patients have to be stable (PR or SD) after first-line chemotherapy in order to be enrolled. A total of 12 to 24 patients are planned. Patients will remain on the dose throughout the trial. It is intended to administer at least 4 cycles (21 d each), or until progression or 2nd line therapy becomes necessary.

Official Title
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An Open-label, Phase Ib, Dose-escalation Trial on the Safety, Tolerability, Pharmacokinetics, Immunogenicity, Biological Effects and Antitumor Activity of EMD 521873 in Combination With Local Irradiation (20 Gy) of Primary Tumors or Metastases in Subjects With Non-small Cell Lung Cancer Stage IIIb With Malignant Pleural Effusion or Stage IV With Disease Control (Partial Response or Stable Disease) After Application of 4 Cycles of Platinum-based, First-line Chemotherapy

Conditions
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Lung Cancer, Non Small Cell Lung Cancer

Intervention / Treatment
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* Biological: EMD 521873


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed NSCLC stage IIIb with malignant pleural effusion or stage IV Pulmonary primary tumor or at least one NSCLC metastasis in the lung measuring at least 1 cm in diameter and eligible for local radiation with 20 Gy Disease control (partial remission or stable disease) after 4 cycles of platinum-based first-line chemotherapy whereby the time between the last dose of first-line chemotherapy and start of trial treatment should not be longer than 8 weeks Male or female, aged ≥18 years of age Signed written informed consent Effective contraception for male and female subjects of childbearing age ECOG performance status 0 or 1 Adequate hematological function defined by WBC ≥3 x 10^9/L, neutrophils ≥1.5 x 10^9/L, lymphocyte count ≥0.5 x 10^9/L, platelet count ≥100 x 10^9/L; hemoglobin ≥9 g/dL Estimated creatinine clearance ≥50 mL/min according to the Cockcroft - Gault formula or 24-h urine sampling Adequate hepatic function defined by a total bilirubin level ≤1.5 times the upper limit of normal (ULN), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤5 x ULN Exclusion Criteria: Requirement for immunosuppressive treatment with the exception of inhalative corticosteroids or low-dose systemic corticosteroids (prednisone equivalent dose ≤10 mg/day) Systemic autoimmune disease (e.g. lupus erythematodes, rheumatoid arthritis) Organ transplant recipients Active infections (including HIV, hepatitis B and C, tuberculosis) Known or clinically suspected brain metastases Active cardiovascular/cerebrovascular disease (e.g. symptomatic coronary vascular disease, congestive heart failure ≥ NYHA II, LVEF <50%, ventricular arrhythmia requiring medication, myocardial infarction or stroke) within previous 6 months Pericardial effusion Major impairment in pulmonary function: forced expir¬atory volume in 1 second (FEV1) <50% and diffusion capacity for carbon monoxide (DLCO) <50% of normal limit Any other significant disease that in the Investigator's opinion would exclude the subject from the trial Known conditions associated with necroses of non-tumor bearing tissues (e.g. esophageal or gastroduodenal ulcers, ischemic bowel disease, chronic inflammations) Pregnancy or lactation Radiotherapy, chemotherapy, major surgery, biological therapy or any investigational drug within 30 days prior to the start of trial treatment Requirement for concurrent systemic anticancer treatment (chemotherapy, biological therapy) Pretreatment with anti-EGFR antibodies or tyrosine kinase inhibitors Participation in another interventional clinical trial within the past 30 days before start of trial treatment Known alcohol or drug abuse Any psychiatric condition that would prohibit the understanding or rendering of the informed consent Legal incapacity or limited legal capacity

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: 1<br> | Biological: EMD 521873<br>* After local irradiation (5 x 4 Gy) given over 5 consecutive days and 2 treatment free days cohorts of 3-6 subjects will receive EMD 521873 (as a 1h-infusion) on 3 consecutive days in 3-week cycles at dose levels of 0.15, 0.30, and 0.45 mg/kg, respectively.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the safety and tolerability of EMD 521873 given in combination with local irradiation of pulmonary primary tumor/metastases and to determine whether the maximum tolerated dose (MTD) is reached with EMD 521873 doses of up to 0.45 mg/kg. |  | Incidence of DLTs occurring during the first cycle (21 days) of administration of any dose of EMD 521873 following radiotherapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the pharmacokinetics (PK) of EMD 521873 in combination with local tumor irradiation |  | First 4 cycles of treatment | 
| Evaluate the immunogenicity of EMD 521873 in combination with local tumor irradiation by measuring the induction of anti-EMD 521873 antibodies |  | First 4 cycles of treatment in each cycle, then every 4 cycles | 
| Collect evidence of best overall response, changes in tumor marker levels and circulating tumor cell numbers after treatment with EMD 521873 in combination with local tumor irradiation |  | First 4 cycles of treatment | 
| Collect evidence of best overall response after second-line therapy and duration of the response when it is shown |  | At one year of follow up | 
| Evaluate progression-free survival and overall survival |  | At one year of follow up | 
| Evaluate biological/immune responses following treatment with EMD 521873 by assessing changes in relevant parameters including leukocyte subset analysis |  | First 4 cycles of treatment | 
| Evaluate biological/immune responses following treatment with EMD 521873 by assessing changes in relevant parameters including: molecular markers of immune activation (e.g. cytokines/chemokines, IL-2 receptor and neopterin) |  | First 4 cycles of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NSCLC, immunocytokine, radiation, interleukin-2, immunotherapy, maintenance therapy