Immunotherapy With Racotumomab in Advanced Lung Cancer

Study Overview
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Brief Summary
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This is a prospective, randomized, open label, parallel-group, multicenter phase III study to evaluate the efficacy and safety of active specific immunotherapy with racotumomab plus best supportive care versus best supportive care in patients with advanced NSCLC who have achieved an Objective Response (Partial or Complete Response) or Stable Disease with standard first-line treatment. Also immunological parameters will be evaluated. Best supportive therapy will be administered to all patients in the study according to institutional standards and includes any subsequent onco-specific therapies. 1082 patients will be included in the study, with non-small cell lung cancer in stages IIIA (non-resectable), IIIB or IV.

Official Title
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A Prospective, Randomized, Multicenter, Open Label Phase III Study of Active Specific Immunotherapy With Racotumomab Plus Best Support Treatment Versus Best Support Treatment in Patients With Advanced Non-small Cell Lung Camcer.

Conditions
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NSCLC, Lung Cancer, Non-small Cell

Intervention / Treatment
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* Biological: Racotumomab
* Other: Best Support Treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Voluntarily signed informed consent. Cytologic or histologically diagnosed NSCLC in stages IIIA (non-resectable) or IIIB or IV (TNM). In continuous complete or partial remission or stable disease according to Response Evaluation Criteria in Solid Tumours (RECIST) after standard first-line treatment. Imaging studies documenting the response to first-line therapy must be available for evaluation by the investigator. Time lapse of 21 to 56 days between the end of onco-specific treatment and start of vaccination. Patients must have recovered from any acute toxicity produced by previous therapy. Age greater than or equal to 18 years, either sex. Eastern Cooperative Oncology Group performance status less than 2. Adequate organ function, defined as follows: 8.1. Electrocardiogram (ECG) without significant anomalies, performed in the 7 days preceding entry 8.2. Haemoglobin greater than or equal to 90 g/L 8.3. Total white blood cell count (WBC) greater than or equal to 3.0 x 10^9/L 8.4. Absolute neutrophil count (ANC) greater than or equal to 1.5 x 10^9/L 8.5. Platelet count greater than 100 x 10^9/L 8.6. Total bilirubin less than or equal to 1.5 fold the maximum normal value at the place of evaluation or 2.5 fold the maximum normal value in case of liver metastases 8.7. Glutamic-oxaloacetic transaminase/aspartate aminotransferase (GOT/AST), and glutamic-pyruvic transaminase/alanine aminotransferase (GPT/ALT), less than or equal to 2.5 fold the maximum normal value at the place of evaluation (in case of liver metastasis, less than 5 fold the maximum normal value) 8.8. Creatinine less than or equal to 2 mg/dL (less than or equal to 176 µmol/L) Known hepatitis B virus carriers who have liver function tests within the accepted limits are eligible Exclusion Criteria: Pregnant or breastfeeding patients Known hypersensitivity to any component of the formulation Fertile patients of either sex who do not use adequate contraceptive methods while on treatment Disease progression prior to randomization Recurrent NSCLC, who relapse less than one year after completing curative intent therapy Patients receiving other investigational medication (including investigational immunotherapy for NSCLC) or having received such medication within 30 days before entering the protocol Autoimmune diseases or chronic decompensated diseases Acute allergic disorders or a history of severe allergic reactions Known brain metastases History of demyelinating disease or inflammatory disease of the central nervous system or the peripheral nervous system Non-controlled intercurrent diseases, including active infections, symptomatic congestive heart failure, unstable chest angina or heart arrhythmia, as well as mentally incapable patients Other malignant diseases except non- melanoma skin cancer, in situ carcinoma of the cervix, incidental prostate cancer (T1a, Gleason less than or equal to 6, prostate specific antigen (PSA) less than 0.5 ng/ml) or any other tumour having received adequate treatment and evidencing a disease-free period greater than or equal to 5 years Receiving chronic therapy for more than 10 days at doses of prednisone greater than 10 mg/day (or equivalent) at the moment of the inclusion. Inhaled and topical corticosteroids are allowed. Active hepatitis C or positive tests for human immunodeficiency virus (HIV)

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Racotumomab plus Best Support Treatment<br>Patients will receive Racotumomab and Best Support Treatment, which includes any further onco-specific therapy for progressive disease. | Biological: Racotumomab<br>* Patients will receive best support treatment and vaccination with racotumomab. The vaccination schedule is as follows: 5 doses (1mg/mL each), intradermally, every 2 weeks (induction period) followed by monthly vaccinations until any criteria for discontinuation are met. If disease progression occurs and further onco-specific therapy is indicated, the patient will be able to continue in the study and vaccination will not be interrupted unless criteria for vaccine discontinuation are met.<br>* Other names: 1E10;|
| Active Comparator: Best Support Treatment<br>Patients will receive best support treatment for advanced NSCLC including onco-specific therapies when disease progresses. | Other: Best Support Treatment<br>* Patients will receive best support treatment for advanced NSCLC as per each institution's standards, including onco-specific therapies when disease progresses.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | A comparison of survival in the subgroup of inoperable stage IIIA and dry IIIB will be performed in 757 (approximately 70% of the study population) | Until date of death or last censored observation, on average upto 17 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Adverse events as a measure of safety and tolerability | Safety will be evaluated at each study visit according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0 and will include physical examination with vital signs, performance status as per the Eastern Cooperative Oncology Group scale(ECOG scale), laboratory tests and clinical history. | Until death, on average during 17 months | 
| Progression Free Survival | Tumour evaluations will be performed every 2 months and evaluated as per Response Evaluation Criteria in Solid Tumors (RECIST). | From randomization until date of first documented progression of disease, assessed as per RECIST 1.0 during an expected average of 17 months | 
| Determination of IgM and IgG antibody titers against N-Glycolil-GM3 ganglioside |  | Baseline | 
| Determination of IgM and IgG antibody titers against N-Glycolil-GM3 ganglioside for Racotumomab Group |  | Month 3 | 
| Determination of IgM and IgG antibody titers against N-Glycolil-GM3 ganglioside for Racotumomab Group |  | Month 6 | 
| Determination of IgM and IgG antibody titers against N-Glycolil-GM3 ganglioside for Racotumomab Group |  | Month 9 | 
| Determination of IgM and IgG antibody titers against N-Glycolil-GM3 ganglioside for Racotumomab Group |  | Month 12 | 
| Determination of IgM and IgG antibody titers against N-Glycolil-GM3 ganglioside for Racotumomab Group |  | After the first year, every 3 months, on average for 17 months | 
| Determination of gamma interferon by ELISPOT (enzyme-linked immunosorbent spot) assay. |  | Baseline | 
| Determination of gamma interferon by ELISPOT (enzyme-linked immunosorbent spot) assay for Racotumomab Group. |  | Month 3 | 
| Determination of gamma interferon by ELISPOT (enzyme-linked immunosorbent spot) assay for Racotumomab Group. |  | Month 6 | 
| Determination of gamma interferon by ELISPOT (enzyme-linked immunosorbent spot) assay for Racotumomab Group. |  | Month 9 | 
| Determination of gamma interferon by ELISPOT (enzyme-linked immunosorbent spot) assay for Racotumomab Group. |  | Month 12 | 
| Evaluation of the reactivity if the antibodies against X63 tumor line (mouse myeloma) for Racotumomab Group |  | Baseline | 
| Evaluation of the reactivity if the antibodies against X63 tumor line (mouse yeloma) for Racotumomab Group |  | Month 3 | 
| Evaluation of the reactivity if the antibodies against X63 tumor line (mouse myeloma) for Racotumomab Group |  | Month 6 | 
| Evaluation of the reactivity if the antibodies against X63 tumor line (mouse myeloma) for Racotumomab Group |  | Month 9 | 
| Evaluation of the reactivity if the antibodies against X63 tumor line (mouse myeloma) for Racotumomab Group |  | Month 12 | 
| Evaluation of the reactivity if the antibodies against X63 tumor line (mouse myeloma) for Best Support Treatment Group |  | Baseline | 
| Evaluation of the reactivity if the antibodies against X63 tumor line (mouse myeloma) for Best Support Treatment Group |  | Month 4 | 
| Determination of IgM and IgG antibody titers against N-Glycolil-GM3 ganglioside for Best Support Treatment Group |  | Baseline | 
| Determination of IgM and IgG antibody titers against N-Glycolil-GM3 ganglioside for Best Support Treatment Group |  | Month 4 | 
| Determination of gamma interferon by ELISPOT (enzyme-linked immunosorbent spot) assay for Best Support Treatment Group. |  | Month 4 | 
| Determination of T supressor cell (Treg cell) frequency by immunostaining and flow cytometry. |  | Baseline | 
| Determination of T supressor cell (Treg cell) frequency by immunostaining and flow cytometry in the Racotumomab Group. |  | Month 3 | 
| Determination of T supressor cell (Treg cell) frequency by immunostaining and flow cytometry in the Racotumomab Group. |  | Month 6 | 
| Determination of T supressor cell (Treg cell) frequency by immunostaining and flow cytometry in the Racotumomab Group. |  | Month 9 | 
| Determination of T supressor cell (Treg cell) frequency by immunostaining and flow cytometry in the Racotumomab Group. |  | Month 12 | 
| Determination of T supressor cell (Treg cell) frequency by immunostaining and flow cytometry in the Best Support Treatment Group. |  | Month 4 | 
| Evaluation of the reactivity of the antibodies against the patients tumoral tissue (whenever samples are available) |  | Baseline | 
| Evaluation of the reactivity of the antibodies against the patients tumoral tissue (whenever samples are available) in the Racotumomab Group. |  | Month 3 | 
| Evaluation of the reactivity of the antibodies against the patients tumoral tissue (whenever samples are available) in the Racotumomab Group. |  | Month 6 | 
| Evaluation of the reactivity of the antibodies against the patients tumoral tissue (whenever samples are available) in the Racotumomab Group. |  | Month 9 | 
| Evaluation of the reactivity of the antibodies against the patients tumoral tissue (whenever samples are available) in the Racotumomab Group. |  | Month 12 | 
| Evaluation of the reactivity of the antibodies against the patients tumoral tissue (whenever samples are available) in the Best Support Treatment Group. |  | Month 4 | 
| Measurement of pro-inflammatory and anti-inflammatory cytokines |  | Baseline | 
| Measurement of pro-inflammatory and anti-inflammatory cytokines in the Racotumomab Group |  | Month 3 | 
| Measurement of pro-inflammatory and anti-inflammatory cytokines in the Racotumomab Group |  | Month 6 | 
| Measurement of pro-inflammatory and anti-inflammatory cytokines in the Racotumomab Group |  | Month 9 | 
| Measurement of pro-inflammatory and anti-inflammatory cytokines in the Racotumomab Group |  | Month 12 | 
| Measurement of pro-inflammatory and anti-inflammatory cytokines in the Best Support Treatment Group |  | Month 4 | 
| Determination of anti-idiotypic IgG response |  | Baseline | 
| Determination of anti-idiotypic IgG response in the Racotumomab Group. |  | Month 3 | 
| Determination of anti-idiotypic IgG response in the Racotumomab Group. |  | Month 6 | 
| Determination of anti-idiotypic IgG response in the Racotumomab Group. |  | Month 9 | 
| Determination of anti-idiotypic IgG response in the Racotumomab Group. |  | Month 12 | 
| Determination of anti-idiotypic IgG response in the Best Support Treatment Group. |  | Month 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NSCLC, Lung cancer, small-cell, advanced lung cancer, therapeutic vaccine, anti-idiotypic vaccine, 1E10