TG4010 and Nivolumab in Patients With Lung Cancer

Study Overview
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Brief Summary
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This phase II trial studies how well TG4010 and nivolumab work in previously treated patients with non-small cell lung cancer. Vaccines that are made from a gene-modified virus, such as TG4010, may help the body build an effective immune response to kill tumor cells. Monoclonal antibodies, such as nivolumab, interfere with the ability of tumor cells to grow and spread. Giving TG4010 and nivolumab together may work better in previously treated patients with non-small cell lung cancer.

Detailed Description
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PRIMARY OBJECTIVES: To evaluate the efficacy of nivolumab plus TG4010 (modified vaccinia virus Ankara [MVA]-human mucin 1 [MUC1]-interleukin-2 [IL2] vaccine) in previously treated patients with stage IV non squamous non-small cell lung cancer (NSCLC) with respect to objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. SECONDARY OBJECTIVES: Define the safety and toxicity profile of nivolumab plus TG4010 by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4. Determine progression-free survival by RECIST 1.1. Determine overall survival. Determine the duration of response and the occurrence of responses over time. Determine the rate and duration of stable disease. Determine the disease control rate.

Official Title
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Phase II Trial of TG4010 Plus Nivolumab in Previously Treated Patients With Metastatic Non-Small Cell Lung Cancer (NSCLC)

Conditions
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Recurrent Non-Small Cell Lung Carcinoma, Stage I Non-Small Cell Lung Cancer, Stage II Non-Small Cell Lung Cancer, Stage IIIA Non-Small Cell Lung Cancer, Stage IIIB Non-Small Cell Lung Cancer, Stage IV Non-Small Cell Lung Cancer

Intervention / Treatment
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* Biological: TG4010
* Biological: Nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed non-squamous NSCLC; patients with adenocarcinoma must have had epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutational testing; those with an actionable mutations/rearrangements are excluded Stage IIIB or IV patients must have progressed after a platinum based chemotherapy; a maximum of 3 previous systemic regimens are allowed (one regimen can be a tyrosine kinase inhibitor); patients with stage I-IIIB NSCLC who have progressed within 6 months of a full dose platinum based regimen as adjuvant therapy or with radiotherapy are eligible; patients who received weekly low dose chemotherapy with radiation only are not eligible At least one measurable lesion by computed tomography (CT) scan or magnetic resonance imaging (MRI) based on RECIST version 1.1 Performance status (PS) 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale Minimum life expectancy of 3 months Hemoglobin >= 10.0 g/dL White blood cells (WBC) >= 3.0 x 10^9/L Neutrophils >= 1.5 x 10^9/L Total lymphocyte count >= 0.5 x 10^9/L Platelet counts >= 100 x 10^9/L Serum alkaline phosphatase =< 3 x upper limit of normal (ULN) in absence of liver or bone metastases and =< 5 x ULN in patients with documented bone or liver metastases Total bilirubin =< 1.5 x ULN Serum transaminases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) =< 2.5 x ULN in the absence of liver metastases and =< 5 x ULN in case of liver metastases Glomerular Filtration Rate >= 60 mL/min (according to Modification of Diet in Renal Disease [MDRD] formula or Cockcroft & Gault formula) Serum albumin >= 30 g/L Effective contraception during the study period and for 5 months after the last study treatment administration (male and female patient) Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll Ability to understand and the willingness to sign a written informed consent Exclusion Criteria: Patients having active central nervous system (CNS) metastases; patients adequately treated and neurologically returned to baseline (except for residual signs of symptoms related to the CNS treated) for at least 2 weeks prior to enrolment are allowed; in addition, patients must be either off corticosteroids or on a stable or decreasing dose of < 10 mg daily prednisone or equivalent Prior exposure to cancer immunotherapy including any immune checkpoint inhibitor and/or cancer vaccines Prior history of other malignancy except: Basal cell carcinoma of skin Cervical intra-epithelial neoplasia Other cancer curatively treated with no evidence of disease for at least 2 years Patients under chronic treatment with systemic corticosteroids or other immunosuppressive drugs (e.g. cyclosporine) for a period of at least 4 weeks and whose treatment was not stopped 1 week prior to start of the study treatment (day 1 [D1] of cycle 1) Positive serology for human immunodeficiency virus (HIV) or hepatitis C virus (HCV); presence in the serum of the antigen hemoglobin (HBs) Patient with any underlying medical condition that the treating physician considers might be aggravated by treatment or which is not controlled (e.g. elevated troponin or creatinine, uncontrolled diabetes) Patients with major surgery or radiotherapy within 4 weeks prior to the start of the study treatment (i.e. D1 of cycle 1); however, prior surgery or radiation therapy aimed at local palliation or attempted local disease control (except in case of thoracic radiotherapy) is permitted but has to be completed one week before treatment start Pregnant or nursing (lactating) women, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test (> 10 mIU/mL); pregnancy is ruled out by a beta hCG test completed if necessary with an ultrasound Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, UNLESS they are: Women whose sexual orientation precludes intercourse with a male partner Women whose partners have been sterilized by vasectomy or other means Using a highly effective method of birth control (i.e. one that results in a less than 1% per year failure rate when used consistently and correctly, such as implants, injectables, combined oral contraceptives, and some intrauterine devices [IUDs]; periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) is not acceptable) Patient with an organ allograft Known allergy to eggs, gentamicin, or platinum containing compounds Hypersensitivity to the active substance or to any of the excipients Participation in a clinical study with an investigational product within 4 weeks prior to the start of the study treatment (i.e. D1 of cycle 1) Patient unable or unwilling to comply with the protocol requirements Subject has active, known or suspected autoimmune disease, including systemic lupus erythematodes, Hashimoto thyroiditis, scleroderma, polyarteritis nodosa, or autoimmune hepatitis Subject has any peripheral neuropathy >= National Cancer Institute (NCI) CTCAE grade 2 at enrollment Subject has a history of interstitial lung disease, history of slowly progressive dyspnea and unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary hypersensitivity pneumonitis or multiple allergies; any lung disease that may interfere with the detection or management of suspected drug-related pulmonary toxicity History of any of the following cardiovascular conditions within 12 months of enrollment: cardiac angioplasty or stenting, myocardial infarction, unstable angina, coronary artery by-pass graft surgery, symptomatic peripheral vascular disease, class III or IV congestive heart failure, as defined by the New York Heart Association Left ventricular ejection fraction (LVEF) less than the lower limit of normal (LLN) as assessed by echocardiography

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: Treatment TG4010 + nivolumab<br>Patients receive TG4010 SC once per week for courses 1-3 and every 2 weeks for courses thereafter and nivolumab IV over 30 minutes every 2 weeks. Courses repeat every 14 days for up to 2 years in the absence of disease progression or unacceptable toxicity. | Biological: TG4010<br>* Given SC<br>* Other names: MVA-MUC1-IL2 Vaccine;Biological: Nivolumab<br>* Given IV<br>* Other names: Opdivo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR defined as the proportion of patients whose best overall response (BOR) is either complete response (CR) or partial response (PR) according to RECIST 1.1 | Proportions of patients with a best overall response of CR or PR will be presented with exact 95% confidence intervals and p-value associated to the binomial test (with null proportion as reference). Will be performed on the Evaluable patient set. The analysis will be repeated on intent-to-treat (ITT) for confirmation. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease control rate defined as the proportion of patients whose BOR is either CR, PR or SD, assessed by RECIST 1.1 |  | Up to 2 years | 
| Duration of response (DOR) defined as patients whose best overall response is CR or PR (confirmed response) |  | Time from the first documented response (CR or PR) until the event defined as first documented disease progression, assessed for up to 2 years | 
| Incidence of adverse events reported per CTCAE v4.0 |  | Up to 100 days after last study treatment administration | 
| Overall survival (OS) defined by RECIST 1.1 |  | Time from enrollment until death from any cause, assessed for up to 2 years | 
| Progression free survival (PFS) defined by RECIST 1.1 |  | Time from enrollment to the date of first documented radiographic tumor progression or death due to any cause, whichever occurs first, assessed for up to 2 years | 
| Stable disease (SD) rate defined as the proportion of patients whose BOR is SD, assessed by RECIST 1.1 |  | Up to 2 years |