MIDRIX4-LUNG Dendritic Cell Vaccine in Patients With Metastatic Non-small Cell Lung Cancer

Study Overview
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Brief Summary
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MIDRIX4-LUNG is a novel tetravalent autologous dendritic cell vaccine in metastatic non-small cell lung cancer patients. This first-in-human study aims to primarily establish maximal tolerated dose of MIDRIX4-LUNG administered i.v.

Detailed Description
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Immunotherapy, in the shape of immune checkpoint inhibitors, is transforming the therapeutic landscape of non-small cell lung cancer. Checkpoint inhibitors can deliver durable tumor regressions, however only a minority of patients derive this kind of benefit, even with recent combinatorial approaches. It is clear from these clinical results that the full anti-tumoral power of the immune system is not being leveraged yet. Vaccination aims to prime and/or expand tumor antigen-targeting T-cells and induce immunological memory against later disease relapse. Whereas immune checkpoint blockade boosts inactivated responses of effector T cells, vaccination can potentially activate naive T cells with tumor specificity and in this way broaden the tumor-specific immune responses that are the target of immune checkpoint inhibition. However, the optimal vaccination modality for NSCLC still needs to be established. Dendritic cells (DCs) are specialized antigen presenting leukocytes that are now recognized as the central controllers of the immune response. The DCs unique capacity to induce robust, highly antigen-specific cytotoxic T-cell responses has led to the use of in vitro-generated autologous DCs as cancer vaccines. The investigators have developed a method for the rapid production of DCs with all the required features for the induction of anti-tumor immunity. The cells are particularly potent in inducing type 1-polarized T-helper cell and antigen-specific cytolytic T-cell responses. The DCs are loaded with a proprietary selection of 4 antigens that cover >90% of all NSCLC patients. With the objective of ultimately combining this DC vaccine with immune checkpoint inhibition, the investigators will first establish feasibility and maximal tolerated dose of DC vaccination as monotherapy using an intra-patient dose escalation scheme.

Official Title
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Phase Ia Study of MIDRIX4-LUNG, a Tetravalent Autologous Dendritic Cell Vaccine, in Patients With Metastatic Non-small Cell Lung Cancer

Conditions
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Non-small Cell Lung Cancer Metastatic

Intervention / Treatment
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* Biological: Dendritic cell immunotherapy
* Biological: Antigen-specific DTH
* Biological: Control DTH


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female patients older than 18 years with histologically or cytologically proven diagnosis of non-small cell lung cancer, newly diagnosed or recurrent stage IV, or stage IIIB not amenable to radical chemoradiotherapy (TNM 8th Edition), and for which no standard-of-care therapy is applicable or available at the time of enrollment Documented brain metastasis must be either asymptomatic or stabilized after adequate radiotherapeutic treatment as per institutional practice WHO-ECOG performance status 0 to 2 and absence of any persisting and assessable toxicity > CTC grade 2 due to a previous therapy (e.g. brain radiotherapy) Before patient registration and screening, written informed consent must be given for the interventional study and for the Prelevation and storage of human tissues and cells according to ICH/GCP and institutional practice. Adequate organ function, including: Adequate bone marrow reserve: absolute neutrophil count > 1.5*10E9/L, platelet count > 100*10E9/L, and Hb > 9.0 g/dL Sufficient renal function as defined by eGFR > 40 ml/min Sufficient hepatic function as defined by total bilirubin ≤1.5× ULN OR direct bilirubin within normal limits for participants with total bilirubin levels >1.5× ULN; AST and ALT ≤ 2.5x ULN Having passed all tests defined in the institutional Leukapheresis Donor Fitness Screening, including: Adequate peripheral vein access to perform leukapheresis Adequate coagulation function defined as international normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN and activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless the participant is receiving anticoagulant therapy Negative test results for HBs-antigen, anti-HBc-serology, anti-HCV serology, anti-HIV1-2 serology, anti-CMV IgM, anti-Syphilis (Treponema pallidum) serology Negative test results for Epstein-Barr virus (IgG and IgM) and for toxoplasmosis (IgG and IgM) For female participants: a negative serum beta-HCG test result less than 1 week before the day of leukapheresis For female participants with child-bearing potential, the willingness to follow contraceptive guidance and pregnancy testing during the projected duration of the trial (see Appendix B for Contraceptive Guidance and Pregnancy Testing) For male participants having a partner with child-bearing potential: agreement to use contraception during the projected duration of the trial, starting with the screening visit through 90 days after the last dose of trial treatment. Sperm donation must have been performed before anti-cancer treatment as per standard practice Exclusion Criteria: Presence of oncogenic driver genomic alterations for which a targeted therapy is available Concomitant participation in another clinical interventional trial Prior treatment with autologous or allogeneic dendritic cell-based vaccines NSCLC with large-cell neuro-endocrine or sarcomatoid histology Prior malignancy, except for adequately treated basal cell, superficial or in situ cancer of the bladder or the cervix, or other cancer for which the patient has been disease-free for at least five years. Dermatological pathology interfering with the in vivo immunomonitoring readout (DTH skin test) Untreated brain metastases with neurological symptoms or brain metastasis requiring a daily intake of steroids of > 10 mg oral prednisolone or equivalent. Disease requiring chronic treatment with systemic glucocorticosteroids with a daily dose > 10 mg oral prednisolone or equivalent, or other immunosuppressive drugs. Inhaled corticosteroids and topical corticosteroids on skin sites other than those used for DTH are allowed. Chronic or active concomitant infection requiring active therapy, including including HIV, viral hepatitis (HBV, HCV), CMV or fungal infection Autoimmune disease requiring active treatment at the time of the study Organ allograft Chronic comorbidity (such as asthma, COPD, heart failure, renal failure, arterial hypertension or diabetes mellitus) that is uncontrolled or not stabilized under medication at the time of study enrollment, OR stable yet severe enough to constitute an unwarranted high risk for the investigational cellular therapy. For female participants: pregnancy or lactation, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 90 days after the last dose of trial treatment Any organic brain syndrome or other significant psychiatric abnormality which would comprise the ability to give informed consent and preclude participation in the full protocol and follow-up. Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.

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
Interventional Model Description: intra-patient dose escalation scheme
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DC immunotherapy<br>Intra-patient dose escalation of intravenous MIDRIX4-LUNG autologous DC vaccine | Biological: Dendritic cell immunotherapy<br>* Intravenous infusions of MIDRIX4-LUNG DCs every 2 weeks, using an intra-patient dose escalation scheme progressing along the following range: 10 x10E6 DCs (minimal dose), 20 x 10E6 DCs, 40 x 10E6 DCs, 80 x 10E6 DCs, 100 x 10E6 DCs (maximal dose), until exhaustion of the batch or occurrence of grade ≥3 toxicity event<br>* Other names: DC vaccination;Biological: Antigen-specific DTH<br>* Intradermal injection of 1 x 10E6 MIDRIX4-LUNG DCs at baseline and after completion of all i.v. DC vaccination rounds. This is used for assessment of induction of antigen-specific immune responses as part of in vivo immunomonitoring (delayed-type hypersensitivity cutaneous reaction as test read-out)<br>* Other names: In vivo immunomonitoring - positive test;Biological: Control DTH<br>* Intradermal injection of 1 x 10E6 MIDRIX-CTRL DCs at baseline and after completion of all i.v. DC vaccination rounds. This is used for assessment of background (i.e. non-antigen-specific) reactivity (delayed-type hypersensitivity cutaneous reaction as test read-out)<br>* Other names: In vivo immunomonitoring - negative control;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity as defined by common toxicity criteria v5.0 | Safety and tolerability of preparing and administrating an autologous dendritic cell-based vaccine in advanced non-small cell lung cancer patients. | From the day of leukapheresis until 3-4 weeks after the last vaccine dose level, i.e. 3 to 5 months depending on the number of doses that can be administered | 
| Maximal tolerated dose | The maximal tolerated dose will be defined from the intra-patient dose excalation scheme | From the day of leukapheresis until 3-4 weeks after the last vaccine dose level, i.e. 3 to 5 months depending on the number of doses that can be administered | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Success rate (%) of producing sufficient dendritic cells for vaccination | Feasibility of producing sufficient dendritic cell for vaccination in advanced NSCLC | From the day of leukapheresis until the last vaccine dose level, i.e. 2 to 4 months depending on the number of doses that can be administered | 
| Number of vaccine-induced immunological responses as measured by in vitro immunomonitoring assays. | Biological activity of the vaccine (elicitation of immune responses against vaccine antigens) using a series of in vitro assays probing for antigen-specific T-cell reactivity | From the day of leukapheresis until 3-4 weeks after the last vaccine dose level, i.e. 3 to 5 months depending on the number of doses that can be administered. Whenever possible, repeat testing will be performed 3 and 6 months after the last vaccine dose. | 
| Number of vaccine-induced immunological responses as measured by in vivo immunomonitoring test. | Vaccine-induced antigen-specific immunological responses as measured by delayed-type hypersensitivity skin reaction | From the day of leukapheresis until 3-4 weeks after the last vaccine dose level, i.e. 3 to 5 months depending on the number of doses that can be administered. Whenever possible, repeat testing will be performed 3 and 6 months after the last vaccine dose. | 
| Clinical activity of this type of vaccine as reflected by relapse-free survival | Relapse-free survival (months), based on objective tumor measurements per RECIST 1.1 | From the day of leukapheresis onwards during 1 year | 
| Clinical activity of this type of vaccine as reflected by median progression-free survival | Median progression-free survival (months), based on objective tumor measurements per RECIST 1.1 | From the day of leukapheresis onwards during 1 year | 
| Clinical activity of this type of vaccine as reflected by progression-free survival at landmark timepoints (%) | Progression-free survival at landmark timepoints (%), based on objective tumor measurements per RECIST 1.1 | From the day of leukapheresis onwards during 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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dendritic cell, vaccine, immunotherapy