This is a phase I/IIa open, uncontrolled, international, prospective clinical trial, in an out-patient setting, in patients with stage IIIB/IV NSCLC.

The phase I part of the study consists of a dose escalation phase, in which the recommended dose (RD) for the phase IIa part of the study will be established based on the incidence of dose-limiting toxicities (DLT). In the phase IIa part of the study, additional patients will be included at the RD, to confirm the safety and explore the activity of that dose.

This study will take place in Switzerland (2 sites) and Germany (11 sites).

Medical Need:

Lung cancer is the leading cause of cancer mortality in developed countries; about 87% of lung cancers are of the NSCLC type. Patients with more advanced but non-metastatic disease (IIIA or IIIB) usually undergo chemotherapy and/or radiation therapy, with or without secondary surgical resection. Patients with progression after chemotherapy and/or radiotherapy may receive second-line treatment with targeted therapies. Despite these aggressive treatments, only about 5% of patients with metastatic disease survive for 5 or more years. Given these dismal statistics, it is clear that new therapeutic approaches for treatment of NSCLC are urgently needed.

Potential Benefits:

CV9201 is an mRNA-based vaccine for the treatment of human NSCLC that is based on CureVac's RNActive® technology.

As an mRNA-based vaccine, CV9201 features several advantages over other approaches: it is highly specific, there is no restriction to the patient's MHC genotype, and it does not need to cross the nuclear membrane to be active. Finally, in the absence of reverse transcriptase, RNA can not be integrated into the genome.

For the planned first-in-man study, CV9201 will be administered in 5 doses. The phase I part of this phase I/IIa study is a dose finding study, to determine the RD for the phase IIa part.

Inclusion Criteria:

1. Male or female and age ≥ 18 yrs and ≤ 75

2. Histologically or cytologically confirmed and documented stage IIIB /IV NSCLC

3. Documented stable disease or objective response according to RECIST criteria after initial chemotherapy or chemo-radiotherapy for advanced, unresectable disease:

   • Patients must have received a minimum of two cycles of standard chemotherapy, and adequate and effective radiotherapy if used in conjunction with chemotherapy (sequentially or concomitantly). Prophylactic brain radiation is allowed.
   • Surgery, radiotherapy and/ or chemotherapy can have been previously administered for non-advanced disease.
   • All therapies must be completed 4 weeks before start of study treatment.

4. Performance status: Eastern Cooperative Oncology Group (ECOG) 0 - 1

5. Life expectancy > 6 months as assessed by the investigator

6. Adequate organ function:

   • Bone marrow function: hemoglobin ≥ 100 g/L; white blood cell count (WBC) ≥ 3.0 x 109/L; lymphocyte count ≥ 1.0 x 109/L; absolute neutrophil count (ANC) ≥ 1.5 x 109/L; platelet count ≥ 100 x 109/L
   • Hepatic: aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 times upper limit of normal (ULN) (≤ 5 x ULN if hepatic metastases present); bilirubin ≤ 1.5 x ULN
   • Renal: Creatinine ≤ 2 mg/ dL and creatinine clearance ≥ 45 mL/ min

7. Patients of child-producing potential must agree to use contraception while enrolled in the study and for one month after the last immunization

8. Written informed consent must be obtained prior to conducting any study-specific procedures.

Exclusion Criteria:

1. History of anti-cancer therapy for advanced disease other than initial chemotherapy or chemo-radiotherapy or surgery
2. Immunotherapy within 4 weeks prior to study enrollment, including cytokines such as G-CSF, GM-CSF or interferons
3. Treatment with investigational anti-cancer agents during initial therapy for advanced disease or any investigational agents within 4 weeks prior to study enrollment
4. Concurrent anti-tumor therapy or concurrent immunotherapy such as lectins, unspecific immunostimulants, etc.
5. Previous anti-cancer immunotherapy comprising RNA-transfected dendritic cells or DNA vaccines targeting any tumor-associated antigens
6. Concurrent systemic steroids except topical (inhaled, topical, nasal) for the last 28 days, except replacement therapy
7. Concurrent major surgery or planned surgery
8. Prior splenectomy
9. Documented history of active autoimmune disorders requiring systemic immunosuppressive therapy, (e.g., sarcoidosis, lupus erythematosus, rheumatoid arthritis, glomerulonephritis or systemic vasculitis), excepting autoimmune thyroiditis with only thyroid hormone replacement and stable disease > 1 year
10. Primary or secondary immune deficiency
11. Active allergy requiring continuous medication or active infections requiring anti-infectious therapy
12. Seropositive for HIV, HBV or HCV
13. History of other malignancies over the last 5 years (except basal cell carcinoma of the skin or carcinoma in situ of the cervix)
14. Uncontrolled medical condition considered as high risk for the treatment with an investigational drug including unstable diabetes mellitus, vena-cava-syndrome, known ascites and/or uncontrolled pleural effusion.
15. Brain metastases (symptomatic or asymptomatic) or leptomeningeal involvement
16. Symptomatic congestive heart failure (NYHA 3 and 4); unstable angina pectoris within 6 months prior to enrollment; significant cardiac arrhythmia, history of stroke or transient ischemic attack
17. History of seizures, encephalitis or multiple sclerosis
18. Gastric ulcer or inflammatory bowel disease or Crohn's disease or ulcerative colitis; no active diverticulitis
19. Active drug abuse or chronic alcoholism
20. Patients being committed to an institution by virtue of an order issued either by the judicial or the administrative authorities