Trial of RNActive®-Derived Cancer Vaccine and Local Radiation in in Stage IV Non Small Cell Lung Cancer (NSCLC)

An Exploratory, Open-label Phase Ib Study of RNActive®-Derived Cancer Vaccine and Local Radiation as Consolidation and Maintenance Treatment in Patients With Stage IV NSCLC and a Response or Stable Disease After First-line Chemotherapy or Therapy With an EGFR Tyrosine Kinase Inhibitor

The purpose of this study is to determine whether the new RNActive derived lung cancer vaccine CV9202 in combination with local radiation therapy is safe, tolerable and immunogenic for the consolidation and maintenance treatment of stage IV non small cell lung cancer (NSCLC) after first-line chemotherapy or therapy with an EGFR tyrosine kinase inhibitor.

The Phase Ib study is the first clinical study with the new lung cancer vaccine CV9202. The vaccine is composed of 6 RNActive compounts, each encoding for a different antigen which is overexpressed in NSCLC compared to healthy tissue.

In order to enhance the immunogenic effect of the cancer vaccine, the study treatment will include local radiation (4 x 5 Gy), which is a well-established palliative radiation regimen that can be safely applied to metastatic lesions in the lung, bone, and soft tissue, and is well tolerated.

Patients will be enrolled into 3 strata based on histologic and molecular subtypes as follows:

Stratum 1: Patients with metastatic stage IV NSCLC and non-squamous histology, without activating epidermal growth factor receptor (EGFR) mutations, who have achieved partial response (PR) or stable disease (SD) after at least 4 cycles of platinum- and pemetrexed-based first-line chemotherapy, and an indication for maintenance therapy with pemetrexed.

Stratum 2: Patients with stage IV NSCLC and squamous cell histology, who achieved PR or SD after at least 4 cycles of platinum-based and non-platinum compound first-line chemotherapy.

Stratum 3: Patients with stage IV NSCLC and non-squamous histology, harboring an activating EGFR mutation, who have achieved PR after up to 6 months or SD after 3 - 6 months of treatment with an EGFR TKI.

In each patient, the vaccine will be administered until progression and the need to start a subsequent systemic second-line treatment, or occurrence of unacceptable toxicity requiring treatment discontinuation, whichever comes first.

Key Inclusion Criteria:

1. Patients >= 18 years of age with histologically or cytologically-confirmed stage IV NSCLC, and a confirmed EGFR mutation status in case of non-squamous cell histology

   • Stratum 1: Non-squamous NSCLC without activating EGFR mutation
   • Stratum 2: Squamous NSCLC
   • Stratum 3: Non-squamous NSCLC harboring an activating EGFR mutation

2. PR or SD according to RECIST Version 1.1 after first-line therapy which should have consisted of:

   • Stratum 1: PR or SD after cisplatin or carboplatin and pemetrexed treatment (at least 4 cycles)
   • Stratum 2: PR or SD after cisplatin or carboplatin and a non-platinum compound treatment (at least 4 cycles)
   • Stratum 3: PR after up to 6 months or SD after at least 3 and up to 6 months of gefitinib or erlotinib treatment

3. For patients in stratum 1, maintenance therapy with pemetrexed should be indicated as to the investigator's opinion

4. Presence of at least one tumor lesion that is eligible for radiation with 4 x 5 GY, and at least one additional measurable tumor lesion according to RECIST Version 1.1.

   Tumor lesions eligible for radiation are:

   • Bone metastases
   • Lymph nodes in the paraclavicular, axillary or cervical regions
   • Skin or subcutaneous metastases
   • For patients in strata 1 and 2 only: Thoracic lesions (centrally located lung tumor, lymph nodes in the lung hilus or mediastinum)

5. Performance Status: Eastern Cooperative Oncology Group (ECOG) 0 to 1

Key Exclusion Criteria:

1. Previous active immunotherapy for NSCLC (including vaccination, therapy with anti-CTLA4 antibodies)

2. Estimated life expectancy ≤ 3 months

3. Need for immunosuppressive treatment including daily systemic steroid doses of ≥ 10 mg prednisone equivalent per day

4. Active skin disease (e.g. atopic dermatitis) in the areas for vaccine injection (upper arms or thighs) not allowing intradermal injections into areas of healthy skin

5. Concurrent or planned major surgery

6. Prior splenectomy or prior allogeneic bone marrow transplantation

7. History of pneumonitis

8. Documented history or active autoimmune disorders with the exception of vitiligo, diabetes mellitus type 1 or autoimmune thyroiditis requiring hormone replacement only

9. Primary or secondary immune deficiency

10. Allergies to any components of the study drug including allergy to protamine hydrochloride (e.g. allergy to protamine-containing insulin) or fish allergy

11. Seropositive for HIV, HBV, HCV or any other infection requiring anti-infection therapy

12. For patients in stratum 3: persisting >= grade 3 skin rash at time of enrollment

13. Known brain metastases with the exception of stable metastases being treated with stereotactic radiation or surgery)

    **Local German Amendment: 13. Brain metastases (symptomatic or asymptomatic) or leptomeningeal involvement

14. Uncontrolled medical condition considered as high risk for the treatment with an investigational drug (e.g. unstable diabetes mellitus, vena-cava-syndrome, uncontrolled pleural effusion, pericardial effusion, symptomatic congestive heart failure (New York Heart Association 3 or 4), unstable angina pectoris/myocardial infarction within the previous 6 months, significant cardiac arrhythmia, history of stroke or transient ischemic attack within the previous 6 months, severe hypertension according to WHO criteria, and uncontrolled systolic blood pressure ≥ 180 mmHg at the time of enrollment

15. For patients planned to undergo radiation of thoracic lesions: inadequate lung function dependent on the intended tumor volume and location to be irradiated (to be assessed by the radio oncologist)

16. History of encephalitis or multiple sclerosis

17. Active inflammatory conditions such as inflammatory bowel disease