Cellular Immunotherapy Synergize Chemotherapy in Patients With Stage IV NSCLC

A Randomized Phase II Study to Evaluate Efficacy and Safety of DCVAC/LuCa Added to Chemotherapy With Carboplatin and Pemetrexed vs Chemotherapy Alone in Patients With Stage IV Non-small Cell Lung Cancer

This is a randomized, open-label, phaseⅡ study evaluating efficacy and safety of DC (dendritic cells) vaccine concurrent with chemotherapy compared to chemotherapy alone in patients with stage IV NSCLC (non small cell lung cancer) with wild-type EGFR (epidermal growth factor receptor).

Screening period: Patients will be screened for eligibility for the clinical study within a 4-week period.

Randomization and leukapheresis periods: When the patients meet all entry criteria, they will be randomized in a ratio of 1:1 into one of the following two groups:

Group A (experimental group): Treatment with DC in addition to chemotherapy with 4-6 cycles of pemetrexed/carboplatin as first-line induction chemotherapy followed by pemetrexed as maintenance therapy. These patients will undergo leukapheresis within 1 week after randomization before start of treatment.

Group B (control group): Chemotherapy with 4-6 cycles of pemetrexed/carboplatin as first-line induction chemotherapy followed by pemetrexed as maintenance therapy.

Treatment periods:

Standard of care chemotherapy will be administered to patients in both treatment groups in cycles. Each chemotherapy cycle will be 3 weeks long. Patients in the group A will start with chemotherapy 2-5 days after leukapheresis, and patients in the group B will start with chemotherapy within 2 weeks after randomization.

Induction chemotherapy period

Pemetrexed in combination with carboplatin will be administered on Day 1 of each 3-week chemotherapy cycle. After 2 cycles of chemotherapy, tumor response will be evaluated according to RECIST v. 1.1. Patients with progressive disease or intolerance to chemotherapy will terminate study treatment but will be followed for survival. Patients with complete response, partial response, or stable disease will continue chemotherapy with carboplatin and pemetrexed for a total of 6 cycles . After at least a total of 4 cycles of chemotherapy, patients can be administered pemetrexed maintenance chemotherapy.

Maintenance chemotherapy period

During the Maintenance chemotherapy period, patients will receive pemetrexed of each 3-week chemotherapy cycle. Chemotherapy with pemetrexed will be administered in up to a total of 21 cycles or until disease progression or development of intolerance.

DCVAC

Patients in the group A will start with DC treatment on Day 15 of chemotherapy Cycle 3 provided.During the Induction chemotherapy period, DC will be administered on Day 15 of each subsequent 3-week chemotherapy cycle of chemotherapy. During the Maintenance chemotherapy period, DC will be administered on Day 15 of every other 3-week chemotherapy cycle.

Follow-up periods: Patients who complete or discontinue all study treatments after Cycle 3 before disease progression will undergo disease evaluation by CT scan every 3 months until progression of the disease.Patients who discontinue all study treatments before or at Cycle 2 for any reason or those who complete or discontinue all study treatments after Cycle 3 after disease progression will be followed up for survival. The survival data will be collected every 3 months by directly contacting the patient (or a relative/caretaker) by phone until death from any reason or termination of the study. The clinical study will be terminated when at least 45 PFS (progression-free survival) events have been reached, which is assumed to happen approximately 24 months after start of treatment of the first patient included in the study.

Inclusion Criteria:

1. Histologically or cytologically confirmed stage IV, non-squamous, wild-type EGFR,ALK-negative NSCLC

2. Signed ICF and ability to comply with this protocol

3. 18 years of age or older

4. ECOG performance status of 0-1

5. Patients must have measurable disease as defined by RECIST v. 1.1

6. Systematic treatment naive with respect to the currently diagnosed NSCLC

7. Patients must have recovered from toxicity of previous therapy. Recovery is defined as less than or equal to grade 2 toxicity according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (except alopecia).

8. Sufficient hematologic and organ function for leukapheresis and chemotherapy:

   • WBC equal to or higher than 4×10^9 /L
   • Neutrophil equal to or higher than 1.5×10^9 /L
   • PLT equal to or higher than 100×10^9 /L
   • Hemoglobin equal to or higher than9 g/dL (90 g/L)
   • Total bilirubin less than or equal to 1.5 times upper limit of normal (benign hereditary hyperbilirubinemias, eg, Gilbert's syndrome are permitted)
   • Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) should be less than or equal to 3 times upper limit of normal. ALP, AST, and ALT less than or equal to 5 times upper limit of normal is acceptable if liver has tumor involvement.
   • Creatinine clearance equal to or higher than 45 mL/min (calculated with the standard Cockcroft and Gault formula)

9. Women of childbearing potential and sexually active males must agree to use an accepted and effective method of contraception (hormonal or barrier methods, abstinence) prior to study entry and for the duration of the treatment plus 3 months

Exclusion Criteria:

1. Known active/untreated CNS metastases

2. Any known primary immunodeficiency

3. Any preexisting medical condition requiring long term chronic steroid or immunosuppressive therapy

4. HIV positivity, hepatitis B and/or C infection, syphilis

5. Past or current history of malignant neoplasm other than lung carcinoma, except for adequately treated non-melanoma skin cancer, in situ carcinoma of the cervix, or other cancer curatively treated and with no evidence of disease for at least five years

6. Patient's significant co-morbidities:

   • Cardiovascular diseases - unstable angina pectoris, uncontrolled hypertension, myocardial infarction or ventricular arrhythmia or stroke within a 6-month period before randomization, congestive heart failure or cardiac arrhythmia not controlled by treatment
   • Active severe infections or other severe medical condition

7. Participation in a clinical study using experimental therapy and immunotherapy,monoclonal antibodies within the last 4 weeks prior to study entry

8. Pregnant or breastfeeding woman

9. History of severe hypersensitivity to pemetrexed and carboplatin and their ingredients, and to DCVAC ingredients