Safety and Tolerability of CVHNLC Plus Pembrolizumab in Patients With Squamous Non Small-Cell Lung Cancer (sqNSCLC)

Dose Escalation (Metastatic 1L Maintenance sqNSCLC) The Dose Escalation Part will be comprised of 3 dose cohorts with a starting dose of 100 μg (dose level 1). Once the starting dose is established as safe, further dose levels of 200 μg and 400 μg may be explored. Depending on safety assessment guided by a Bayesian Logistic Regression Model (BLRM) design intermediate dose levels may be explored. In case the HTD is exceeded at 100 μg, a lower dose level of 50 μg may be explored.

Approximately 3 to 6 patients will be enrolled per dose level/cohort. To better understand the safety and tolerability of CVHNLC, additional patients may be enrolled in enrichment cohorts at dose levels that have previously been determined to be safe in at least 3 patients. This may be before or while proceeding with the next higher dose. An enrichment cohort may have up to 10 patients enrolled.

Each dose level will start with the staggered enrollment of 3 patients. There will be a 2-week interval between the first CVHNLC administration of the first patient and the first CVHNLC administration of the second patient. The same approach will be used between the second and third patient. If the cohort is enriched with further patients, subsequent patients may be treated concurrently once the second patient has completed the 2 weeks after the first CVHNLC administration. The enrollment is followed by a safety data review by the Safety Review Team (SRT) after all patients in each cohort have completed their 4 weeks DLT evaluation period. Non-evaluable patients (patients that discontinue/withdraw during the DLT assessment period for a reason other than DLT) may be replaced.

Safety will be continuously monitored by the Sponsor's Safety Physician, Sponsor's Medical Responsible Person (MRP) and the medical monitor with a focus on DLTs, Grade ≥ 3 AEs occurring after the DLT period, SAEs, and AESIs. After completion of the DLT evaluation period in all patients enrolled in a dose cohort, the SRT will review the safety data from the respective and all previous dose cohorts together with the Coordinating Investigator and decide about the next steps e.g.:

• Escalation of the dose to the next level.
• Enrollment of additional patients at the same or lower dose level.
• Stop or pause enrollment in the Dose Escalation Part of the trial.

At the end of the Dose Escalation Part, an independent Data Safety Monitoring Board (DSMB) will recommend a dose for the Dose Expansion Part (RDE) based on review of the complete safety data from the Dose Escalation Part and the Sponsor will decide on the RDE.

Dose Expansion Part (Metastatic 1L sqNSCLC) The optional Dose Expansion Part will include patients with histologically confirmed metastatic sqNSCLC not amenable for surgical or locoregional therapy and eligible for 1L treatment with pembrolizumab and platinum-based chemotherapy (carboplatin/paclitaxel). Patients should not have received any prior systemic treatment for metastatic disease. Previous (neo-)adjuvant treatment is only permitted if there are at least 12 months between end of such treatment and development of metastatic disease. Patients will receive CVHNLC plus 4 cycles of carboplatin and paclitaxel and pembrolizumab (3-weekly) followed by pembrolizumab maintenance therapy. Patients who discontinue prematurely from chemotherapy due to toxicity may continue on CVHNLC plus pembrolizumab. The first dose of CVHNLC will be administered one week prior to chemotherapy to avoid the immune suppressive effect from concomitant administration of steroids as premedication/supportive medication to chemotherapy treatment. Once chemotherapy is completed, CVHNLC administration will be aligned with pembrolizumab treatment to reduce patient visit burden.

The Dose Expansion Part will start with a safety lead-in, where the first 6 patients will be evaluated with focus on treatment-related AEs, SAEs, and AESIs after having completed the Day 29 visit, before continuing the enrollment. The safety data will be reviewed by the SRT and in addition by the DSMB, which will give a recommendation on dosage for treatment continuation. Patients will receive CVHNLC plus pembrolizumab for up to 12 months or until disease progression or undue toxicity. Patients not progressing after this period may continue on pembrolizumab outside of the trial according to standard of care.