Synthetic Clinical Trial Protocol Protocol Title A Randomized, Open-Label, Phase II Study of OVX-330 in Combination With Standard-of-Care Therapy Versus Standard-of-Care Therapy Alone in Patients With Previously Untreated, Metastatic Non-Small Cell Lung Cancer Protocol Number: OVX330-NSCLC-2027-02 Version: 1.0 Date: October 8, 2026 Sponsor: Helix Oncology, Inc. (synthetic) Phase: II Study Type: Interventional Allocation: Randomized, 1:1 Blinding: Open-label Estimated Enrollment: 180 participants Study Duration: 6 months per participant (primary endpoint) Geographic Scope: United States, Canada, Australia (synthetic) 1. Background and Rationale Advanced non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. Patients with metastatic disease have limited therapeutic options despite recent advances in immunotherapy and targeted agents. OVX-330 is a novel investigational small-molecule inhibitor designed to potentiate immune response and enhance standard-of-care efficacy. This Phase II study is designed to evaluate whether OVX-330 combined with standard-of-care therapy improves progression-free survival (PFS) compared with standard-of-care therapy alone in patients with previously untreated, metastatic NSCLC. 2. Study Objectives Primary objective Evaluate the effect of OVX-330 plus standard-of-care therapy on progression-free survival (PFS) at 6 months compared with standard-of-care therapy alone. Secondary objectives Evaluate overall survival (OS) at 12 months. Determine the objective response rate (ORR) per RECIST 1.1. Evaluate disease control rate (DCR). Characterize the safety and tolerability of OVX-330 in combination with standard-of-care therapy. Evaluate time to progression. Assess patient-reported outcomes and quality of life. Exploratory objectives Evaluate PFS and ORR by baseline disease burden. Explore biomarkers predictive of treatment response. Characterize pharmacokinetic exposure of OVX-330. Evaluate patient adherence to combination therapy. 3. Study Population Patients with previously untreated, histologically or cytologically confirmed, metastatic (stage IV) non-small cell lung cancer. Target population: 180 patients Age: 18–75 years 4. Key Inclusion Criteria Patients must: Be 18–75 years of age. Have histologically or cytologically confirmed metastatic NSCLC (stage IV per AJCC 8th edition). Have received no prior systemic anti-cancer therapy for metastatic disease. Have ECOG performance status 0 or 1. Have at least one measurable lesion per RECIST 1.1. Have adequate organ and marrow function: ANC ≥1,500/μL, platelets ≥100,000/μL, hemoglobin ≥9.0 g/dL, creatinine ≤1.5×ULN, AST/ALT ≤2.5×ULN (or ≤5×ULN if liver metastases). Be willing and able to comply with study procedures and assessments. Provide written informed consent. 5. Key Exclusion Criteria Patients will be excluded for: Untreated symptomatic brain or leptomeningeal metastases. Prior therapy with compounds targeting similar pathways. Severe renal impairment (creatinine clearance <30 mL/min). Significant hepatic disease (Child-Pugh B or C). Active malignancy other than NSCLC within 2 years. Uncontrolled hypertension or cardiovascular disease. Active infection requiring systemic therapy. Pregnancy or breastfeeding. Known hypersensitivity to investigational product or excipients. Concurrent participation in another clinical trial. 6. Treatment Arms Arm Treatment Participants A OVX-330 (100 mg daily) + standard-of-care 90 B Standard-of-care therapy alone 90 Standard-of-care therapy is platinum-based chemotherapy (pemetrexed + cisplatin or carboplatin) administered per institutional guidelines. 7. Study Schedule Visit Timing Major Activities Screening Day −14 to −1 Eligibility, consent, imaging, labs, ECG Baseline/Randomization Day 1 Randomization, vital signs, baseline imaging, first dose Cycle 1, Day 8 Week 1 Labs, safety assessment Cycle 1, Day 15 Week 2 Labs, safety assessment Cycle 1, Day 22 Week 3 Labs, safety assessment Week 4 Assessment Week 4 Imaging, labs, AE review Week 8 Assessment Week 8 Imaging, labs, AE review Week 12 Assessment Week 12 Imaging, labs, PROs, AE review Week 16 Assessment Week 16 Imaging, labs, AE review Week 20 Assessment Week 20 Imaging, labs, AE review Primary Endpoint Week 24 Imaging, labs, ECG, PFS status, AE review Follow-up Week 32 OS status, final assessment 8. Primary Endpoint Progression-free survival (PFS) at 6 months, defined as the time from randomization to disease progression (per RECIST 1.1) or death from any cause, whichever occurs first. 9. Secondary Endpoints Overall survival (OS) at 12 months. Objective response rate (ORR) per RECIST 1.1. Disease control rate (DCR) = complete response + partial response + stable disease. Time to progression (TTP). Duration of response. Incidence and severity of adverse events and serious adverse events. Dose intensity of both arms. Patient-reported outcomes (quality of life and symptoms). 10. Safety Assessments Safety monitoring will include: Adverse events (AEs) and serious adverse events (SAEs). Vital signs (blood pressure, heart rate, temperature). Physical examination. Hematology (CBC with differential). Chemistry (electrolytes, renal function, hepatic function). Coagulation studies. 12-lead electrocardiogram (ECG). Pregnancy testing where applicable. Concomitant medications review. Cumulative toxicity assessment. AEs will be graded per NCI CTCAE v5.0 and coded using MedDRA. 11. Randomization Patients will be randomized 1:1 using an interactive web response system (IWRS). Randomization will be stratified by: ECOG performance status (0 vs 1) Baseline disease burden (sum of longest diameter <100 mm vs ≥100 mm per RECIST 1.1) Geographic region (North America vs Australia/other) 12. Statistical Analysis The primary analysis will use the intention-to-treat (ITT) population. PFS will be analyzed using a log-rank test, comparing OVX-330 + SoC versus SoC alone. Kaplan-Meier curves will be presented with 95% confidence intervals for median PFS. The treatment hazard ratio will be reported with a two-sided 95% confidence interval. A two-sided α = 0.05 will be used for the primary hypothesis test. 13. Sample Size Assuming: PFS hazard ratio: 0.65 (OVX-330 + SoC vs SoC alone) Median PFS (SoC alone): 5.0 months Median PFS (OVX-330 + SoC): 7.7 months (approximately 54% improvement) Two-sided α = 0.05 Power: 85% Dropout/loss to follow-up: 10% The planned enrollment is 180 patients (90 per arm). 14. Data Collection The study will capture: Patient-level data Demographics Medical history (including prior malignancies) Eligibility assessment Comorbidities Smoking history Baseline disease characteristics Clinical and pathology data Histology and stage Molecular markers (PD-L1 status, mutation status if available) ECOG performance status Baseline imaging and measurements Treatment exposure and modifications Dose and duration of both study and standard-of-care therapies Dose reductions, interruptions, and discontinuations Reasons for modifications Adherence data Efficacy assessments Tumor measurements (RECIST 1.1) Response assessments Imaging reports PFS and OS status Safety data Adverse events and serious adverse events Laboratory results ECG findings Vital signs Concomitant medications Patient-reported outcomes Quality-of-life questionnaires Symptom assessments Treatment satisfaction surveys Trial operational data Visit completion status Protocol deviations Enrollment tracking AE reporting timelines Data queries and resolution