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RECORD 2: CLINICAL STUDY PROTOCOL — PROTOCOL AMENDMENT 3.0
STUDY CODE: BV-402 (SUBSTANTIVE SAFETY AMENDMENT)
DATE OF APPROVAL: AUGUST 22, 2026
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SECTION 4: PARTICIPANT ELIGIBILITY CRITERIA

4.1 Inclusion Criteria
Candidates are eligible for enrollment only if all of the following criteria apply:
1. Age 18 years or older at the time of signing informed consent.
2. Histologically or cytologically confirmed metastatic solid tumor refractory to standard 
systemic therapy.
3. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.
4. Adequate bone marrow and organ function documented within seven (7) days prior to Cycle 1, Day 1:
   a. Absolute neutrophil count (ANC) >= 1,500/mcL.
   b. Platelet count >= 100,000/mcL.
   c. Total serum bilirubin <= 1.2 x ULN (tightened from 1.5 x ULN).
   d. Serum AST and ALT <= 1.5 x ULN (tightened from 2.5 x ULN); in patients with documented, 
   radiographically verified hepatic metastases, AST and ALT <= 2.5 x ULN remains acceptable.
   e. Serum creatinine <= 1.2 x ULN or calculated creatinine clearance >= 60 mL/min.
5. Prior systemic anti-cancer therapy, including targeted therapies and immunotherapy, must 
have concluded at least forty-two (42) days prior to Cycle 1, Day 1 (increased from 28 days to 
ensure comprehensive immune washout).

4.2 Exclusion Criteria
Candidates are excluded from enrollment if any of the following criteria apply:
1. Active or untreated central nervous system (CNS) metastases.
2. Uncontrolled intercurrent illness including active systemic bacterial or viral infection.
3. Known positive serology for HIV or active Hepatitis B/C.
4. History of Grade 2 or higher immune-related pneumonitis, colitis, nephritis, or myocarditis 
from prior checkpoint inhibitors (broadened exclusion threshold from Grade 3 to Grade 2).
5. Concomitant use of strong CYP3A4 inhibitors or inducers within fourteen (14) days of study initiation.

SECTION 5: INVESTIGATIONAL PRODUCT DOSAGE AND ADMINISTRATION

5.1 Dosing Schedule
Investigational product BV-402 will be administered as an intravenous (IV) infusion over 
60 minutes on Day 1 of each fourteen (14) day cycle (Q2W).
Following the observation of two dose-limiting hepatic toxicities (DLTs) in Cohort 2 under 
Protocol v2.1, the recommended starting dose for all subsequent cohorts is reduced to 100 mg Q2W.
Intra-patient dose escalation is formally terminated and prohibited.

5.2 Dose Reductions
If dose reduction is required due to adverse drug reactions:
- Dose reduction (Level -1): 75 mg Q2W.
- Dose reduction below 75 mg is not permitted. Any patient experiencing recurrent Grade >= 2 
toxicity at the 75 mg dose level must be permanently discontinued from study treatment.

SECTION 7: SAFETY REPORTING AND REGULATORY MONITORING

7.3 Expedited Safety Reporting
The Principal Investigator must report any Serious Adverse Event (SAE), Grade >= 3 
hepatotoxicity, or suspected immune-related adverse event (irAE) to the Sponsor Medical 
Monitor and reviewing Institutional Review Board (IRB) within twenty-four (24) hours of site 
awareness (expedited from 72 hours).
