A Clinical Study for the Efficacy and Safety of BL0020 Injection in Patients With Small Cell Lung Cancer Transformed From Non-Small Cell Lung Cancer Following EGFR TKI Therapy

An Open-Label, Single-Arm Phase I/II Clinical Study to Evaluate the Efficacy and Safety of BL0020 Injection in Patients With Small Cell Lung Cancer Transformed From Non-Small Cell Lung Cancer Following EGFR TKI Therapy

The primary treatment option for non-small cell lung cancer (NSCLC) adenocarcinoma with activating epidermal growth factor receptor (EGFR) mutation is EGFR tyrosine kinase inhibitor (TKI). After a certain period of treatment with EGFR TKI, acquired resistance emerges most frequently with a secondary mutation, p.T790M, followed by MET amplification. Interestingly, up to 3-14% of patients experience histological transformation into small cell lung cancer (SCLC), which has an aggressive clinical course and a poor prognosis.

The transformed SCLC retains the original EGFR mutation but significantly down regulates EGFR protein expression, eliminating its dependence on EGFR signaling while simultaneously acquiring a neuroendocrine phenotype. In nearly all cases, bi-allelic inactivation of both TP53 and RB1 is observed. However, little is known about the clinical outcomes of transformed SCLC, with limited studies arguing that their outcomes are similar to those of de novo SCLC, where the median overall survival is approximately 9 to 10 months after the transformation.

At present, there is no standard treatment regimen for patients with SCLC transformed from NSCLC following EGFR TKI therapy.

BL0020 is a polymer-drug conjugate consisting of Topoisomerase I inhibitor SN-38 (7-ethyl-10-hydroxycamptothecin) conjugated by a peptide linker to a PEG-modified poly(ε-L-lysine) polymer. In the ongoing first-in-human study of BL0020, significant efficacy has been observed with BL0020 monotherapy in SCLC patients who have relapsed or progressed following at least first-line platinum-based systemic treatment.

Based on previous clinical and preclinical outcomes that show similar disease characteristics between SCLC transformed from NSCLC following EGFR TKI therapy and de novo SCLC, this study is designed to evaluate the clinical efficacy and safety of BL0020 in patients with transformed SCLC.

Inclusion Criteria:

1. Volunteer to participate in the study, be able to understand the requirements of a clinical study, and willingness to sign a written informed consent form.

2. Aged ≥ 18 years, male or female.

3. Patients with initial diagnosis of EGFR-mutated NSCLC and histologically or cytologically confirmed transformation to SCLC following treatment with EGFR tyrosine kinase inhibitor.

4. After transformation to SCLC, the patient's prior treatment history must meet one of the following criteria:

   • Progression after only receiving platinum-based treatment regimens.
   • No prior systemic therapy for SCLC.

5. Eastern Cooperative Oncology Group (ECOG) performance status score 0 or 1 at screening.

6. Life expectancy ≥ 12 weeks.

Exclusion Criteria:

1. Patients with symptomatic brain metastases or carcinoma meningitis. Note:

   • Patients with treated brain metastases may participate in this study if the patient has completed radiotherapy or surgery for brain metastases ≥ 4 weeks prior to study entry, and neurologically stable ≥ 4 weeks after radiotherapy or surgery treatment [i.e., no new findings on brain imaging and no new neurologic deficits from brain metastasis on screening examination, and high doses of corticosteroids (> 10 mg prednisone daily or equivalent) were not required within 4 weeks prior to enrollment].
   • Patients with brainstem metastases or spinal cord compression (detected by radiographic imaging, even if they did not have symptoms) were not eligible.

2. Patients who have a history of another primary malignancy (with the exception of patients with cured basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ of uterine cervix). A patient who has had no evidence of disease from another primary cancer for 3 or more years is allowed to participate in the study.

3. Patients with tumors that had invaded important blood vessels as shown in the screening imaging and that the investigators assessed were highly likely to cause fatal bleeding during the study.

4. Patients whose pericardial effusion, pleural effusion or ascites remain uncontrollable after intervention.

5. Patients with Gilbert's syndrome disease.

6. Patients who have a known diagnosis of Human Immunodeficiency Virus (HIV) infection or HIV antibody test positive during screening.

7. Patients with active hepatitis C or chronic hepatitis B at screening ("active hepatitis" defined as HCV RNA level ≥ 200 IU/mL for hepatitis C or HBV DNA level ≥ 2000 IU/mL for hepatitis B at screening). In addition, eligible hepatitis B or hepatitis C patients must agree to antiviral treatment according to the treatment guidelines.

8. Patients who have not sufficient baseline organ function.

9. Those who are known to be allergic to the active ingredient or excipients of the investigational product BL0020 Injection, or who have a predisposition to allergy.

10. Patients who are taking anticoagulant therapy (prophylactic use of low-dose aspirin [≤ 100 mg/day] or low molecular weight heparin is allowed).

11. Those who have received live or attenuated vaccines (e.g., measles, mumps, rubella, varicella, yellow fever, rabies, BCG, typhoid vaccine, etc.) within 4 weeks before enrollment or scheduled to receive during the study.

12. Pregnant or lactating women.

13. Patients who are assessed disqualified to join clinical studies by investigator due to any causes.