A Phase Ib/II Clinical Trial of M701 in the Treatment of Malignant Pleural Effusions Caused by NSCLC

A Phase 1, Multicenter, Open-label, Dose-increasing Study to Evaluate the Safety, Tolerability, PK/PD and Preliminary Efficacy of M701, a Recombinant Epcam and CD3 Bispecific Antibody , in Patients With Malignant Pleural Effusions Caused by NSCLC

This is a phase 1/phase 2, multicenter, open-label study to evaluate the safety, tolerability, PK, PD, immunogenicity and preliminary efficacy of M701 in patients with treatment of malignant pleural effusions caused by NSCLC.

This study is consisted of two phase, Phase Ib and II:

Phase 1b includes dose escalation phase and cohort expansion phase. In dose escalation phase, up to 4 dose-escalation cohorts will be sequentially enrolled with regular "3+3" design. DLTs will be evaluated during the first treatment cycle, which is 28 days. In cohort expansion phase, after the RP2D was identified, participants were enrolled in an open-ended manner. Participants were assigned to groups A(3 injections), B (4 injections)and C(6 injections) on a 1:1:1 basis to evaluate the dose frequency.

Phase II:The dose and dosing frequency of M701 drug for the Phase II clinical trial were determined based on a combination of the tolerance1 and efficacy of M701 in the Phase Ib trial. Then the participants were randomly divided into two groups: the test group(M701) and the control group(cisplatin or pleural effusions suctions). The pleural effusions response (ORR) and Puncture Free Survival （PuFS）will be evaluated.

Inclusion Criteria:

1. Aged >18 years and ≤ 75 years, male or female.
2. Histologically or cytologically confirmed advanced non-small cell lung cancer that has progressed after at least one line of systemic anti-tumor treatment (including subjects with local malignant pleural effusion progression or inadequately controlled).
3. Malignant pleural effusion requiring intrathoracic perfusion treatment (malignant pleural effusion should be diagnosed histologically or cytologically), with moderate or above amount of pleural effusion (the depth of pleural effusion by B-mode ultrasound in sitting position is ≥ 4 cm, and the actual drainage volume of pleural effusion is ≥ 500 mL), and the study physician judges that clinical intervention is required.
4. If the subject received latest systemic treatment regimen at least 1 course (at least 21 days for targeted therapy) and poorly controlled pleural effusion , then no washout interval is required.
5. Any toxicity from prior antineoplastic therapy should have recovered to Grade 0-1 as determined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) V5.0, except alopecia, pigmentation, and Grade ≤ 2 neuropathy, hypothyroidism on hormone replacement therapy, or other adverse events that are confirmed to be chronic.
6. ECOG score (PS) of 0-1 (for subjects with inadequately controlled malignant pleural effusion of whom ECOG score is 2 can be enrolled).
7. An expected survival ≥ 12 weeks. 8.8.Organ functions must meet the following criteria: Hemogram (no transfusion of blood or blood products, no correction with granulocyte-colony stimulating factor (G-CSF) or other hematopoietic stimulating factors within 14 days before the first dose): absolute neutrophil count (ANC) ≥ 1.5 109/L, platelet (PLT) ≥ 100 109/L, and hemoglobin (HGB) ≥ 85 g/L; Hepatic function: total bilirubin (TBIL) ≤ 1.5 × ULN, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × ULN (AST and ALT ≤ 5 × ULN in case of liver metastasis), serum albumin > 28 g/L; Renal function: Serum creatinine (Cr) ≤ 1.5 × ULN.

9.Understand and voluntarily sign the written informed consent form.

Exclusion Criteria:

1. Subjects with recurrent pleural effusion within 4 weeks after the last intrathoracic perfusion treatment and requiring clinical intervention.
2. Subjects who have received intrathoracic infusion of immune drugs, such as PD-1, PD-L1, CTLA-4, and other immune checkpoint inhibitors (excluding interleukins).
3. Subjects with malignant pleural effusion requiring clinical intervention on both sides, or those in whom adequate drainage of pleural effusion is not possible due to objective reasons (including loculated pleural effusion), or complicated with chylothorax, or with moderate or greater pericardial effusion, or pneumothorax.
4. Subjects with central nervous system (CNS) metastases resulting in clinical symptoms or requiring therapeutic intervention; patients with previously treated brain metastases can be enrolled if they are asymptomatic and have stable disease as indicated by imaging examination ≥ 4 weeks before the first dose and do not require corticosteroids or anticonvulsant therapy.
5. Subjects with known history of severe allergy to any ingredient of M701 or similar macromolecular antibody drugs.
6. Subjects with contraindications to thoracentesis.
7. Subjects who have undergone major surgery within 4 weeks before the first dose.
8. Subjects combined with active infection that have not been controlled to a clinically stable state within the previous 3 days before randomization.
9. Subjects who require long-term hormone or immunosuppressive therapy, such as active autoimmune diseases, maintenance therapy after organ transplantation, but patients with the following conditions are allowed to be screened: type I diabetes; hypothyroidism that can be controlled by replacement therapy only; skin diseases that do not require systemic treatment (e.g., vitiligo, psoriasis, or alopecia).
10. Subjects with severe respiratory diseases or interstitial pneumonia, who are not suitable for enrollment as determined by the investigator.
11. Combined with severe cardiovascular disease, including cardiac insufficiency (New York Heart Association class III-IV), or acute cardiovascular event (such as acute myocardial infarction, acute cerebral infarction, angina pectoris unstable, hemorrhage brain, etc.) or pulmonary embolism within the past 6 months, or received a vascular stent implantation (such as coronary artery stent implantation, intracranial artery stent implantation, etc.) within the past 6 months; or experienced a new venous thrombotic disease such as lower extremity venous thrombosis has occurred within the past 1 month.
12. The mean corrected QT interval (QTcF) > 450 ms (male) or > 470 ms (female) in 3 electrocardiogram (ECG) examinations at screening (only those with QTcF > 450 ms (male) or > 470 ms (female) at the first ECG examination should be retested to obtain the mean corrected value of 3 retests); family or personal history of long or short QT syndrome; clinically significant history of arrhythmia, or implantation of defibrillation device for ventricular arrhythmia.
13. History of malignancy (other than the study tumor) within 3 years prior to the date of first dose of investigational drug (except for squamous or basal cell carcinoma of the skin, carcinoma in situ of the cervix or breast, or other non-invasive diseases that are considered by the investigator and the sponsor to be cured with minimal risk of recurrence within 3 years).
14. Combined with active chronic hepatitis B (e.g., hepatitis B surface antigen [HBsAg]-positive and/or hepatitis B core antibody (HBcAb)-positive, with HBV-DNA quantification ≥1×10⁴ copies/mL or ≥2000 IU/mL), active hepatitis C (hepatitis C antibody-positive, and [e.g., hepatitis C virus (HCV-RNA) higher than the analytical method] antibody-positive, with HCV-RNA ≥ the lower limit of detection), [,] human immunodeficiency virus (HIV) antibody-positive or active syphilis, HIV antibody-positive infection (syphilis-specific antibody-positive and syphilis non-specific antibody-positive);
15. Pregnant or lactating women; men or women who plan to have children within 6 months after the end of this clinical study.
16. Subjects with a history of confirmed neurological or mental disorders who cannot cooperate with the treatment and follow the doctor's advice as judged by the investigator.
17. Other conditions that the investigator considers unsuitable for participating in this clinical study.