A Study of NI-1801 in Patients With Mesothelin Expressing Solid Cancers

Study Overview
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Brief Summary
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Study LCB-1801-001 is an open-label, Phase 1, dose escalation (Part A) and expansion (Part B), first-in-human clinical study of NI-1801 in subjects with advanced, metastatic, or recurrent solid malignancies expressing mesothelin (MSLN). The dose escalation part (Part A) of the study will evaluate the safety and tolerability of escalating doses of NI-1801, administered intravenously (IV) to determine the maximum tolerated dose (MTD) and non-tolerated toxic dose (NTD) of both the first dose and subsequent doses of NI-1801. The expansion part (Part B) will further evaluate the safety and efficacy of NI-1801 administered at or below the MTD in up to 20 subjects in order to determine the recommended Phase 2 dose (RP2D). Treatments will be administered in 28-day cycles for up to 6 months until confirmed disease progression, unacceptable toxicity, or subject/Investigator decision to withdraw. NI-1801 treatment can extend beyond 6 cycles for those patients who do not have disease progression.

Official Title
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A Phase 1, Open-label, Dose Finding Study of NI-1801, a Bispecific Mesothelin x CD47 Engaging Antibody, in Patients With Mesothelin Expressing Solid Cancers

Conditions
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Epithelial Ovarian Cancer, Triple Negative Breast Cancer, Non-squamous Non-small-cell Lung Cancer

Intervention / Treatment
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* Biological: NI-1801


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria: Adults ≥ 18 years of age at the time of signing the informed consent form. Histologically or cytologically confirmed diagnosis of epithelial ovarian cancer (high-grade serous or endometroid), triple-negative breast cancer, or non-squamous non-small cell lung cancer. MSLN expression with staining intensity of ≥ 2+ as per IHC in ≥ 60 % of tumor cells. Patients with advanced, metastatic, or recurrent disease after at least 1 prior systemic treatment for the primary malignancy and who have failed treatment with, are intolerant to, or are not candidates for available therapies that are known to confer a clinical benefit to patients with these tumor entities. Measurable disease according to the revised RECIST guideline version 1.1 Eastern Cooperative Oncology Group performance status 0-1. Adequate organ function Adequate contraception Life expectancy of at least 2 months. Main Exclusion Criteria: Patient has known hypersensitivity to NI-1801 or any of the constituent compounds. Radiotherapy to the target lesions within 4 weeks prior to the first NI-1801 infusion. Prior anti-cancer therapy including chemotherapy, hormonal therapy, and investigational agents within 2 weeks or within ≤ 5 half-lives prior to starting NI-1801 dosing (up to a maximum of 4 weeks), whichever is longer. Other investigational therapies must not be used, i.e., treatment within another clinical trial is not permitted, while the patient is on study. Severe cardiac dysfunction (NYHA classification III-IV). Significant hepatic dysfunction (serum bilirubin ≥ 1.5 mg/dL or AST and/or ALT ≥ 2.5 times normal level), unless related to liver metastasis. Uncontrolled active systemic bacterial, viral, fungal, or other infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment), or intravenous anti-infective treatment within 2 weeks prior to first dose of NI-1801. Patients with concomitant active malignancy, requiring ongoing systemic treatment. Patients with known CNS metastases. Platelet count < 100 x 10^9/L (transfusion support within 14 days before the test is not allowed). Hemoglobin < 10.0 g/dL. Prior RBC transfusion is permitted. ANC < 1 x 10^9/L (the use of colony stimulating factors, G-CSF or GM-CSF, within 14 days before the test is not allowed). Pregnancy and lactation. Significant medical diseases or conditions, including laboratory abnormalities, as assessed by the Investigators and Sponsor, that would substantially increase the risk-benefit ratio of participating in the study. This includes, but is not limited to, acute myocardial infarction within the last 6 months, unstable angina, uncontrolled diabetes mellitus, and severely immunocompromised state, major surgery ≤ 4 weeks prior to starting NI-1801. Prior treatment with a CD47, SIRPα, or MSLN targeting agent. Patients in whom acute toxic effects of any prior radiotherapy, chemotherapy, or surgical procedure have not resolved to Grade ≤ 1 or returned to baseline except for alopecia (any grade), anemia, and peripheral neuropathy (for the latter, recovery to Grade ≤ 2 is acceptable).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NI-1801<br> | Biological: NI-1801<br>* All treatments will be administered in 28-day cycles. Each subject will receive the assigned dose of NI-1801 on Cycle 1, Day 1. Subsequent doses will be given once weekly (QW) in Cycles 1 and 2 (e.g., Days 1, 8, 15, and 22), and once every two weeks (Q2W) in Cycles 3 through 6 (e.g., Days 1 and 15). NI-1801 treatment can extend beyond 6 cycles for those patients who do not have disease progression.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events (AEs) | Number of patients with AEs | Up to 12 months | 
| Dose Limiting Toxicity (DLT) | Is defined as any of the toxicities occurring within the DLT window (Cycle 1, Days 1 to 28) except those that are clearly and incontrovertibly due to extraneous causes. | Up to 12 months | 
| Non-Tolerated Dose (NTD) | Is defined as a dose level at which 2 or more of up to 6 evaluable patients in a cohort experience a DLT in the 4-week DLT window. | Up to 12 months | 
| Maximum Tolerated Dose (MTD) | Is defined as the last cohort below the NTD with 0 or 1 out of 6 evaluable subjects experiencing a DLT during the 4-week DLT window. | Up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | Is defined as the proportion of patients who achieve a partial response (PR) or better better, i.e., PR + complete response (CR), of the defined target lesions compared to baseline. | Up to 12 months | 
| Disease Control Rate (DCR) | Is defined as the proportion of patients who achieve a clinical benefit from NI-1801 treatment, i.e., CR + PR + stable disease (SD). | Up to 12 months | 
| Best Overall Response (BOR) | Is defined as the best response recorded from start of NI-1801 treatment until the first date that recurrent or progressive disease is objectively documented. | Up to 12 months | 
| Time to Response | Is defined as the time from the first NI-1801 dose date to the date of first documented response (i.e., PR or better) | Up to 12 months | 
| Duration of Response | Is defined as the time from the earliest date of documented response (i.e., CR or PR) to the first date that disease progression, recurrence of disease, or death, whichever occurs first, is objectively documented | Up to 12 months | 
| Progression Free Survival | Is defined as the time from the first dose of NI-1801 to progressive disease or death from any cause, whichever occurs first | Up to 12 months | 
| Overall Survival | Is defined as the time from the first dose of NI-1801 to death from any cause | Up to 12 months | 
| Pharmacokinetics - Cmax | Maximum concentration of drug | Up to 12 months | 
| Pharmacokinetics - tmax | Time to maximum concentration | Up to 12 months | 
| Pharmacokinetics - t1/2 | Terminal Half-life | Up to 12 months | 
| Pharmacokinetics - AUC | Area under the curve | Up to 12 months | 
| Pharmacokinetics - CL | Total body clearance | Up to 12 months | 
| Presence of anti-drug antibodies (ADA) | Detection of ADAs in patients | Up to 12 months | 
| Frequency of anti-drug antibodies (ADA) | Frequency of ADAs in patients | Up to 12 months | 
| Functional impact of anti-drug antibodies (ADA) | ADAs impact on Cmax and AUC as well as response variables | Up to 12 months |