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

Main Inclusion Criteria for the Single Agent Dose Escalation and the Combination with Pembrolizumab:

• Adults ≥ 18 years of age at the time of signing the informed consent form
• Histologically or cytologically confirmed diagnosis of epithelial OC (high-grade serous or endometroid), TNBC, or non-squamous NSCLC. For the combination with pembrolizumab, only subjects with histologically or cytologically confirmed diagnosis of epithelial OC (high-grade serous or endometroid), non-squamous NSCLC and ductal pancreatic adenocarcinoma.
• MSLN expression with staining intensity of ≥ 2+ as per IHC in ≥ 40% of tumor cells. Staining for MSLN expression can be performed using archival tumor tissue and is foreseen to be performed at the institution's pathology. A slice for centralized IHC assessment for validation and biomarker analysis is mandatory.
• 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(3)
• Patients treated in either the single agent recommended dose expansion cohort or in the combination with pembrolizumab cohort should have accessible lesions at screening for baseline and on treatment biopsies.
• Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1.
• Negative pregnancy test at inclusion.
• Life expectancy of at least 2 months.

Main Inclusion Criteria for the Randomized study arm:

• Female patients ≥ 18 years of age.
• Patients must have a confirmed diagnosis of high-grade serous epithelial ovarian cancer.
• Patients must have platinum-resistant disease:

3.1. Patients who have only had 1 line of platinum-based therapy must have received at least 4 cycles of platinum, must have had a response (CR or PR) and then progressed between greater than 3 months and ≤ 6 months after the date of the last dose of platinum.

3.2. Patients who have received 2 or 3 lines of platinum therapy must have progressed on or within 6 months after the date of the last dose of platinum

• Patients must have progressed radiographically on or after their most recent line of therapy.
• Patients must be willing to provide an archival tumor tissue block or slides, or undergo procedure to obtain a new biopsy using a low risk, medically routine procedure for IHC confirmation of MSLN expression.
• MSLN expression with staining intensity of ≥ 2+ as per IHC in ≥ 40% of tumor cells. Staining for MSLN expression can be performed using archival tumor tissue and can be done at the institution's pathology. A slice for centralized IHC assessment for validation and biomarker analysis is mandatory.
• Patients must have at least one lesion that meets the definition of measurable disease by RECIST v1.1 (radiologically measured by the Investigator).
• Patients must have received at least 1 but no more than 3 prior systemic lines of anticancer therapy, and for whom single-agent therapy is appropriate as the next line of treatment:

• Adjuvant ± neoadjuvant considered one line of therapy
• Maintenance therapy (e.g., bevacizumab, PARP inhibitors) will be considered as part of the preceding line of therapy (i.e., not counted independently)
• Therapy changed due to toxicity in the absence of progression will be considered as part of the same line (i.e., not counted independently)
• Hormonal therapy will be counted as a separate line of therapy unless it was given as maintenance
• ECOG PS of 0 or 1
• Time from prior therapy:

• Systemic antineoplastic therapy (5 half-lives or 4 weeks, whichever is shorter)
• Focal radiation completed at least 2 weeks prior to first dose of study drug
• Patients must have stabilized or recovered (Grade 1 or baseline) from all prior therapy-related toxicities.
• Major surgery must be completed at least 4 weeks prior to first dose and have recovered or stabilized from the side effects of prior surgery.
• Patients must have adequate hematologic, liver and kidney functions
• Patients or their legally authorized representative must be willing and able to sign the informed consent form (ICF) and to adhere to the protocol requirements.
• Negative pregnancy test at inclusion

Main Exclusion Criteria for the Single Agent Dose Escalation and the Combination with Pembrolizumab:

• 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. The maximum required washout period will thus not exceed 4 weeks prior to the day of first treatment with NI-1801. Note: Low dose steroids (oral prednisone or equivalent ≤ 20 mg per day, including systemic or topic use), localized noncentral nervous system (CNS) radiotherapy of non-target lesions, and treatment with bisphosphonates and RANKL inhibitors are not criteria for exclusion.
• Other investigational therapies must not be used, i.e., treatment within another clinical trial is not permitted, while the patient is on study. COVID-19 vaccination is allowed only starting from Cycle 2 (if not completed before study inclusion).
• 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.
• Patients with known human immunodeficiency virus (HIV) infection or known history or serological evidence of prior hepatitis B or C virus infection. Active SARS-COV2 infection.
• 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 lower than 100 x 10^9/L (transfusion support within 14 days before the test is not allowed).
• Hemoglobin lower than 10.0 g/dL. Prior RBC transfusion is permitted.
• ANC lower than 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.
• History of psychiatric illness or substance abuse likely to interfere with ability to comply with protocol requirements or give informed consent.
• Significant medical diseases or conditions, including laboratory abnormalities, as assessed by the Investigators and Sponsor, which 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).
• People who are detained through a court or administrative decision, receiving psychiatric care against their will, adults who are the subject of a legal protection order (under tutorship/curatorship), people who are unable to express their consent, and people who are subject to a legal guardianship order.

Furthermore, subjects presenting with any of the following criteria will not be included in the sub-study (combination with pembrolizumab cohort):

• History of/active non-infectious pneumonitis or interstitial lung disease.
• Known hypersensitivity to pembrolizumab or excipients.
• Participants with an active, known or suspected autoimmune disease. Participants with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
• Prior organ or tissue allograft.
• History of Grade ≥ 3 toxicity related to prior T-cell agonist or checkpoint inhibitor therapy, except those that are unlikely to re-occur with standard countermeasures.
• History of myocarditis, regardless of etiology.

Main Exclusion Criteria for the Randomized study arm:

• Patients with clear cell, mucinous, or sarcomatous histology, mixed tumors containing any of the above histology, or low-grade or borderline ovarian tumor.
• Patients with primary platinum-refractory disease, defined as disease that did not respond to (CR or PR) or has progressed within 3 months of the last dose of first line platinum-containing chemotherapy.
• Patients with prior wide-field radiotherapy (RT) affecting at least 20% of the bone marrow.
• Patients with serious concurrent illness or clinically relevant active infection, including, but not limited to the following:

• Active hepatitis B or C infection (whether or not on active antiviral therapy)
• HIV infection
• Active cytomegalovirus infection
• Any other concurrent infectious disease requiring IV antibiotics within 2 weeks before starting study drug Note: Testing at screening is not required for the above infections unless clinically indicated
• Patients with history of multiple sclerosis or other demyelinating disease and/or Lambert-Eaton syndrome (paraneoplastic syndrome)
• Patients with clinically significant cardiac disease including, but not limited to, any one of the following:

• Myocardial infarction ≤ 6 months prior to first dose
• Unstable angina pectoris
• Uncontrolled congestive heart failure (New York Heart Association greater than class II)
• Uncontrolled ≥ Grade 3 hypertension (per CTCAE)
• Uncontrolled cardiac arrhythmias
• Patients assigned to PLD stratum only: Left ventricular ejection fraction (LVEF) below the institutional limit of normal as measured by echocardiography (ECHO) or multigated acquisition (MUGA) scan
• History of hemorrhagic or ischemic stroke within six months prior to randomization
• History of cirrhotic liver disease (Child-Pugh Class B or C)
• Previous clinical diagnosis of non-infectious interstitial lung disease (ILD), including noninfectious pneumonitis
• Patients with prior hypersensitivity to monoclonal antibodies.
• Women who are pregnant or lactating.
• Patients with prior treatment with a CD47, signal regulatory protein (SIRP) alpha, or MSLN targeting agent.
• Patients with central nervous system (CNS) metastases.
• Patients with a history of other malignancy within 3 years prior to randomization.
• Prior known hypersensitivity reactions to study drugs and/or any of their excipients.