A Phase 1, Open-Label, Dose Finding Study of NI-1801, a Bispecific Mesothelin X CD47 Engaging Antibody, As a Single Agent, in Combination with Anti-PD-1 Antibody, and in Combination with Weekly Paclitaxel (Standard of Care) in Patients with Mesothelin Expressing Ovarian, Pancreatic, Non-Small-Cell-Lung and Triple-Negative Breast Cancers
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 patients with advanced, metastatic, or recurrent solid malignancies expressing mesothelin (MSLN). The dose escalation part (Part A) of the main study will evaluate the safety and tolerability of escalating doses of NI-1801 to determine the maximum tolerated dose (MTD) and non-tolerated toxic dose (NTD) of NI-1801. The expansion part (Part B) of the main study will further evaluate the safety and efficacy of NI-1801 administered at or below the MTD in up to 10 additional subjects in order to determine the recommended Phase 2 dose (RP2D). Treatments will be administered in 28-day cycles for up to 12 months until disease progression, unacceptable toxicity, or Investigator/patient decision to withdraw study consent. The dose escalation part (Part A) of the sub-study will evaluate the safety and tolerability of escalating doses of NI-1801 in combination with anti-PD-1 antibody. The expansion part (Part B) of the sub-study will further evaluate the safety and efficacy of NI-1801 administered in combination with anti-PD-1 antibody at or below the MTD. In the randomized cohort, the experimental arm will receive the investigational drug NI-1801 at the P2RD every two weeks in combination with weekly administration of paclitaxel (80 mg/m\^2) over 4-week cycles. The control arm will be treated with weekly paclitaxel at the same regimen representing one of the standards of care (SoC) in this population. This trial specifically targets patients with platinum-resistant ovarian cancer. This cohort will be made up of 20 evaluable patients, 10 per arm.
• 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.
• 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:
‣ 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.
‣ 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