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Adults with leptomeningeal metastasis from solid tumors will be treated with 177Lu-DTPA-omburtamab, which is a radioactive labelling of a murine monoclonal antibody targeting B7-H3.

Part 1 is a dose-escalation phase with a 3+3 sequential-group design in which patients will receive a dosimetry dose followed by maximum of five 5-week cycles of treatment doses of intracerebroventricular 177Lu-DTPA-omburtamab.

Part 2 is a cohort-expansion phase in which patients will receive a treatment at the recommended dose determined in Part 1, until confirmed LM progression, unacceptable toxicity, or for maximum of 5 cycles, whichever comes first; however, the total number of cycles will be determined based upon data from Part 1 (e.g., the dosimetry data) to minimize the risk of radiation necrosis and decreased neurological function End of treatment will take place within 5 weeks after the last cycle and thereafter the patients will be enter the follow-up period. The patients will be followed for up until one year after first dose (Part 1) and 2 years after first dose (Part 2).

Inclusion Criteria:

• Primary ductal or lobular breast cancer, non-small cell lung cancer, or malignant melanoma
• Type I or Type II LM with a "confirmed" or "probable" diagnosis according to EANO-ESMO guidelines 2017
• Life expectancy more than 2 months, as judged by the Investigator
• ECOG Performance status 0, 1, or 2
• Acceptable hematological status and liver and kidney function
• Written informed consent obtained in accordance with local regulations
• Presence of an intracerebroventricular access device before first dosing

Exclusion Criteria:

• Obstructive or symptomatic communicating hydrocephalus
• Progressive systemic (extra-leptomeningeal) disease
• Uncontrolled life-threatening infection
• Ventriculo-peritoneal shunts without programmable valves. Ventriculo-atrial or ventriculo-pleural shunts
• Received craniospinal irradiation (for intraparenchymal or dural metastases) or intrathecal cytotoxic anti-cancer therapy less than 3 weeks prior to first dose of 177Lu-DTPA-omburtamab
• Severe non-hematologic organ toxicity; specifically, any renal, cardiac, hepatic, pulmonary, or gastrointestinal system toxicity Grade 3 or above prior to enrolment
• Grade 4 nervous system disorder. Hearing loss or stable neurological deficits due to brain tumor are allowed
• Unacceptable coagulation function prior to first dosing defined as INR Grade 2 or above
• Female of childbearing potential, who are pregnant, breast-feeding, intend to become pregnant, or are not using highly effective contraceptive methods or male who is not using highly effective contraceptive method
• Other significant disease or condition that in the investigator's opinion would exclude the patient from the trial.
• Smallest diameter of treated or untreated nodular or linear leptomeningeal metastasis >0.5 cm on MRI (Part 2 only)