177Lu-DTPA-Omburtamab Radioimmunotherapy for Leptomeningeal Metastasis From Solid Tumors (Breast, NSCLC, Malignant Melanoma)

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

Official Title
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A Phase I/II Trial of Intracerebroventricular 177Lu DTPA Omburtamab Radioimmunotherapy for Leptomeningeal Metastasis From Solid Tumors

Conditions
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Leptomeningeal Metastasis, Solid Tumor, Adult

Intervention / Treatment
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* Biological: radiolabeled DPTA-omburtamab


Participation Criteria
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Eligibility Criteria
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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)

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
Interventional Model Description: Patients will receive up to five cycles of intracerebroventricular 177Lu-DTPA-omburtamab. Safety and efficacy will be investigated during treatment and follow-up period.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 177Lu-DTPA-omburtamab<br>Intracerebroventricular administration of 177Lu-DTPA-omburtamab for up to five cycles. | Biological: radiolabeled DPTA-omburtamab<br>* Biological, radiolabeled DPTA-omburtamab<br>* Other names: Drug: 177Lu-DTPA-omburtamab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events (AEs) and serious adverse events (SAEs) | Safety will be evaluated by the incidence of AEs and SAEs graded according to CTCAE version 5.0. The maximum tolerated dose and the recommended phase 2 dose (RP2D) will be determined in Part 1 | 1 year | 
| Incidence of AEs and SAEs | In Part 2, safety will be evaluated by the incidence of AEs and SAEs graded according to CTCAE version 5.0, at the RP2D defined in Part 1 | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum radioactivity count of lutetium-177 in blood | The time for maximum absorbed radiation dose | 2 weeks | 
| Elimination half-life of lutetium-177 radioactivity in blood | The time for eliminating half of the radioactivity in blood | 2 weeks | 
| Absorbed radiation dose of lutetium-177 in blood and cerebrospinal fluid (CSF) | Time-activity curves of radioactivity measurements in blood and CSF will be modeled to deliver absorbed doses in blood and CSF | 2 weeks | 
| Dosimetry analysis of lutetium-177 | Whole-body dosimetry by gamma camera scans and single-photon emission computed tomography (SPECT) | 2 weeks | 
| Maximum Plasma Concentration [Cmax] in CSF | Concentration of 177Lu-DTPA-omburtamab in CSF | 7 weeks | 
| Maximum Plasma Concentration [Cmax] in serum | Concentration of 177Lu-DTPA-omburtamab in serum | 7 weeks | 
| Elimination Half Life in CSF | Concentration of 177Lu-DTPA-omburtamab in CSF | 7 weeks | 
| Elimination Half Life in serum | Concentration of 177Lu-DTPA-omburtamab in serum | 7 weeks | 
| Response | Objective response rate (ORR) will be defined as the proportion of all evaluable patients achieving a response as the best overall response at the time of assessment | 2 years | 
| Investigator-assessed Duration of Response (DoR) | DoR is defined as the time from first response to LM progression | 2 years | 
| Progression-free Survival (PFS) | PFS is defined as the time from first treatment to date of LM progression or death from any cause, whichever comes first | 2 years | 
| Overall Survival (OS) | OS is defined as the time from first treatment to date of death | 2 years |