Leptomeningeal Metastasis, Solid Tumor, Adult
Conditions
Brief summary
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
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).
Interventions
BIOLOGICALradiolabeled DPTA-omburtamab
Biological, radiolabeled DPTA-omburtamab
Sponsors
Y-mAbs Therapeutics
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of adverse events (AEs) and serious adverse events (SAEs) | 1 year | 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 |
| Incidence of AEs and SAEs | 2 years | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absorbed radiation dose of lutetium-177 in blood and cerebrospinal fluid (CSF) | 2 weeks | Time-activity curves of radioactivity measurements in blood and CSF will be modeled to deliver absorbed doses in blood and CSF |
| Dosimetry analysis of lutetium-177 | 2 weeks | Whole-body dosimetry by gamma camera scans and single-photon emission computed tomography (SPECT) |
| Maximum Plasma Concentration [Cmax] in CSF | 7 weeks | Concentration of 177Lu-DTPA-omburtamab in CSF |
| Maximum Plasma Concentration [Cmax] in serum | 7 weeks | Concentration of 177Lu-DTPA-omburtamab in serum |
| Elimination Half Life in CSF | 7 weeks | Concentration of 177Lu-DTPA-omburtamab in CSF |
| Maximum radioactivity count of lutetium-177 in blood | 2 weeks | The time for maximum absorbed radiation dose |
| Response | 2 years | 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 |
| Investigator-assessed Duration of Response (DoR) | 2 years | DoR is defined as the time from first response to LM progression |
| Progression-free Survival (PFS) | 2 years | PFS is defined as the time from first treatment to date of LM progression or death from any cause, whichever comes first |
| Overall Survival (OS) | 2 years | OS is defined as the time from first treatment to date of death |
| Elimination Half Life in serum | 7 weeks | Concentration of 177Lu-DTPA-omburtamab in serum |
| Elimination half-life of lutetium-177 radioactivity in blood | 2 weeks | The time for eliminating half of the radioactivity in blood |
Countries
United Kingdom, United States
Outcome results
None listed