Leptomeningeal Disease
Conditions
Brief summary
To determine the safety of intrathecal (IT) PD1 antibody for Intrathecal application of PD1 antibody in metastatic solid tumors with leptomeningeal disease of solid tumors.
Detailed description
Leptmeningeal disease (LMD) is an aggressive subtype of metastatic disease in the central nervous system (CNS) and has a poor prognosis with a median overall survival of a few months.The IT-PD1 trial group wants to contribute to an improvement of this situation for LMD patients by using an intrathecal application route for the PD1 antibody, i.e. a drug that has shown clinical efficacy in the underlying tumor via the intravenous route.
Interventions
DRUGNivolumab [Opdivo]
Nivolumab (OPDIVO®) is a marketed pharmaceuticals material authorized in the European Union. This study uses an off-label route of administration of nivolumab. Subjects with leptomeningeal disease in solid tumours with an approved indication for intravenous treatment with the PD1 antibody will receive an intrathecal application of nivolumab. A total of six i.th. applications will be performed every 14 days. The intrathecal administration will be performed via an Ommaya reservoir or another intraventricular catheter.
Sponsors
University Hospital Tuebingen
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a single arm phase 1 trial with two parts. For part I (3+3 Design) there will be four cohorts: Cohort 1 with a fix dose of 20 mg, Cohort 2 with a fix dose of 30 mg, Cohort 3 with a fix dose of 40 mg and Cohort 4 with a fix dose of 50 mg. The dosage in the expansion part II will be fixe dosage for all patients depending on the results from Part I
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Main Inclusion Criteria: 1. Patient aged ≥ 18 years at the time of signing the informed consent 2. Existing ability to understand and voluntarily sign an informed consent document prior to any study related assessments/procedures 3. Patient is at good risk ( NCCN guidelines version 1.2021) 4. Existence of the following Tumor board protocol confirmations: clinical recommendation for intrathecal therapy and evaluation of trial enrolment & statement on the potential necessity of additional systemic treatment of metastatic tumor outside the CNS 5. Existing ability to adhere to the study visit schedule and other protocol requirements 6. Existing agreement to refrain from donating blood while on study drug and for 30 days after discontinuation from this study treatment 7. Karnofsky performance score \> 50% 8. Diagnosis of LMD by CSF and/or MRI (details see Study protocol) 9. If radiation therapy was performed please confirm: Participants eligible for IT-PD1 should have completed their radiation therapy due to clinical indication \> 2 weeks prior to enrollment into the trial 10. Neurological examination (NANO scale) acc. Nayak et al., 2017 performed 11. MRI assessment at screening is based on the LANO scorecard acc. to Le Rhun et al., 2019 12. Existing ability to undergo intrathecal therapy via an intraventricular catheter (e.g. Ommaya reservoir) 13. Primary tumor tissue for the assessment of PD-1 and PD-L1 is optional at the timepoint of inclusion and enrollment but does need to be shipped before end of the trial. 14. Existing willingness of female patient of childbearing potential and male patient with female partner of childbearing potential to use highly effective contraceptive methods during treatment and for 150 days (male or female, see SmPC) after the last dose (details see Study protocol) Main
Exclusion criteria
1. Women during pregnancy and lactation. 2. Previous intrathecal nivolumab application. 3. Patient at poor risk (NCCN guidelines version 1.2021) 4. The following differential diagnoses to LMD are
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Assessment of Adverse Events for Dose Limiting Toxicities [Safety and Tolerabillity] | up to 4 months after last dose | This trial will investigate the maximum tolerable dose and safety of intrathecal PD1 antibody administration in LMD of metastatic solid tumors with a registered indication for treatment with intravenous PD1 antibody or PD-1L antibody. The safety endpoints will be assessed by a review of adverse events and serious adverse events according to CTCAE up to 4 months days after last dose.Subjects will undergo 6 cycles each 14 days in duration and a safety visit 7 days after the 3th dosage and 7 days after the 6th dosage.The appropriate dose for the expansion phase (Part II) is based on the results in Part I (dose escalation phase) and will define the maximum tolerable fix dose in Part II. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | last follow-up, up to 4 months after last dose | The secondary endpoint is overall survival defined as the time interval from the date of first study administration to the date of progression. |
Countries
Germany
Contacts
Primary ContactGhazaleh Tabatabai, Prof.Dr.
Outcome results
None listed