Clinical trial NCT05112549: Intrathecal Application of PD1 Antibody in Metastatic Solid Tumors With Leptomeningeal Disease (IT-PD1/ NOA 26)
Official title: Intrathecal Application of PD1 Antibody in Metastatic Solid Tumors With Leptomeningeal Disease (IT-PD1/ NOA 26)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Leptomeningeal Disease
Lead sponsor: University Hospital Tuebingen
Sponsor class: OTHER
First posted: 2021-11-09
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
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
Primary purpose: TREATMENT

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.

Eligibility 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 exclusion criteria: a. Aseptic, meningitis b. Viral meningitis, c. Bacterial meningitis
5. History of hypersensitivity to monoclonal antibodies
6. Participation in other clinical AMG or MDR trials or observation period of competing trials or if there is otherwise a high risk of insurance law issues intervening between two studies and if the participation affects the primary endpoint of the IT-PD1 study. In case of uncertainty, competing insurances must be contacted prior to participation
7. A clinical condition that in the opinion of the investigator would interfere with the evaluation or interpretation of patient safety or trial results or that would prohibit the understanding of informed consent and compliance with the requirements of the protocol
8. Any treatment-related toxicities from prior systemic anti-tumor or immune therapy not having resolved to CTCAE version 5.0 grade 1, with the exception of alopecia
9. Patient with confirmed history of current autoimmune disease
10. Patients with any disease resulting in permanent immunosuppression or requiring permanent immunosuppressive therapy
11. Existence of clinically significant active infection (details see study protocol)
12. Inability to undergo MRI with contrast agent
13. The underlying primary tumor has not a registered and authorized indication in the European Union for intravenous treatment with Nivolumab, Pembrolizumab or Atezolizumab (details see study protocol). In addition, leptomeningeal disease of solid tumors with a high tumor mutational burden is also eligible.
14. Existence of abnormal laboratory values for the following values in hematology, coagulation parameters, liver and renal function (details see study protocol)
15. Patients who have received live or attenuated vaccine therapy used for prevention of infectious disease within 4 weeks of the first IT application of nivolumab
16. Patients requiring chronic systemic corticosteroid therapy (\> 10 mg prednisone or equivalent per day) or any other immunosuppressive therapies (including anti-TNF-a therapies)

Primary outcomes:
measure: Assessment of Adverse Events for Dose Limiting Toxicities [Safety and Tolerabillity]
timeFrame: up to 4 months after last dose
Secondary outcomes:
measure: Overall Survival
timeFrame: last follow-up, up to 4 months after last dose
Other outcomes:
Locations:
city: Bonn
country: Germany
facility: Universitätsklinikum Bonn
city: Freiburg
country: Germany
facility: University Hospital Freiburg, Neurosurgery
city: Heidelberg
country: Germany
facility: University Hospital Heidelberg, Neurooncology
city: Heilbronn
country: Germany
facility: SLK-Kliniken Heilbronn GmbH Klinik
city: Mannheim
country: Germany
facility: University Hospital Mannheim, Neurology Clinic
city: München
country: Germany
facility: Klinikum rechts der Isar/Technische Universität München
city: Stuttgart
country: Germany
facility: Katharinenhospital Stuttgart
city: Tübingen
country: Germany
facility: University Hospital Tübingen, Neurooncology
city: Ulm
country: Germany
facility: University Hospital Ulm, ECTU - Early Clinical Trail Unit
Study officials:
affiliation: University Hospital Tuebingen
name: Ghazaleh Tabatabai, Prof.Dr.
role: STUDY_DIRECTOR
References: