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Intrathecal Application of PD1 Antibody in Metastatic Solid Tumors With Leptomeningeal Disease (IT-PD1/ NOA 26) (IT-PD1)

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ClinicalTrials.gov Identifier: NCT05112549
Recruitment Status : Recruiting
First Posted : November 9, 2021
Last Update Posted : November 3, 2022
Information provided by (Responsible Party):
University Hospital Tuebingen

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.

Condition or disease Intervention/treatment Phase
Leptomeningeal Disease Drug: Nivolumab [Opdivo] Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 46 participants
Allocation: N/A
Intervention Model: Sequential Assignment
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

Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Intrathecal Application of PD1 Antibody in Metastatic Solid Tumors With Leptomeningeal Disease (IT-PD1/ NOA 26)
Actual Study Start Date : October 12, 2021
Estimated Primary Completion Date : September 30, 2025
Estimated Study Completion Date : September 30, 2026

Resource links provided by the National Library of Medicine

Drug Information available for: Nivolumab

Arm Intervention/treatment
Experimental: intrathecal Nivolumab

This is a prospective, interventional, open label, multicenter phase I trial in leptomeningeal disease in subjects with solid tumor that have a registered indication for intravenous treatment with PD1 antibody. Subject 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 Follow-up phase will start four weeks after the last dose and will continue monthly (up to 4 Follow-up visits in total).The study consists of two parts:

Part I "dose - escalation phase" (3 + 3 design) with 4 cohorts and each subject will receive an intrathecal nivolumab treatment with a fixed predefined dose (20 mg, 30 mg, 40 mg or 50 mg). On each dose level, exposure of subjects to intrathecal nivolumab will follow a staggered approach. Part II "dose expansion phase": subjects will receive an intrathecal PD1 treatment with a fixe dose, depending on the results from Part I.

Drug: Nivolumab [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.

Primary Outcome Measures :
  1. Assessment of Adverse Events for Dose Limiting Toxicities [Safety and Tolerabillity] [ Time Frame: 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 Outcome Measures :
  1. Overall Survival [ Time Frame: 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.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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 available
  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 trials or observation period of competing trials
  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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05112549

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Contact: Ghazaleh Tabatabai, Prof.Dr. +49 (0) 7071 - 2985018 ghazaleh.tabatabai@uni-tuebingen.de

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University Hospital Freiburg, Neurosurgery Not yet recruiting
Freiburg, Germany, 79106
Contact: Oliver Schnell, Prof. Dr.         
University Hospital Heidelberg, Neurooncology Not yet recruiting
Heidelberg, Germany, 69120
Contact: Antje Wick, Dr.         
SLK-Kliniken Heilbronn GmbH Klinik Recruiting
Heilbronn, Germany, 74078
Contact: Uwe Martens, Prof. Dr.         
University Hospital Mannheim, Neurology Clinic Recruiting
Mannheim, Germany, 68167
Contact: Michael Platten, Prof. Dr.         
Katharinenhospital Stuttgart Not yet recruiting
Stuttgart, Germany, 70565
Contact: Gerhard Illerhaus, Prof. Dr.         
University Hospital Tübingen, Neurooncology Recruiting
Tübingen, Germany, 72076
Contact: Ghazaleh Tabatabai, Prof. Dr.    497071/29-83269    ghazaleh.tabatabai@uni-tuebingen.de   
University Hospital Ulm, ECTU - Early Clinical Trail Unit Recruiting
Ulm, Germany, 89081
Contact: Regine Mayer-Steinacker, Dr.         
Sponsors and Collaborators
University Hospital Tuebingen
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Study Director: Ghazaleh Tabatabai, Prof.Dr. University Hospital Tuebingen
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Responsible Party: University Hospital Tuebingen
ClinicalTrials.gov Identifier: NCT05112549    
Other Study ID Numbers: IT-PD1
2021-001795-42 ( EudraCT Number )
First Posted: November 9, 2021    Key Record Dates
Last Update Posted: November 3, 2022
Last Verified: November 2022

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Meningeal Neoplasms
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Nervous System Diseases
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action