Intrathecal application of PD-1 antibody in metastatic solid tumors with leptomeningeal disease

Phase 1

Recruiting

Conditions: leptomeningeal disease
MedDRA version: 21.1Level: LLTClassification code: 10070973Term: Leptomeningeal disease Class: 10029104
Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Registration Number: CTIS2024-514068-14-00

Lead Sponsor: niversitaetsklinikum Tuebingen AöR

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Recruiting

Sex: All

Target Recruitment: 49

Inclusion Criteria

Must be = 18 years at the time of signing the informed consent, Neurological examination (NANO scale) (Nayak et al., 2017), MRI: the assessment at baseline and for subsequent time points should be based on the LANO scorecard (see appendix) according to (Le Rhun et al., 2019), Ability to undergo intrathecal therapy via an intraventricular catheter (e.g. Ommaya reservoir), 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, Female Patient of childbearing potential1 and male patients with female partner of childbearing potential1 is willing to use highly effective contraceptive methods during treatment and for 150 days (male or female, see SmPC) after the last dose. Recommendations highly effective contraceptive methods are: a. combined hormonal contraception associated with inhibition of ovulation (oral-, intravaginal, -transdermal) b. progestogen-only hormonal contraception associated with inhibition of ovulation (pral injectable, implantable), c. intrauterine device (IUD), d. intrauterine hormone - releasing system (IUS), e. bilateral tubal occlusion, f. vasectomized partner2, g. sexual abstinence3 1 For the purpose of this document, a female is considered of childbearing potential (FCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. For the purpose of this document, a man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy. 2Vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner of the WOCBP trial participant and that the vasectomized partner has received medical assessment of the surgical success 2 In the context of this guidance sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject., Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures, Patients with a good risk” status as defined by the NCCN guidelines (version 1.2021), Tumor board protocol confirming: - a clinical recommendation for intrathecal therapy and evaluation of trial enrollment - a statement on the potential necessity of additional systemic treatment of metastatic tumor outside the CNS, Able to adhere to the study visit schedule and other protocol requirements, All subjects must agree to refrain from donating blood while on study drug and for 28 days after discontinuation from this study treatment, Patients with Karnofsky performance score > 50%, Diagnosis of LMD by CSF and/or MRI a. A thorough CSF evaluation must be performed in every patient prior to the inclusion in this trial

Exclusion Criteria

Women during pregnancy and lactation, Patients with any disease resulting in permanent immunosuppression or requiring permanent immunosuppressive therapy., Clinically significant active infection, for example: a. Presence of human immunodeficiency virus b. Active hepatitis B virus/hepatitis C virus. HIV infection or active Hepatitis B or C infectionor active infections requiring oral or intravenous antibiotics or that can cause a severe disease and pose a severe danger to lab personnel working on patients’ blood or tissue (e.g. rabies), Inability to undergo MRI with contrast agent., The underlying primary tumor has not a registered and authorized indication in the European Union for intravenous treatment with Nivolumab, Pembrolizumab or Atezolizumab. The solide tumor registered are, i.e. melanoma, non-small cell lung cancer (NSCLC), Malignant pleural mesothelioma (MPM),renal cell carcinoma (RCC), Classical Hodgkin lymphoma (cHL), squamous cell cancer of the head and neck (SCCHN), urrothelial carcinoma, muscle invasive urothelial carcinoma (MIUC), colorectal cancer (CRC) with Mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H), esophageal squamous cell carcinoma (ESCC), Adjuvant treatment of esophageal cancer (EC) or gastro-oesophageal junction cancer (GEJC), Gastric gastro-oesophageal junction (GEJ) or oesophageal adenocarcinoma, triplenegative breast carcinoma. In addition, leptomeningeal disease of solid tumors with a high tumor mutational burden is also eligible., Abnormal laboratory values for the following values in haematology, coagulation parameters, liver and renal function: a. Haemoglobin < 8 g/dl b. White blood cell count < 2.0 x 109/L) c. Platelet count decrease < 50 x 109/L d. Bilirubin > 2.5 x upper limit of normal (ULN) according to the performing laboratory‘s reference range. Note that benign hereditary hyperbilirubinemia e.g. Gilbert‘s syndrome is permitted. e. Alanine aminotransferase > 3 x ULN f. Aspartate aminotransferase > 3 x ULN g. Serum creatinine increase > 1.5 x ULN, 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., Patients requiring chronic systemic corticosteroid therapy (> 10 mg prednisone or equivalent per day) or any other immunosuppressive therapies (including anti-TNF-a therapies)., Previous intrathecal Nivolumab application., Patient at poor risk” (NCCN guidelines version 1.2021)., The following differential diagnoses to LMD are exclusion criteria: a. Aseptic meningitis b. Viral meningitis c. Bacterial meningitis, History of hypersensitivity to monoclonal antibodies., 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., 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., 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., Patient with confirmed hisory of curr

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To assess the maximum tolerable dose and safety of intrathecal (IT) PD-1 antibody administration;Secondary Objective: Overall survival;Primary end point(s): To assess the maximum tolerable dose and safety of intrathecal (IT) PD-1 antibody administration

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s):Overall survival

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