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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universitaetsklinikum Tuebingen AöR

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

12 Oct 2021 → ongoing

Decision date (initial)

2024-05-24

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-514068-14-00

EudraCT number

2021-001795-42

ClinicalTrials.gov

NCT05112549

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety

To assess the maximum tolerable dose and safety of intrathecal (IT) PD-1 antibody administration

Secondary objectives 1

1. Overall survival

Conditions and MedDRA coding

leptomeningeal disease

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Must be ≥ 18 years at the time of signing the informed consent
2. Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures
3. Patients with a “good risk” status as defined by the NCCN guidelines (version 1.2021)
4. 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
5. Able to adhere to the study visit schedule and other protocol requirements
6. All subjects must agree to refrain from donating blood while on study drug and for 28 days after discontinuation from this study treatment
7. Patients with Karnofsky performance score > 50%
8. 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. The reason is that a positive CSF cytology is considered the gold standard for LMD diagnosis. Furthermore, a thorough CSF evaluation Protocol EUDRACT 2021-001795-42 IT-PD1 Date/Version: 17.11.2023, V4 IT-PD1, protocol Page: 42 of 104 will allow the thorough assessment of potential differential diagnoses (for example viral meningitis, bacterial meningitis, aseptic meningitis, sarcoidosis etc.) b. Presence of malignant cells on CSF cytology. The frequency of CSF evaluation is based on guideline of the German Society of Neurology: Please note that the first lumbar puncture is only 50-60% sensitive. Repeat collection increases sensitivity up to approximately 80%. Thus, a negative first CSF evaluation should at least be repeated once. According to guidelines from the German Society for Neurology each CSF collection should draw enough, i.e. at least 5- 10 ml CSF and should be processed within one hour of collection. c. MRI diagnosis of LMD: pial enhancement, pial nodular manifestations (as defined per LANO criteria, see appendix). d. A positive CSF cytology and an MRI evidence is enough to determine the LMD diagnosis. e. Please note that approximately 20% of patients with symptomatic LMD might lack positive CSF cytology even upon repeated puncture. In these cases, the LMD diagnosis can also be performed based on cerebral/spinal MRI manifestations and by exclusion of differential diagnosis. f. In the absence of diagnostic findings for LMD in the CSF: patients must present with typical clinical and MRI signs of LMD (Le Rhun et al., 2017). If the CSF has signs of pleocytosis (BUT NOT any malignant, atypical or suspicious cells) the differential diagnosis for CSF pleocytosis (aseptic meningitis, viral meningitis, bacterial meningitis) must be excluded. g. Some centers perform biopsies of leptomeninges for obtaining a LMD diagnosis. The LMD diagnosis will be based on histology and should be documented accordingly. Yet, a histological diagnosis of LMD is NOT required for the inclusion in this trial.
9. If radiation therapy had occurred: Please make sure that a documentation of the past radiation therapy is available (including applied dosage and radiation therapy fields): a. Participants eligible for IT-PD1 should have completed their radiation therapy due to clinical indication > 2 weeks prior to enrollment into the trial. b. All LMD patients without an indication for radiation therapy (per investigator‘s choice) can be enrolled immediately
10. Neurological examination (NANO scale) (Nayak et al., 2017)
11. 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)
12. 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. 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.

Exclusion criteria 16

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 hisory of current autoimmune disease.
10. Patients with any disease resulting in permanent immunosuppression or requiring permanent immunosuppressive therapy.
11. 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)
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. 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.
14. 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
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).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. To assess the maximum tolerable dose and safety of intrathecal (IT) PD-1 antibody administration

Secondary endpoints 1

1. Overall survival

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitaetsklinikum Tuebingen AöR

Sponsor organisation

Universitaetsklinikum Tuebingen AöR

Address

Geissweg 3, Innenstadt Innenstadt

City

Tuebingen

Postcode

72076

Country

Germany

Scientific contact point

Organisation

Universitaetsklinikum Tuebingen AöR

Contact name

Prof. Dr. Ghazaleh Tabatabai

Public contact point

Organisation

Universitaetsklinikum Tuebingen AöR

Contact name

Prof. Dr. Ghazaleh Tabatabai

Locations

1 EU/EEA country · 7 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 6 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications