A phase IB clinical trial on neoadjuvant and intraoperative intracranial administration of triple immune checkpoint blockade plus myeloid dendritic cells in patients with recurrent high-grade glioma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

UZ Brussel

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Pathological Conditions, Signs and Symptoms [C23]

Trial duration

20 Nov 2024 → ongoing

Decision date (initial)

2024-11-20

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-517842-33-01

EudraCT number

2016-003699-36

ClinicalTrials.gov

NCT03233152

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Safety

To document the safety and feasibility of of the proposed investigational treatment regimen, consisting of neoadjuvant intratumoral triple ICI administration, followed by a MSR with peroperative intracerebral triple ICI plus myDC injections, and subsequent adjuvant biweekly ICav and IV nivolumab administrations.

Secondary objectives 3

1. To estimate the progression-free survival (PFS) of study patients
2. To estimate overall survival (OS) of study patients
3. Neuro-cognitive function, psycho emotional disturbances and HR-QoL

Conditions and MedDRA coding

glioblastoma

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Subjects must have signed and dated an approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject care
2. Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, tumor biopsies, and other requirements of the study
3. Patients with a confirmed prior histopathological diagnosis of glioblastoma (= WHO grade IV, IDH-wildtype glioma) or astrocytoma (= WHO grade III or IV, IDH-mutant glioma) are eligible for study participation;
4. Diagnosis of glioblastoma recurrence and/or progression following prior treatment with surgery consisting of a total or partial tumor resection, radiation therapy and temozolomide chemotherapy (recurrence/progression is defined as significant [according to the investigators assessment] growth and/or recurrence of the glioblastoma tumor mass on sequential MRI of the brain);
5. The following disease characteristics should be present: a) Presence of a measurable tumor lesion that is characterized by gadolinium (Gd) enhancement on T1-MRI of the brain (with a longest diameter of > 10 mm and a perpendicular diameter of >5mm). b) No evidence of clinically relevant spontaneous intra-tumor hemorrhage on baseline MRIimaging or in the prior disease history;
6. The recurrent tumor mass should be amenable to a safe stereotactic (or open) biopsy [according to the investigators assessment];
7. ECOG performance status score of 0, 1 or 2;
8. An interval of at least 4 months (: 16 weeks) after the end of postoperative radiation therapy for the high-grade glioma, unless progression is confirmed on an MRI of the brain obtained > 4 week after the first observation of progression; and with an interval of at least 4 weeks after the last administration of temozolomide;
9. Male or female, 18 years of age or older;
10. Resolution of all acute treatment related adverse effects of prior surgical procedures, radiotherapy and temozolomide to NCI CTCAEv5.0 grade 0 or 1 except for alopecia;
11. Adequate organ function as defined by the following criteria: a) Total serum bilirubin < 1.5 x ULN (patients with Gilbert’s disease exempt who should have bilirubin < 2x ULN) b) AST and ALT < 2.5 x upper limit of normal (ULN); c) Serum creatinine ≤1.5 x ULN or calculated creatinine clearance ≥60 mL/min d) Absolute neutrophil count (ANC) > 1500/mm³ without growth factor support e) Platelets > 75 000 cells/mm³ f) Hemoglobin ≥9 g/dL (which may be obtained by transfusion or growth factor support) g) FT4 hormone levels within normal range
12. Subjects requiring systemic treatment with either corticosteroids (> 8 mg daily methylprednisolone equivalent) or other immunosuppressive medications within 14 days of study enrollment. Inhaled or topical steroids are permitted in the absence of active autoimmune disease.
13. Adequate venous access to undergo a leukapheresis procedure.
14. Female patients must be surgically sterile or be postmenopausal (A postmenopausal state is defined as no menses for 12 months without an alternative medical cause). If a female patient is a woman of childbearing potential (WOCBP) they must agree to use highly effective contraception measures during the period of therapy, which should be continued for at least 5 months following the last dose of nivolumab as indicated in the SmPC. A list of highly effective contraceptive measures is included in appendix 2. All female patients with reproductive potential must have a negative pregnancy test (serum or urine) prior to enrollment and pregnancy testing should be conducted within 24h prior to the first dose of immune checkpoint inhibitors and thereafter monthly until 5 months following the last dose of study treatment. Women must not be breastfeeding at initiation of screening.

Exclusion criteria 17

1. Contra-indication for a maximal safe resection of the recurrent high-grade glioma;
2. Contra-indication for the insertion of an intracavitary catheter connected to a subcutaneous Ommaya reservoir;
3. Ventriculo-peritoneal drain;
4. Contraindication for evaluation by Gd-enhanced MRI, FET-PET of the brain or wholebody contrast enhanced CT;
5. Prior treatment on a nivolumab and/or ipilimumab trial;
6. Prior treatment with an anti-CTLA-4 or anti-PD-1/-L1 targeted therapy;
7. Gastrointestinal abnormalities including: a) Inability to take oral medication. b) Requirement for intravenous alimentation. c) Prior surgical procedures affecting absorption including gastric resection. d) Treatment for active peptic ulcer disease in the past 6 months. e) Malabsorption syndromes. f) Active gastrointestinal bleeding, unrelated to cancer, as evidenced by hematemesis, hematochezia or melena in the past 3 months without evidence of resolution
8. Evidence of pre-existing uncontrolled hypertension as documented by baseline blood pressure reading. The baseline systolic blood pressure reading must be ≤140 mm Hg, and the baseline diastolic blood pressure readings must be ≤90 mm Hg. If baseline blood pressure reading exceeds the inclusion values a second blood pressure reading (taken at least 1 hour apart) must be documented in order to confirm the absence of uncontrolled hypertension. Patients whose hypertension is controlled by antihypertensive therapies are eligible;
9. Concurrent treatment: a) In another therapeutic clinical trial; b) No requirement for permanent therapeutic anticoagulation therapy.
10. Subjects with active, known, or suspected autoimmune disease are not eligible. Subjects with type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment are permitted to enroll.
11. Active uncontrolled seizure disorder
12. Myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure or any unstable arrhythmia, cerebrovascular accident or transient ischemic attack, within the 12 months prior to study drug administration. No current or recent (within 1 month) use of a thrombolytic agent or a thrombo-embolic event
13. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness;
14. Serious uncontrolled medical disorder or active infection that would impair their ability to receive study treatment;
15. History of a malignancy (other than glioma) except those treated with curative intent for skin cancer (other than melanoma) or in situ breast or cervical cancer or those treated with curative intent for any other cancer with no evidence of disease for 5 years;
16. Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that would impart, in the judgment of the investigator, excess risk associated with study participation or study drug administration, or which, in the judgment of the investigator, would make the patient inappropriate for entry into this study;
17. Dementia or significantly altered mental status that would prohibit the understanding or rendering of informed consent and compliance with the requirements of this protocol;

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Incidence of adverse events (AE) that will be collected on a continuous basis. Type, frequency, and severity will be reported descriptively and graded according to Common Terminology Criteria for Adverse Events version 5 (CTCAEv5).

Secondary endpoints 3

1. Progression-free survival (PFS); defined as the time from the date of the first neoadjuvant dose administration during the stereotactic biopsy until the earliest date of documented disease progression or death due to any cause estimated by Kaplan-Meier survival estimates; including median, 6- months- and yearly survival rates with 95% confidence intervals.
2. Overall survival (OS); defined as the time from the date of the first neoadjuvant dose administration during the stereotactic biopsy until the date of death due to any cause estimated by Kaplan-Meier survival estimates; including median, 6- months- and yearly survival rates with 95% confidence intervals.
3. Assessment of the neuro-cognitive function, psycho-emotional disturbances and HR-QoL during study treatment at baseline, in week 27, and every 26 weeks thereafter until progression of disease, death, withdrawal of consent, or lost to follow-up.

Investigational products

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

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

UZ Brussel

Sponsor organisation

UZ Brussel

Address

Laarbeeklaan 101

City

Jette

Postcode

1090

Country

Belgium

Scientific contact point

Organisation

UZ Brussel

Contact name

Lise Collart

Public contact point

Organisation

UZ Brussel

Contact name

Lise Collart

Locations

1 EU/EEA country · 1 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 11 files

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

Application history

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