Dose Finding Study of [177Lu]Lu-NeoB in Newly Diagnosed Glioblastoma and in Recurrent Glioblastoma

Phase Ib Dose Finding Study Assessing Safety and Activity of [177Lu]Lu-NeoB in Combination With Radiotherapy and Temozolomide in Subjects With Newly Diagnosed Glioblastoma and as a Single Agent in Recurrent Glioblastoma

This study will investigate different doses of [177Lu]Lu-NeoB in combination with RT and TMZ in participants with newly diagnosed glioblastoma, with methylated or unmethylated promoter, to assess the safety and efficacy of [177Lu]Lu-NeoB in combination with the SoC and in recurrent glioblastoma as single agent, to identify the recommended dose and to also explore the safety of the PET imaging agent [68Ga]Ga-NeoB and characterize its uptake in the tumor area.

Study Overview

• Status: Active, not recruiting
• Conditions: Newly Diagnosed and Recurrent Glioblastoma
• Intervention / Treatment: Drug: [177Lu]Lu-NeoB; Drug: [68Ga]Ga-NeoB; Other: Temozolomide

Detailed Description

Newly diagnosed glioblastoma:

Glioblastoma is the most common and aggressive type of primary brain tumor, with a high mortality rate. The current standard of care (SoC) in newly diagnosed glioblastoma includes the combination of the alkylating agent Temozolomide (TMZ) with Radiotherapy (RT). The hypothesis of this study is to improve the outcome for participants by combining the current standard of care with the radioligand therapy [177Lu]Lu-NeoB.

Participants with newly diagnosed glioblastoma enrolled into this trial will be treated with the standard regimen TMZ and RT, combined with [177Lu]Lu-NeoB every 4 weeks (Q4W) for 6 administrations. In cases where participants tolerate and benefit from [177Lu]Lu-NeoB, they can receive an additional 4 doses (total up to 10 dose administrations). During this period, regular safety and efficacy assessments are planned on a weekly basis.

The primary objective of this trial is to identify the recommended dose of [177Lu]Lu-NeoB in combination with TMZ and RT in participants with newly diagnosed glioblastoma and to characterize the safety and tolerability of this treatment. For this reason, participants will be enrolled and treated in cohorts with increasing dose levels and the totality of available data will be used to define the recommended dose. Contrast enhanced MRI assessments are to be repeated every 8 weeks. Participants with newly diagnosed glioblastoma will undergo a baseline [68Ga]Ga-NeoB PET/CT or PET/MRI after the surgery/biopsy of the tumor.

Recurrent glioblastoma:

Participants with recurrent glioblastoma (GBM) carry a dismal prognosis and a short survival. Median overall survival (OS) is approximately 12 months on a population level, 15-18 months in clinical trial populations, and 5-year survival is less than 10%. GBM is one of the lowest long-term survival rates of malignant brain tumors with a 5-year overall relative survival of only 6.8%.

The primary objective in recurrent glioblastoma is to determine the recommended dose of [177Lu]Lu-NeoB as single agent and to characterize the safety and tolerability of this treatment. For this reason, participants will be enrolled and treated in cohorts with increasing dose levels and the totality of available data will be used to define the recommended dose.

In this study, all participants with recurrent glioblastoma will undergo [68Ga]Ga-NeoB PET scan to assess GRPR expression during the screening period.

Treatment Duration:

[177Lu]Lu-NeoB will be given every 4 weeks for up to 6 administrations in newly diagnosed glioblastoma (24 weeks in duration) and every 3 weeks for up to 6 administrations (18 weeks in duration) in recurrent glioblastoma. In cases where participants tolerate and benefit from [177Lu]Lu-NeoB, they could receive up to 4 additional doses (up to 37 weeks in newly diagnosed glioblastoma and up to 30 weeks in recurrent glioblastoma).

Follow-up Duration:

During the follow-up period of 24 months. Participants will be monitored for safety and efficacy with contrast-enhanced MRI every 8 weeks until confirmed disease progression. Follow-up for survival will be monitored every 12 weeks thereafter.

A full and final analysis will be performed when all participants across all groups have completed the 24- months follow-up period.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 1

Contacts and Locations

Study Locations

• France
  • Cote D Or
    • Dijon, Cote D Or, France, 21034
      • Novartis Investigative Site
• Germany
  • Essen, Germany, 45147
    • Novartis Investigative Site
  • München, Germany, 80377
    • Novartis Investigative Site
• Italy
  • RE
    • Reggio Emilia, RE, Italy, 42123
      • Novartis Investigative Site
• Portugal
  • Porto, Portugal, 4200-072
    • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28040
    • Novartis Investigative Site
  • Madrid, Spain, 28009
    • Novartis Investigative Site
  • Andalusia
    • Granada, Andalusia, Spain, 18014
      • Novartis Investigative Site
  • Barcelona
    • Badalona, Barcelona, Spain, 08916
      • Novartis Investigative Site
    • L'Hospitalet de Llobregat, Barcelona, Spain, 08907
      • Novartis Investigative Site
• United States
  • California
    • Los Angeles, California, United States, 90095
      • University of California LA
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Denver
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Ctr
  • Ohio
    • Cleveland, Ohio, United States, 44106-5028
      • Univ Hosp Cleveland Medical Center
  • Utah
    • Salt Lake City, Utah, United States, 84103
      • Uni of Utah Huntsman Cancer Inst

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria/Common Criteria (Group 1 - Newly diagnosed glioblastoma, Group 2 - Recurrent glioblastoma):

1. Signed informed consent must be obtained prior to participation in the study
2. Age >= 18 years
3. Histologically confirmed glioblastoma according to WHO classification established following either a surgical resection or biopsy
4. Participants who are receiving corticosteroid treatment with dexamethasone, must be treated with a dose of =<4 mg/day (or other corticosteroids at equivalent dose) for a minimum of 7 days before initiation of study treatment

5. Adequate bone marrow and organ function as defined by the following laboratory values obtained prior to receiving the first study treatment:

   1. Absolute Neutrophil Count (ANC) >= 1.5 x 10^9/L
   2. Platelet count >= 100 x 10^9/L
   3. Hemoglobin >= 10.0 g/dL
   4. Creatinine clearance >= 60 mL/min calculated by the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) creatinine equation .
   5. Aspartate transaminase (AST) or Alanine transaminase (ALT) =< 3.0 x ULN
   6. Total bilirubin (TBIL) < 1.5 × ULN (any elevated bilirubin should be asymptomatic at enrollment) except for participants with Gilbert's syndrome who may only be included if the total bilirubin is =< 3.0 × ULN or direct bilirubin =< 1.5 × ULN
   7. Serum lipase ≤ 1.5 x ULN. For serum lipase > ULN - =< 1.5 x ULN, value must be considered not clinically significant and not associated with risk factors for acute pancreatitis

Key Inclusion Criteria/Newly diagnosed glioblastoma (Group 1):

9. Availability of tumor tissue representative of glioblastoma from definitive surgery or biopsy, to support biomarker analysis 10. Presence of gadolinium enhancement at the tumor region in the pre-surgery MRI

Key Inclusion Criteria/Recurrent glioblastoma (Group 2) 11. Presence of [68Ga]Ga-NeoB uptake by PET/CT or PET/MRI at the tumor region 12. Having first or second glioblastoma recurrence, after standard therapy that includes prior radiation therapy (RT) and at least 12 weeks from completion of RT 13. Evidence of recurrent disease (RD) demonstrated by disease progression using modified Response Assessment in Neuro-Oncology (mRANO) criteria. RD must be documented with at least one bi-dimensionally measurable contrast-enhancing lesion with clearly defined margins by MRI scan, with minimal diameters of 10 mm, according to mRANO criteria. For those participants who will undergo a second surgery for recurrence, pre-surgery MRI will be used for confirmation of RD.

14. If a second surgery is performed for glioblastoma recurrence, the following criteria must be met:

1. residual and measurable disease post-surgery is not required but surgery must have confirmed the recurrence diagnosis by MRI.
2. surgery completed at least 2 weeks prior to study treatment initiation, with post-surgery recovery without any complications related to surgical procedure.

Key Exclusion Criteria/Common Criteria (Group 1 - Newly diagnosed glioblastoma, Group 2 - Recurrent glioblastoma):

1. Additional, concurrent, or active therapy for glioblastoma outside of the present study 4. History or current diagnosis of impaired cardiac function, clinically significant cardiac disease, or ECG abnormalities indicating significant risk of safety for study participants such as:

a. Documented myocardial infarction (MI), angina pectoris, cardiomyopathy, symptomatic pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to study entry b. Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following: i. Risk factors for Torsade de Pointes (TdP) including uncorrected hypocalcemia, hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia ii. Concomitant medication(s) with a known risk to prolong the QT interval and/or known to cause Torsade de Pointes that cannot be discontinued or replaced by safe alternative medication (e.g., within 5 half-lives or 7 days prior to starting study drug) iii. Inability to determine the Fridericia QT correction formula (QTcF) interval c. Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third-degree AV block) d. Resting QTcF >= 450 msec (male) or >= 460 msec (female) e. Left Ventricular Ejection Fraction (LVEF) <50% as determined by echocardiogram (ECHO) or Multiple Gated Acquisition (MUGA) scan f. Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) >=160 mmHg and/or Diastolic Blood Pressure (DBP) >=100 mm Hg, with or without anti-hypertensive medication.

5. History of another active malignancy in the previous 3 years prior to study entry, except participants with prior history of superficial bladder cancer, any in situ carcinoma or basal or squamous cell skin cancer treated curatively

Key Exclusion Criteria/Newly diagnosed glioblastoma (Group 1):

17. Any prior treatment for glioma of any grade, including: prolifeprospan 20 with carmustine wafer, intracerebral agent, radiation treatment, chemotherapy or immunotherapy

Key Exclusion Criteria/Recurrent glioblastoma (Group 2) 18. Previous treatment with bevacizumab for the treatment of glioblastoma with therapeutic intent, or with bevacizumab as supportive therapy (e.g., edema reduction) within 60 days of initiation of study treatment 19. More than two prior lines of systemic therapy, more than one surgical resection for recurrent disease and treatment with an intracerebral/intracranial agent prior to starting [177Lu]Lu-NeoB. Administration in adjuvant setting counts as a line of prior systemic treatment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: [177Lu]Lu-NeoB in Combination with Radiotherapy (RT) and Temozolomide (TMZ); In newly diagnosed glioblastoma	Drug: [177Lu]Lu-NeoB; Radiopharmaceutical solution for infusion; Other Names: Lu-NeoB; Drug: [68Ga]Ga-NeoB; Either provided as Kit for the radiopharmaceutical preparation of [68Ga]Ga-NeoB or as ready to use radiopharmaceutical solution for injection; Other Names: Ga-NeoB; Other: Temozolomide; Capsules/ lyophilized powder in single-dose vial for reconstitution.
Experimental: [177Lu]Lu-NeoB as Single Agent; In recurrent glioblastoma	Drug: [177Lu]Lu-NeoB; Radiopharmaceutical solution for infusion; Other Names: Lu-NeoB; Drug: [68Ga]Ga-NeoB; Either provided as Kit for the radiopharmaceutical preparation of [68Ga]Ga-NeoB or as ready to use radiopharmaceutical solution for injection; Other Names: Ga-NeoB

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence and nature of Dose Limiting Toxicity (DLTs)	A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness/injury, or concomitant medications that occurs within the DLT observation period of [177Lu]Lu-NeoB. The National Cancer Institute Common Terminology Criteria for Adverse events (NCI CTCAE) version 5.0 will be used for all grading. In Group 1 (newly diagnosed GBM), the DLT observation period is defined as a total of 8 weeks (56 days) from the first administration of [177Lu]Lu-NeoB, to cover the entire duration of concomitant RT and TMZ combination with the first two administrations of [177Lu]Lu-NeoB. In Group 2 (recurrent GBM), the DLT observation period is 6 weeks (42 days) starting from the first administration of [177Lu]Lu-NeoB (at Week 1 Day 1) and accounting for assessment of the safety profile during 2 full cycles of [177Lu]Lu-NeoB.	Up to 8 weeks (newly diagnosed glioblastoma (GBM)) or 6 weeks (recurrent GBM) after the first administration of [177Lu]Lu-NeoB

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence and severity of Adverse Events (AEs) and serious Adverse Events (SAEs), changes in laboratory parameters, vital signs and Electrocardiogram (ECGs)	The distribution of adverse events will be done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters.	From date of enrollment till 28 days after end of Treatment, assessed up to approximately 17 months
Overall Survival (OS)	OS is defined as the time from date of first dose to date of death due to any cause. If a participant is not known to have died, then OS will be censored at the latest date the participant was known to be alive (on or before the cut-off date).	From date of first dose to date of death due to any cause, assessed up to approximately 17 months
Incidence and severity of AEs following [68Ga]Ga-NeoB administration	Incidence and severity of AEs following [68Ga]Ga-NeoB administration at screening will be done via the analysis of frequencies for Adverse Event (AEs), Serious Adverse Event (SAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters.	At date of screening and every 8 weeks until disease progression.
Concentration of [177Lu]Lu-NeoB in blood over time	Venous whole blood samples will be collected for activity-based pharmacokinetics characterization of [177Lu]Lu-NeoB. Blood concentration of [177Lu]Lu-NeoB will be summarized with descriptive statistics.	Cycle 1: Day1 (Pre-dose (before start of infusion), end of infusion, 0.5, 1, 2, 4 and 6 hours (hr) post-dose/post-infusion (p.i.)), Day2 (24 hr p.i), Day3 (48 hr p.i), Day8 (168 h p.i) (1 cycle= 3 weeks (recurrent GBM) or 4 weeks (newly diagnosed GBM))
Observed maximum blood concentration (Cmax) of [177Lu]Lu-NeoB	Venous whole blood samples will be collected for activity-based pharmacokinetics characterization of [177Lu]Lu-NeoB. Cmax will be listed and summarized using descriptive statistics.	Cycle 1: Day1 (Pre-dose (before start of infusion), end of infusion, 0.5, 1, 2, 4 and 6 hours (hr) post-dose/post-infusion (p.i.)), Day2 (24 hr p.i), Day3 (48 hr p.i), Day8 (168 h p.i) (1 cycle= 3 weeks (recurrent GBM) or 4 weeks (newly diagnosed GBM))
Time of maximum observed drug concentration occurrence (Tmax) of [177Lu]Lu-NeoB	Venous whole blood samples will be collected for activity-based pharmacokinetics characterization of [177Lu]Lu-NeoB. Tmax will be listed and summarized using descriptive statistics.	Cycle 1: Day1 (Pre-dose (before start of infusion), end of infusion, 0.5, 1, 2, 4 and 6 hours (hr) post-dose/post-infusion (p.i.)), Day2 (24 hr p.i), Day3 (48 hr p.i), Day8 (168 h p.i) (1 cycle= 3 weeks (recurrent GBM) or 4 weeks (newly diagnosed GBM))
Area under the blood concentration-time curve (AUC) of [177Lu]Lu-NeoB	Venous whole blood samples will be collected for activity-based pharmacokinetics characterization of [177Lu]Lu-NeoB. AUC will be listed and summarized using descriptive statistics.	Cycle 1: Day1 (Pre-dose (before start of infusion), end of infusion, 0.5, 1, 2, 4 and 6 hours (hr) post-dose/post-infusion (p.i.)), Day2 (24 hr p.i), Day3 (48 hr p.i), Day8 (168 h p.i) (1 cycle= 3 weeks (recurrent GBM) or 4 weeks (newly diagnosed GBM))
Total systemic clearance for intravenous administration (CL) of [177Lu]Lu-NeoB	Venous whole blood samples will be collected for activity-based pharmacokinetics characterization of [177Lu]Lu-NeoB. CL will be listed and summarized using descriptive statistics.	Cycle 1: Day1 (Pre-dose (before start of infusion), end of infusion, 0.5, 1, 2, 4 and 6 hours (hr) post-dose/post-infusion (p.i.)), Day2 (24 hr p.i), Day3 (48 hr p.i), Day8 (168 h p.i) (1 cycle= 3 weeks (recurrent GBM) or 4 weeks (newly diagnosed GBM))
Volume of distribution during the terminal phase following intravenous elimination (Vz) of [177Lu]Lu-NeoB	Venous whole blood samples will be collected for activity-based pharmacokinetics characterization of [177Lu]Lu-NeoB. Vz will be listed and summarized using descriptive statistics.	Cycle 1: Day1 (Pre-dose (before start of infusion), end of infusion, 0.5, 1, 2, 4 and 6 hours (hr) post-dose/post-infusion (p.i.)), Day2 (24 hr p.i), Day3 (48 hr p.i), Day8 (168 h p.i) (1 cycle= 3 weeks (recurrent GBM) or 4 weeks (newly diagnosed GBM))
Terminal half-life (T^1/2) of [177Lu]Lu-NeoB	Venous whole blood samples will be collected for activity-based pharmacokinetics characterization of [177Lu]Lu-NeoB. T^1/2 will be listed and summarized using descriptive statistics.	Cycle 1: Day1 (Pre-dose (before start of infusion), end of infusion, 0.5, 1, 2, 4 and 6 hours (hr) post-dose/post-infusion (p.i.)), Day2 (24 hr p.i), Day3 (48 hr p.i), Day8 (168 h p.i) (1 cycle= 3 weeks (recurrent GBM) or 4 weeks (newly diagnosed GBM))
Progression-free survival (PFS)	PFS is defined as the time from the date of first dose to the date of confirmed progression according to modified RANO or death due to any cause. If no PFS event is observed, PFS will be censored at the date of the last adequate tumor assessment prior to data cut-off date and start of new anti-neoplastic therapy, whichever comes first.	From date of first dose to date of confirmed progression, assessed up to approximately 17 months
Absorbed radiation doses of [177Lu]Lu-NeoB in organs and tumor lesions	The [177Lu]Lu-NeoB absorbed dose by body organs and tumor lesions will be determined by calculation of TACs obtained from the radiotracer uptake (as percentage of injected dose) in selected organs and lesions (coming from image quantification).	Cycles 1, 3 and 5: Day 1 (1-4 hours post-dose/post-infusion (p.i.)), Day 2 (24 hours p.i), Day 3 (48 hours p.i), Day 8 (168 hours p.i) (1 cycle = 3 weeks (recurrent GBM) or 4 weeks (newly diagnosed GBM))

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): May 15, 2024
• Primary Completion (Estimated): November 8, 2028
• Study Completion (Estimated): November 8, 2028

Study Registration Dates

• First Submitted: January 17, 2023
• First Submitted That Met QC Criteria: February 13, 2023
• First Posted (Actual): February 22, 2023

Study Record Updates

• Last Update Posted (Actual): May 14, 2026
• Last Update Submitted That Met QC Criteria: May 11, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: MGMT; Glioblastoma,; GBM,; Radioligand Therapy,; RLT,; [68Ga]Ga-NeoB,; [177Lu]Lu-NeoB,; Temozolomide,; TMZ,; O-6-methylguanine-DNA methyltransferase,
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Azoles; Dacarbazine; Triazenes; Imidazoles; Temozolomide
• Other Study ID Numbers: CAAA603C12101; 2022-502134-10-00 (Registry Identifier: EU CT number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No