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 GBM 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.

Newly diagnosed glioblastoma: Glioblastoma (GBM) 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 GBMglioblastoma 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 exceptional cases where participants tolerate and benefit from [177Lu]Lu-NeoB, they can receive an additional 4 doses (total up to 10 dose administrations), resulting in a treatment duration of up to 37 weeks.. During this period, regular safety and efficacy assessments are planned on a weekly basis. The primary objective of this trial is to estimate identify the recommended dose of [177Lu]Lu-NeoB in combination with TMZ and RT in participants with newly diagnosed GBMglioblastoma 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 an expansion cohort, additional participants will be treated to further characterize the safety and tolerability, as well as to collect preliminary efficacy data from this cohort. Contrast enhanced MRI assessments are recommended to be repeated every 8 weeks and patient reported outcomes (PRO) questionnaires will be used to assess the effect of the study treatment on patient reported symptoms and tolerability.. Following treatment, all participants will be followed for up to 5 additional years for safety, progression of disease and survival. 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 carry a dismal prognosis and a short survival. 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. [177Lu]Lu-NeoB will be administered as a single dose every 3 weeks (Q3W) for 6 administrations. Up to 4 additional administrations of [177Lu]Lu-NeoB may be considered if participants tolerate and benefit from [177Lu]Lu-NeoB (total up to 10 dose administrations). In this study, the term "investigational drug" refers to [68Ga]Ga-NeoB as radioligand imaging compound, used to explore GRPR expression and to [177Lu]Lu-NeoB, used as radioligand therapy. The term "study treatment" refers to the combination of [177Lu]Lu-NeoB, temozolomide (TMZ) and radiotherapy (RT).

Glioblastoma,, GBM,, Radioligand Therapy,, RLT,, [68Ga]Ga-NeoB,, [177Lu]Lu-NeoB,, Temozolomide,, TMZ,, O-6-methylguanine-DNA methyltransferase,, MGMT

Either provided as Kit for the radiopharmaceutical preparation of [68Ga]Ga-NeoB or as ready to use radiopharmaceutical solution for injection

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. The DLT observation period is defined as a total of 7 weeks (49-52 days) (+/-3 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. A period of 7 weeks is therefore considered adequate for the assessment of acute toxicities and the totality of data will be used from this extended DLT period to determine the recommended dose (RD).

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.

Time activity curves (TACs) and 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 = 4 weeks)

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: Day 1 (Pre-dose (before start of infusion), At end of infusion, 0.5, 1, 2, 4 and 6 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)

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: Day 1 (Pre-dose (before start of infusion), At end of infusion, 0.5, 1, 2, 4 and 6 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)

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: Day 1 (Pre-dose (before start of infusion), At end of infusion, 0.5, 1, 2, 4 and 6 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)

Area under the blood concentration-time curve from time zero to the time of last quantifiable concentration (AUClast) of [177Lu]Lu-NeoB

Venous whole blood samples will be collected for activity-based pharmacokinetics characterization of [177Lu]Lu-NeoB. AUClast will be listed and summarized using descriptive statistics.

Cycle 1: Day 1 (Pre-dose (before start of infusion), At end of infusion, 0.5, 1, 2, 4 and 6 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)

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: Day 1 (Pre-dose (before start of infusion), At end of infusion, 0.5, 1, 2, 4 and 6 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)

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: Day 1 (Pre-dose (before start of infusion), At end of infusion, 0.5, 1, 2, 4 and 6 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)

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: Day 1 (Pre-dose (before start of infusion), At end of infusion, 0.5, 1, 2, 4 and 6 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)

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.

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).

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.

Key Inclusion Criteria for newly diagnosed glioblastoma: Signed informed consent must be obtained prior to participation in the study Histologically confirmed glioblastoma according to WHO classification established following either a surgical resection or biopsy Adequate bone marrow and organ function as defined by the laboratory values obtained within ≤ 14 days prior to receiving the first study treatment Karnofsky performance status ≥ 60% Key Exclusion Criteria for newly diagnosed glioblastoma: Additional, concurrent, or active therapy for glioblastoma outside of the present study Any prior treatment for glioma of any grade Any prior treatment with a therapeutic radiopharmaceutical Any prior cranial or head and neck external beam radiation prior to the diagnosis of glioblastoma Presence of glioblastoma lesions at the pre-surgery MRI in the proximity to or in the area of critical structures such as the optic nerves, optic chiasm, brainstem and spinal cord Key Inclusion criteria for recurrent glioblastoma: Signed informed consent must be obtained prior to participation in the study Histologically confirmed recurrent glioblastoma according to World Health Organization (WHO) classification established following either a surgical resection or biopsy Adequate bone marrow and organ function as defined by the laboratory values obtained within ≤ 14 days prior to receiving the first study treatment Presence of [68Ga]Ga-NeoB uptake by PET/CT or PET/MRI at the tumor region Karnofsky performance status ≥ 60% Key Exclusion Criteria for recurrent glioblastoma: Any prior treatment with a therapeutic radiopharmaceutical History or current diagnosis of impaired cardiac function History of another active malignancy in the previous 3 years prior to study entry 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