Dose Finding Study of [177Lu]Lu-NeoB in Combination With RT and TMZ in Newly Diagnosed GBM.
Study Details
Study Description
Brief Summary
This study will investigate different doses of [177Lu]Lu-NeoB in combination with RT and TMZ in participants with newly diagnosed GBM with methylated or unmethylated promoter to assess the safety and efficacy of [177Lu]Lu-NeoB in combination with the SoC 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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Detailed Description
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 GBM includes the combination of the alkylating agent Temozolomide (TMZ) with Radiotherapy (RT). The hypothesis of this study is to improve the outcome for patients by combining the current standard of care with the radioligand therapy [177Lu]Lu-NeoB. Patients enrolled into this trial will be treated for up to 32 weeks with the standard regimen TMZ and RT, combined with [177Lu]Lu-NeoB every 4 weeks. In exceptional cases, where patients tolerate and benefit from [177Lu]Lu-NeoB, they can receive 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 the recommended dose of [177Lu]Lu-NeoB in combination with TMZ and RT in participants with newly diagnosed GBM and to characterize the safety and tolerability of this treatment. For this reason, patients 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 patients 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 patients will be followed for up to 5 additional years for safety, progression of disease and survival.
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).
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: [177Lu]Lu-NeoB in Combination with Radiotherapy (RT) and Temozolomide (TMZ)
|
Drug: [177Lu]Lu-NeoB
Radiopharmaceutical solution for infusion
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: Temozolomide
Capsules/ lyophilized powder in single-dose vial for reconstitution.
|
Outcome Measures
Primary Outcome Measures
- Dose Escalation: Incidence and nature of Dose Limiting Toxicity (DLTs) [Up to 7 weeks (49 to 52 days (+/- 3 days)) after the first administration of [177Lu]Lu-NeoB]
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).
- Dose Expansion: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) [From date of enrollment till 28 days after end of Treatment, assessed up to approximately 17 months]
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.
Secondary Outcome Measures
- Dose Escalation and Dose Expansion: Time activity curves (TACs) and absorbed radiation doses of [177Lu]Lu-NeoB in organs and tumor lesions [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)]
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).
- Dose Escalation and Dose Expansion: Concentration of [177Lu]Lu-NeoB in blood over time [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. Blood concentration of [177Lu]Lu-NeoB will be summarized with descriptive statistics.
- Dose Escalation and Dose Expansion: Observed maximum blood concentration (Cmax) of [177Lu]Lu-NeoB [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.
- Dose Escalation and Dose Expansion: Time of maximum observed drug concentration occurrence (Tmax) of [177Lu]Lu-NeoB [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.
- Dose Escalation and Dose Expansion: Area under the blood concentration-time curve from time zero to the time of last quantifiable concentration (AUClast) of [177Lu]Lu-NeoB [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. AUClast will be listed and summarized using descriptive statistics.
- Dose Escalation and Dose Expansion: Total systemic clearance for intravenous administration (CL) of [177Lu]Lu-NeoB [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.
- Dose Escalation and Dose Expansion: Volume of distribution during the terminal phase following intravenous elimination (Vz) of [177Lu]Lu-NeoB [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. Vz will be listed and summarized using descriptive statistics.
- Dose Escalation and Dose Expansion: Terminal elimination half-life (T^1/2) of [177Lu]Lu-NeoB [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.
- Dose Expansion: Progression-Free Survival (PFS) [From the date of first dose to the date of confirmed progression according to modified RANO or death due to any cause, whichever comes first, assessed up to approximately 17 months]
PFS is defined as the time from the date of first dose to the date of confirmed progression according to modified response assessment in neuro-oncology (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.
- Dose Expansion: Overall Survival (OS) [From date of first dose to date of death due to any cause, assessed up to approximately 17 months]
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).
- Dose Escalation and Dose Expansion: Incidence and severity of AEs following [68Ga]Ga-NeoB administration [At date of screening and every 8 weeks until disease progression.]
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.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
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
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Adequate bone marrow and organ function as defined by the following laboratory values obtained within =< 14 days prior to receiving the first study treatment
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Presence of gadolinium enhancement at the tumor region in the pre-surgery MRI
-
Karnofsky performance status >= 60%
Exclusion Criteria:
-
Additional, concurrent, or active therapy for Glioblastoma outside of the present study
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Administration of a radiopharmaceutical with therapeutic intent within a period corresponding to 10 half-lives of the radionuclide used prior to injection of [68Ga]Ga-NeoB
-
History or current diagnosis of impaired cardiac function
-
History of another active malignancy in the previous 3 years prior to study entry
-
Known hypersensitivity to any of the study treatments, their excipients or dacarbazine
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Novartis Pharmaceuticals
Investigators
- Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- CAAA603C12101
- 2022-502134-10-00