Title
AAA601A52101: Phase Ib Dose Finding Study Assessing Safety and Activity of 177LU-Lu-Dota-Tate in Newly Diagnosed Glioblastoma in Combination With Radiotherapy With or Without Temozolomide and in Recurrent Glioblastoma as Single Agent.

Description
The study for each participant consists of a Screening period, a Treatment period and a 12-month Follow-up period.

During the screening period of up to 6 weeks before starting GBM treatment, each participant will be assessed for somatostatin receptor (SSTR) expression by [68Ga]Ga-DOTA-TATE imaging PET/scan.

Eligible participants with newly diagnosed glioblastoma will be assigned to Group 1 :

• Participants in Group 1 (concomitant radiotherapy + temozolomide and temozolomide maintenance) will receive treatment with [177Lu]Lu-DOTA-TATE every 4 weeks +/- 2 days, up to 6 administrations. Radiotherapy and temozolomide will be administered 7 to 10 days after the first administration of [177Lu]Lu-DOTA-TATE. Temozolomide will be administered orally at a dose of 75 mg/m2/day during the concomitant period, concurrently with radiotherapy. Radiotherapy will be delivered at a dose of 2 Gray (Gy)/day, 5 days per week followed by 2 days of rest, for 6 consecutive weeks with a total dose of 60 Gy (without interruption). During the maintenance period, there is an intra-patient dose escalation in temozolomide treatment. The dosage of temozolomide is 150 mg/m2 in Cycle 1 of maintenance period, and then to 200 mg/m2 in Cycle 2 and beyond in the maintenance period, if 150 mg/m2 temozolomide treatment is well tolerated in Cycle 1.

Eligible participants with recurrent glioblastoma will be assigned to Group 3 and will receive [177Lu]Lu-DOTA-TATE as single agent treatment every 3 weeks +/- 2 days.

An infusion of sterile 2.5% Lysine - Arginine amino acid (AA) solution will be co-administered with each [177Lu]Lu-DOTA-TATE dose for renal protection.

Objective
Primary Objectives
To determine the recommended dose of [177Lu]Lu-DOTA-TATE in 3 different groups of Glioblastoma:
Group 1: Newly diagnosed glioblastoma participants with methylated O-6-methylguanine-DNA methyltransferase (MGMT) promoter treated with [177Lu]Lu-DOTA-TATE in combination with concomitant radiotherapy and temozolomide followed by [177Lu]Lu-DOTA-TATE and temozolomide in maintenance.
Group 2: Newly diagnosed glioblastoma participants with unmethylated MGMT promoter treated with [177Lu]Lu-DOTA-TATE in combination with radiotherapy followed by [177Lu]Lu-DOTA-TATE alone.
Group 3: Recurrent glioblastoma participants treated with [177Lu]Lu-DOTA-TATE.
Secondary Objectives
To assess the safety and tolerability of [177Lu]Lu-DOTA-TATE in combination with radiotherapy + temozolomide or with radiotherapy in participants with newly diagnosed glioblastoma and as a single agent in participants with recurrent glioblastoma.
To assess anti-tumor activity of [177Lu]Lu-DOTA-TATE in combination with radiotherapy + temozolomide or with radiotherapy in participants with newly diagnosed glioblastoma or as a single agent in participants with recurrent glioblastoma using modified response assessment in neuro-oncology (RANO) criteria.
To assess pharmacokinetics and dosimetry of [177Lu]Lu-DOTA-TATE in participants with newly diagnosed or recurrent glioblastoma.
To assess the safety and tolerability of [68Ga]Ga-DOTA-TATE in all participants.

Treatment Experimental: Group 1 - Newly diagnosed GB
Participants with newly diagnosed glioblastoma will receive [177Lu]Lu-DOTA-TATE every 4 weeks +/- 2 days, starting 7 to 10 days prior to initiation of Radiotherapy (RT) and Temozolomide (TMZ)

Experimental: Group 3 - Recurrent GB
Participants with recurrent glioblastoma will receive [177Lu]Lu-DOTA-TATE as single agent therapy every 3 weeks +/- 2 days

Key Eligibility Key Inclusion Criteria:

Common Criteria:

Participant is >= 18 years on the day of signing informed consent form

Histologically confirmed glioblastoma

Adequate bone marrow, organ function and electrolyte values

Presence of Gadolinium enhancing tumor in pre-surgery magnetic resonance imaging (MRI)

Karnofsky Performance Score (KPS) >= 70 %

Evidence of recurrent disease demonstrated by disease progression using modified Response Assessment in Neuro-Oncology (mRANO) criteria

KPS >= 60 %

[68Ga]Ga-DOTA-TATE uptake by positron emission tomography/computed tomography (PET/CT) or PET/MRI at the tumor region

Presence of Gadolinium enhancement in the tumor region in MRI at the time of diagnosis of tumor recurrence

A second surgery for glioblastoma is allowed provided that the following criteria are met:



Residual and measurable disease post-surgery is not required but surgery must have confirmed the diagnosis of recurrence

Surgery completed at least 2 weeks prior to study treatment initiation, with post-surgery recovery without any complications related to surgical procedure

Recurrent glioblastoma (Group 3 Dose Expansion only):



Patients experiencing first recurrence of their glioblastoma, after standard or experimental therapy that includes prior EBRT

Participant is receiving additional, concurrent, active therapy for glioblastoma outside of the trial

Extensive leptomeningeal disease

History of another active malignancy in the previous 3 years prior to study entry

Prior administration of a radiopharmaceutical unless 10 or more effective half-lives have elapsed before injection of [68Ga]Ga-DOTA-TATE or [177Lu]Lu-DOTA-TATE

Early disease progression prior to 3 months from the completion of radiotherapy

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

Applicable Disease Sites
Brain/Central Nervous System

Participating Institutions
UW Health Eastpark Medical Center; UW Health University Hospital