A Global, Multicenter, Prospective, Controlled, Open-Label Pivotal Study of Iodofalan (131I) Solution for Injection (TLX101-Tx) Plus Lomustine Versus Lomustine Alone in Patients with Radiographically Confirmed Recurrent Glioblastoma at First Recurrence (IPAX-3)

The primary objective of this study is structured across multiple parts. Part 1a BOIN focuses on dose optimization to determine the maximum tolerated dose (MTD) and recommended dose of TLX101-Tx plus lomustine or TLX101-Tx as monotherapy for subsequent dose-expansion evaluation. Part 1b Dose Expansion Cohort aims to determine the safety, tolerability, and the recommended Phase 3 study dose of TLX101-Tx in combination with lomustine or TLX101-Tx as monotherapy in patients with confirmed first recurrence of glioblastoma. Part 2 Randomized Study evaluates whether TLX101-Tx concomitant with lomustine or TLX101-Tx monotherapy improves overall survival compared to lomustine alone. These objectives are clinically relevant for establishing optimal dosing regimens and assessing survival benefit in patients with recurrent glioblastoma at first recurrence.

The secondary objectives include: • Part 1a and 1b: To determine tumor and normal organ radiation dosimetry for TLX101-Tx in confirmed recurrent glioblastoma patients. • Part 1a and 1b: To characterize the pharmacokinetics and urinary excretion of TLX101-Tx. • Part 1a BOIN: To determine the safety and tolerability of TLX101-Tx in combination with lomustine or TLX101-Tx as monotherapy in patients with confirmed first recurrence of glioblastoma. • Part 1b Dose Expansion Cohort: To determine preliminary efficacy for the MTD treatment regimen. • Part 1b Dose Expansion Cohort: To determine the response rate at the MTD. • Part 2 Randomized Study: To evaluate whether TLX101-Tx concomitant with lomustine or as TLX101-Tx monotherapy improves progression-free survival of patients compared to lomustine alone. • Part 2 Randomized Study: To assess health-related quality of life of patients treated with TLX101-Tx plus lomustine or TLX101-Tx monotherapy. • Part 2 Randomized Study: To assess safety and tolerability.

This clinical trial enrolled a total of **20 participants** diagnosed with **glioblastoma**. The study population included both **male and female subjects** aged **18 years and older**. Participants were required to have a previously confirmed neuropathological diagnosis of glioblastoma, **IDH-wildtype** according to the **WHO 2021 classification**, with radiographic evidence of first recurrence or progressive disease following standard first-line treatment. All participants demonstrated increased **[18F]FET PET tracer uptake** within or in the vicinity of the tumor, with a **TBRmax ≥2.3** as determined by central review. The trial population was selected based on specific clinical characteristics, including an **Eastern Cooperative Oncology Group (ECOG) Performance Status** of 0–2 or **Karnofsky Performance Status (KPS) ≥70**, and adequate hematological, liver, and renal function at screening. Participants were required to have platelet counts ≥100×10⁹/L, **absolute neutrophil count** ≥1.5×10⁹/L, hemoglobin >10 g/dL, total **bilirubin** ≤1.5× the upper limit of normal, and **creatinine clearance** ≥60 mL/min. Patients on a stable, non-increasing dose of **steroids** in the previous 7 days were eligible for inclusion. Female participants of childbearing potential were required to have a negative serum pregnancy test and agree to use highly effective contraception during treatment and for 6 months following the last dose. Male participants were required to use condoms during sexual activity throughout the treatment period and for 3 months after the last dose, with additional contraceptive requirements for female partners of childbearing potential.

This is a global, multicenter, prospective, controlled, open-label pivotal study designed to evaluate the efficacy and safety of **4-L-[131I]iodo-phenylalanine** (also known as **iodofalan** or **TLX101-Tx**) in combination with **lomustine** compared to lomustine alone in patients with radiographically confirmed recurrent **glioblastoma** at first recurrence. The study is structured in two parts: Part 1 consists of a safety and dosimetry lead-in phase, which includes Part 1a employing a Bayesian Optimal Interval (BOIN) design for dose optimization to determine the **maximum tolerated dose** (MTD) and recommended Phase 3 dose (RP3D) of TLX101-Tx plus lomustine or TLX101-Tx as monotherapy, followed by Part 1b, a dose expansion cohort to further assess safety, tolerability, and the recommended Phase 3 study dose. Part 2 is a randomized study comparing TLX101-Tx concomitant with lomustine (or TLX101-Tx monotherapy based on Part 1 data) versus lomustine alone. The investigational medicinal product, 4-L-[131I]iodo-phenylalanine, is administered as a solution for injection via **intravenous administration** at a maximum daily dose of 4 **gigabecquerels** (GBq) and a maximum total dose of 12 GBq over a treatment period of up to 85 days. Lomustine is administered orally as a hard capsule at a maximum daily dose of 110 mg/m² and a maximum total dose of 1000 mg/m² over a treatment period of up to 5 months. The study is classified as a **Phase III** confirmatory trial.

The primary objective of Part 1a is to determine the MTD and recommended dose of TLX101-Tx plus lomustine or TLX101-Tx monotherapy by assessing treatment-emergent adverse events (TEAEs) described as dose-limiting, their frequency, and severity according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (**NCI CTCAE v5.0**). Part 1b aims to determine the safety, tolerability, and recommended Phase 3 study dose through safety assessments including physical examination, vital signs, electrocardiogram (**ECG**) abnormalities, clinical laboratory assessments, and adverse events reported according to NCI CTCAE v5.0, as well as tolerability assessed by health-related quality of life (**HRQoL**) total scores using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (**EORTC QLQ-C30**) and Brain Cancer Module 20 (**EORTC-BN20**) questionnaires, with neurological symptoms assessed using the Neurologic Assessment in Neuro-Oncology (**NANO**) scale. The primary objective of Part 2 is to evaluate whether TLX101-Tx concomitant with lomustine or TLX101-Tx monotherapy improves **overall survival** (OS) compared to lomustine alone, with OS determined from the date of enrollment until death from any cause.

Secondary endpoints for Part 1a and 1b include absorbed radiation doses based on quantitative imaging expressed as milligray per megabecquerel (mGy/MBq) of administered TLX101-Tx to tumor and bone marrow using single-photon emission computed tomography (**SPECT**) imaging, with planar images of the head and tumor volume estimates from computed tomography/magnetic resonance imaging (**CT/MRI**) used to obtain tumor dose estimates. The time course of radioactivity and TLX101 in blood and cumulative urine excretion of radioactivity after administration of TLX101-Tx will be assessed, along with blood and urine **pharmacokinetic** (PK) parameters, with **pharmacokinetic/pharmacodynamic** (PK/PD) modeling performed using venous blood samples and exposure-response analyses to correlate blood PK metrics and/or tumor and organ absorbed doses to efficacy and safety endpoints. Part 1b secondary endpoints include **progression-free survival** (PFS) from the time of enrollment as assessed by central core laboratory using Response Assessment in Neuro-Oncology 2.0 (**RANO 2.0**) criteria or death due to any cause, whichever occurs first, and objective response rate assessed by the central core laboratory according to RANO 2.0. Part 2 secondary endpoints include PFS from the date of enrollment randomization per RANO 2.0 criteria as assessed by the central core laboratory or death due to any cause, whichever occurs first, tolerability assessed by HRQoL total scores on EORTC QLQ-C30 and EORTC-BN20 questionnaires, and safety assessments including physical examination, vital signs, clinical laboratory assessments, and adverse events reported according to NCI CTCAE v5.0.

Principal inclusion criteria require patients to have a previously confirmed neuropathological diagnosis of glioblastoma, **isocitrate dehydrogenase-wildtype** (IDH-wildtype) according to the World Health Organization 2021 classification (**WHO 2021**), and radiographic evidence of first recurrence or progressive glioblastoma according to RANO 2.0 criteria after first-line treatment with biopsy or maximal safe resection and standard radiotherapy or chemoradiotherapy having occurred at least 3 months after the end of prior radiotherapy. Prior first-line therapy may include any systemic antineoplastic treatment other than **nitrosoureas**, tumor-treating fields, or conventionally fractionated or abbreviated radiotherapy with a minimum of 15 fractions. Patients must demonstrate increased fluorine-18 fluoroethyltyrosine positron emission tomography (**[18F]FET PET**) tracer uptake inside or in the vicinity of the tumor, with the uptake clearly discernible from background activity and measurable per PET RANO 1.0 criteria, with a tumor-to-background ratio maximum (**TBRmax**) of at least 2.3 as determined by central review. Tumor debulking for recurrent progressive disease is allowed, provided the patient has post-surgical radiographic evidence for residual tumor according to RANO 2.0 with increased [18F]FET PET uptake (TBRmax ≥2.3) and measurable disease according to PET RANO 1.0 at 4 to 6 weeks post-surgery. Patients must be at least 18 years of age, have the capacity to understand the study and be willing to comply with all protocol requirements, and have an Eastern Cooperative Oncology Group Performance Status (**ECOG PS**) of 0 to 2 or **Karnofsky Performance Status** (KPS) of at least 70. Patients on a stable, not increasing dose of **steroids** in the previous 7 days can be included. Adequate hematological, liver, and renal function at the time of screening is required, including platelets at least 100×10⁹/L, absolute neutrophil count at least 1.5×10⁹/L, hemoglobin greater than 10 g/dL with no red blood cell transfusion in the previous 4 weeks, total bilirubin no more than 1.5 times the upper limit of normal (ULN) or no more than 3 times ULN for patients with **Gilbert's Syndrome**, alanine aminotransferase (**ALT**) or aspartate aminotransferase (**AST**) no more than 5 times ULN for patients with known liver metastases, and **creatinine clearance** at least 60 mL/min determined using the European Kidney Function Consortium formula (**EKFC**). Females of childbearing potential must have a negative serum pregnancy test within 7 days prior to the first dose of investigational drug product, must not be breast-feeding, and must agree to use a highly effective method of contraception during treatment and for 6 months following the last dose. Male patients must agree to use condoms during sexual activity during the treatment period and for 3 months after the last dose of investigational drug product and must not make semen donations during treatment and for 6 months following the last dose, with female partners of childbearing potential agreeing to use a highly effective method of contraception during the treatment period and for 6 months following the last dose.

The estimated recruitment start date is October 6, 2025, and the estimated end date of the study is November 30, 2027. The expected length of participant involvement varies by study part, with Part 1a and 1b participants undergoing dose optimization and expansion phases with treatment periods of up to 85 days for TLX101-Tx and up to 5 months for lomustine, followed by safety and efficacy assessments. Part 2 participants will be followed from randomization until death or study completion to assess overall survival. Study visits include a screening visit to assess eligibility criteria, baseline assessments including [18F]FET PET imaging co-registered with MRI, treatment visits for administration of investigational products, follow-up visits for safety assessments including physical examination, vital signs, ECG, clinical laboratory tests, adverse event monitoring, HRQoL questionnaires (EORTC QLQ-C30 and EORTC-BN20), neurological assessments using the NANO scale, and imaging assessments per RANO 2.0 criteria by central core laboratory, and an end-of-study visit. Dosimetry assessments will be performed using SPECT imaging and planar images to determine absorbed radiation doses to tumor and bone marrow. Pharmacokinetic assessments will include collection of venous blood samples and urine samples to determine the time course of radioactivity and TLX101 in blood and cumulative urine excretion. Conditions that may lead to early termination from the study include dose-limiting toxicities, disease progression, unacceptable toxicity, withdrawal of consent, pregnancy, protocol violations, or investigator decision based on patient safety considerations.

The experimental medication in this clinical trial is **4-L-[131I]iodo-phenylalanine** (also designated as **131I-TLX101** or **TLX101-Tx**), which contains the active substance **4-iodophenylalanine I-131**. This product holds **orphan drug designation** (EU/3/06/363) and is supplied as a **solution for injection**. The medicinal product is administered via **intravenous administration**. The maximum daily dose is **4 gigabecquerels (GBq)**, with a maximum total dose of **12 GBq** over the treatment period. The maximum treatment period extends to **85 days**. The experimental medication may be administered as a **monotherapy** or in combination with lomustine, depending on the results from the dose optimization and expansion phases of the study.

**Lomustine** serves as both a **comparator treatment** and an **auxiliary medicinal product** in this trial. It is classified as a **chemotherapeutic agent** and is formulated as a **hard capsule**. The route of administration is **oral**. The maximum daily dose is **110 milligrams per square meter (mg/m²)**, with a maximum total dose of **1000 mg/m²**. The maximum treatment period for lomustine administration is **5 cycles**. In the comparator arm, lomustine is administered alone, while in the experimental arm, it may be administered concomitantly with the investigational product TLX101-Tx.

The study design includes a dose optimization phase utilizing a **Bayesian Optimal Interval (BOIN)** design to determine the **maximum tolerated dose (MTD)** and the **recommended Phase 3 dose (RP3D)** of TLX101-Tx when used either in combination with lomustine or as monotherapy. A dose expansion cohort follows to further evaluate safety, tolerability, and the recommended dose for the subsequent randomized phase. Participant compliance monitoring and dosing schedules are implemented throughout all study phases to ensure adherence to the protocol-specified treatment regimens and to assess the safety profile of the investigational product.

Efficacy will be assessed through multiple parameters across different parts of the trial. In Part 1b Dose Expansion Cohort, progression-free survival (PFS) will be measured from the time of enrollment as assessed by central core lab using Response Assessment in Neuro-Oncology (RANO) 2.0 criteria or death due to any cause, whichever occurs first. Objective response rate will be assessed by the central core lab according to RANO 2.0 criteria. In Part 2 Randomized Study, the primary efficacy endpoint is overall survival (OS), determined from the date of enrollment until death from any cause. Secondary efficacy assessment in Part 2 includes PFS from the date of enrollment randomization per RANO 2.0 criteria as assessed by the central core lab or death due to any cause, whichever occurs first.

Tolerability will be evaluated through health-related quality of life (HRQoL) total scores using the European Organization for Research and Treatment of Cancer questionnaires (EORTC QLQ-C30 and EORTC-BN20) in both Part 1b Dose Expansion Cohort and Part 2 Randomized Study. Neurological symptoms will be assessed with the Neurologic Assessment in Neuro-Oncology (NANO) scale in Part 1 Safety and Dosimetry Lead-in. In Part 1 Safety and Dosimetry Lead-in, absorbed radiation doses to tumor and bone marrow will be measured based on quantitative imaging, expressed as mGy/MBq of administered TLX101-Tx, using single-photon emission computed tomography (SPECT) imaging. Planar images of the head and tumor volume estimates from computed tomography/magnetic resonance imaging (CT/MRI) will be used to obtain an estimate of the tumor dose per administered activity of iodine-131.