Evaluation of LSTA1 Combined with Temozolomide Versus Temozolomide Alone in Newly Diagnosed Glioblastoma Multiforme: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to evaluate the effect of **LSTA1** in combination with temozolomide (TMZ) on survival in patients with newly diagnosed **Glioblastoma Multiforme** (GBM), compared to a combination of temozolomide and a matching LSTA1 placebo. This objective is clinically relevant as it aims to determine whether the addition of LSTA1 can improve survival outcomes in a patient population with a typically poor prognosis.

Secondary objectives include:

• Determining the effect of LSTA1 on milestone survival endpoints, specifically 12-month and 24-month survival.
• Assessing the impact of LSTA1 on progression-free survival (PFS).
• Evaluating the effect of LSTA1 on response rate.
• Investigating the duration of response (DOR) in responding patients with measurable disease at baseline.
• Determining any impact of LSTA1 in combination with TMZ on quality-of-life measures.

The clinical trial involves participants diagnosed with **Glioblastoma Multiforme**. The study population includes both male and female subjects aged between 18 and 75 years. Participants are required to have newly diagnosed and histologically confirmed intracranial glioblastoma multiforme, as per the 2021 World Health Organization Classification. They must have undergone primary surgical resection followed by a standard radiotherapy regimen in combination with temozolomide. The trial includes individuals with adequate respiratory and cardiac function, as well as sufficient organ and marrow function. Participants must have an Eastern Cooperative Oncology Group Performance Status of 0, 1, or 2, and a life expectancy of at least three months. The trial population was selected based on these criteria, and subjects must be able to undergo serial MRIs. The sponsor has not provided information regarding the total number of participants. The study considers lifestyle factors such as the ability to maintain stable or decreasing doses of corticosteroids for at least 14 days prior to randomization. Adequate contraception is also required for participants. The trial includes a vulnerable population, but specific details about this group are not disclosed.

The clinical trial is a **Phase 2**, double-blind, placebo-controlled, randomized study designed to evaluate the efficacy of **LSTA1** in combination with standard care, **temozolomide**, compared to temozolomide with a matching placebo in subjects with newly diagnosed **Glioblastoma Multiforme** (GBM). The primary objective is to assess the effect of LSTA1 on overall survival, with secondary endpoints including 12-month and 24-month survival rates, progression-free survival, and overall response rate. The trial is expected to run from September 2023 to August 2027, with participant involvement lasting up to 168 weeks.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, adequate organ function, and a confirmed diagnosis of GBM. Following successful screening, participants will be randomized to receive either LSTA1 with temozolomide or temozolomide with placebo. Study visits will include regular assessments to monitor safety, efficacy, and disease progression, with follow-up visits scheduled at specified intervals. The end-of-study visit will occur after the completion of the treatment period or upon early termination.

Involvement in the study may be terminated early if participants experience significant adverse events, disease progression, or withdrawal of consent. Participants must adhere to the protocol, including maintaining stable corticosteroid doses and undergoing regular imaging assessments. The trial's design ensures rigorous monitoring and data collection to evaluate the therapeutic potential of LSTA1 in improving outcomes for patients with GBM.

The clinical trial involves the evaluation of **LSTA1**, a circular peptide with the sequence CRGDKGPDC, which targets tumor vascular endothelium. LSTA1 is administered as a **powder for injection** and is delivered via direct intravenous injection. The maximum daily dose is 3.2 mg/kg, with a total treatment period of up to 25 days. The peptide is not formulated for pediatric use and is provided by Lisata Therapeutics Ireland Limited. Participant compliance with the dosing schedule will be monitored throughout the trial.

**Temozolomide Accord** is utilized as the standard-of-care therapy in this study. It is an anti-neoplastic agent provided in the form of 100 mg hard capsules. The administration route is oral, with a maximum daily dose of 200 mg/m² and a total dose not exceeding 6000 mg/m² over a treatment period of 168 days. Temozolomide is a chemical substance and is supplied by Accord Healthcare S.L.U. Compliance with the dosing regimen will be closely monitored to ensure adherence.

A **placebo** is also employed in this trial to serve as a comparator to LSTA1. The placebo is designed to match the experimental treatment in appearance and administration route, ensuring the study remains double-blind. The placebo is not formulated for pediatric use and is administered according to the same schedule as LSTA1. Participant adherence to the placebo regimen will be monitored to maintain the integrity of the trial results.

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is **overall survival**, defined as the median time from randomization until death due to any cause. Secondary endpoints include 12-month and 24-month survival rates, median progression-free survival (PFS) at 6 and 12 months based on RANO criteria, overall response rate (ORR), disease control rate, duration of response (DOR) for a subset of patients, and scores on the EORTC QLQ-30. These endpoints will be measured and collected at specified intervals throughout the trial duration.