Evaluation of Platinum-Pemetrexed Chemotherapy Plus Lorlatinib in ALK-Positive NSCLC with Extracranial Progression on Lorlatinib

The primary objective of this study is to compare **progression-free survival (PFS)** between patients with **ALK positive Non-Small Cell Lung Cancer (NSCLC)** treated with a combination of Platinum-Pemetrexed-based chemotherapy plus **Lorlatinib** after progression on Lorlatinib, versus retrospective data indicating a PFS of 3.2 months for patients treated with Platinum-Pemetrexed-based chemotherapy alone after Lorlatinib. This comparison is clinically relevant as it aims to determine the efficacy of the combination therapy in extending PFS, which is a critical measure of treatment success in oncology.

Secondary objectives include:

• Describing intracranial PFS in patients treated with the combination therapy after Lorlatinib.
• Describing overall survival (OS) in patients treated with the combination therapy after progression on Lorlatinib.
• Describing the safety profile of the combination therapy.
• Assessing Patient Reported Outcome (PRO) and Quality of Life (QoL) in patients receiving the combination therapy.

The clinical trial involves participants diagnosed with **ALK positive Non-Small Cell Lung Cancer**. The study population includes both male and female subjects, with an age range starting from 18 years and above. Participants are required to have a histologically or cytologically confirmed diagnosis of stage IV ALK positive NSCLC, with measurable disease according to RECIST 1.1 criteria. The trial does not include a vulnerable population. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial population was selected based on specific inclusion criteria, including adequate organ function and a life expectancy of at least 3 months. Lifestyle considerations such as diet and physical activity are not specified. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed as a **single-arm**, phase II interventional study to evaluate the activity and safety of a combination therapy in patients with **ALK positive Non-Small Cell Lung Cancer** (NSCLC) experiencing extracranial disease progression on **lorlatinib**. The trial aims to compare progression-free survival (PFS) between patients treated with a combination of platinum-pemetrexed-based chemotherapy plus lorlatinib and retrospective data of patients treated with platinum-pemetrexed-based chemotherapy alone. The study is expected to commence recruitment on November 1, 2023, and conclude by April 30, 2028.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a histologically or cytologically confirmed diagnosis of stage IV ALK positive NSCLC, measurable disease according to RECIST 1.1, and adequate organ function. The trial will include follow-up visits to monitor treatment response and adverse events, with the primary endpoint being PFS, defined as the time from randomization to the first documented disease progression or death. Secondary endpoints include intracranial PFS, overall survival (OS), and the frequency and severity of adverse events graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

The expected length of participant involvement is up to 54 weeks, depending on the treatment regimen. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or any condition that, in the investigator's opinion, would make continued participation detrimental to the participant's health. The trial will employ a rigorous methodology to ensure the collection of reliable and valid data, contributing to the understanding of the efficacy and safety of the combination therapy in this patient population.

The clinical trial involves the administration of **Carboplatin**, marketed as Carboplatino Hikma 10 mg/ml soluzione per infusione. This medication is provided in the form of a **solution for infusion** and is administered via **intravenous infusion**. The dosage is calculated based on body surface area, with a maximum daily dose of 750 mg/m². The treatment period for Carboplatin is limited to a maximum of 12 cycles, with each cycle corresponding to a time unit of 2 weeks. Participant compliance is monitored through regular assessments of infusion administration and dosage adherence.

**Lorlatinib** is utilized in the study under the brand name Lorviqua, available in two dosages: 100 mg and 25 mg film-coated tablets. This medication is administered **orally** with a maximum daily dose of 100 mg. The total treatment duration for Lorlatinib is up to 54 weeks. Compliance is ensured by monitoring pill counts and patient diaries to track oral intake.

**Pemetrexed**, marketed as Pemetrexed Ever Pharma 25 mg/ml concentrato per soluzione per infusione, is another investigational product in this trial. It is also a **solution for infusion** administered via **intravenous infusion**. The dosing is based on body surface area, with a maximum daily dose of 500 mg/m². The treatment period extends up to 54 weeks, with compliance monitored through infusion records and dosage verification.

**Cisplatin**, under the brand name Cisplatino Accord Healthcare Italia 1 mg/ml concentrato per soluzione per infusione, is included in the study as a **solution for infusion**. It is administered through **intravenous infusion** with a maximum daily dose of 75 mg/m². The treatment duration is capped at 12 cycles, with each cycle lasting 2 weeks. Compliance is tracked through infusion logs and dosage checks.

The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. All medications are chemically synthesized and have been authorized for use in the trial. Participant adherence to the dosing schedule is critical and is closely monitored through various compliance measures, including infusion records, pill counts, and patient diaries.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Progression-Free Survival (PFS)**, defined as the time from randomization to the first documented disease progression or death due to any cause, whichever occurs first. Secondary endpoints include intracranial PFS, overall survival (OS), frequency and severity of adverse events graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, and patient-reported quality of life (QoL) specific to Non-Small Cell Lung Cancer (NSCLC) as measured by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire. This includes the Core 30 (QLQ-C30) and the 13-item Lung Cancer (QLQ-LC13) module, which assess general cancer symptoms, functioning, and lung cancer-specific symptoms and side effects from conventional chemo- and radiotherapy.

The trial will involve the administration of a combination of Platinum-Pemetrexed based chemotherapy plus Lorlatinib in patients with ALK positive NSCLC. The efficacy parameters will be collected and analyzed at various timepoints throughout the study, with the estimated end date set for April 30, 2028. The study will commence recruitment on November 1, 2023, and will follow a structured schedule for measuring and collecting data on the defined endpoints. The trial is designed as a multicenter, single-arm, phase II interventional study, focusing on patients with exclusively extracranial disease progression on Lorlatinib.