A multicenter single-arm phase II interventional study to evaluate the activity and safety of the combination of Platinum-Pemetrexed based chemotherapy plus Lorlatinib in ALK positive Non-Small Cell Lung Cancer (NSCLC) with exclusively extracranial disease progression on Lorlatinib

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centro Di Riferimento Oncologico Di Aviano

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

15 Mar 2024 → ongoing

Decision date (initial)

2024-02-26

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy

To compare PFS between patients treated with PT/pem-based chemotherapy plus Lorlatinib after Lorlatinib versus retrospective data of 3.2 months for patients treated with PT/pem-based chemotherapy after Lorlatinib

Secondary objectives 4

1. To describe intracranial PFS in patients treated with PT/pem-based chemotherapy plus Lorlatinib after Lorlatinib
2. To describe OS in patients treated with PT/pem-based chemotherapy plus Lorlatinib after Lorlatinib progression
3. To describe the safety of PT/pem-based chemotherapy plus Lorlatinib combination
4. To assess Patient Reported Outcome (PRO) and Quality of Life (QoL) in patients treated with PT/pem-based chemotherapy plus Lorlatinib combination

Conditions and MedDRA coding

ALK positive Non-Small Cell Lung Cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Written informed consent prior to beginning specific protocol procedures, including expected cooperation of the patients for the treatment and follow-up, must be obtained, and documented according to the local regulatory requirements
2. Age at the time of signing the informed consent at least 18 years
3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
4. Histologically or cytologically confirmed diagnosis of stage IV ALK positive NSCLC. ALK positivity can be determined by fluorescence in situ hybridization assay (FISH), immunohistochemistry (IHC) or DNA-based next-generation sequencing (NGS)
5. Patients must have measurable disease according to RECIST 1.1 by computed tomography (CT) and magnetic resonance imaging (MRI)
6. patients must be in progression extracranially on Lorlatinib; Lorlatinib may be in first- or further-line, without limitations regarding previously received therapies. If a patient has already received platinum (e.g. in adjuvant setting), the eligibility for PT-pem chemotherapy treatment is at the Investigator discretion
7. Radiologically confirmed multiple extracranial progression on Lorlatinib without progression in the central nervous system (CNS) defined as: • Absence of CNS metastasis • CNS metastasis stable on Lorlatinib and/or stereotactic brain irradiation (SBRT) • Prior radiotherapy must have been completed within 4 weeks of study entry; SBRT must have been completed at least 4 weeks before study entry; and whole-brain radiotherapy at least 4 weeks before study entry. • Patients with previously treated brain metastases are eligible provided they have been clinically stable for at least 4 weeks with no evidence of new or expanding brain metastases
8. Adequate organ function (kidney, bone marrow and liver): - Hematology • Absolute Neutrophil Count (ANC) ≥1.5 x 109 / L • Platelets ≥100 x 109 / L • Hemoglobin ≥10 g/dL (≥6.2 mmol/L) - Hepatic function • Total bilirubin <1.25x UNL. In presence of a documented history of Gilbert syndrome the total bilirubin level must be <3.0x UNL • AST and ALT ≤1.5x UNL. If the liver has tumor involvement AST and ALT must be ≤5x UNL • Alkaline phosphatase ≤2.5x UNL - Renal Function • <1.25x ULN creatinine • Creatinine clearance ≥45 ml/min (according to Cockroft-Gault, if creatinine is above UNL)
9. If feasible, fresh tissue biopsy demonstrating ALK translocation still present (obtained ≤ 3 months before study enrolment), assessed by local laboratory
10. Estimated life expectancy of at least 3 months irrespective of the diagnosis of ALK+ NSCLC
11. For women of childbearing potential and males with partners of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 14 weeks after the last dose of study drugs

Exclusion criteria 5

1. Known hypersensitivity reaction to one of the compounds or substances used in this protocol
2. Diagnosis of any secondary malignancy within the last 3 years, except for: adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, definitively treated nonmetastatic prostate cancer or patients with another primary malignancy who are definitively relapse-free with at least 3 years elapsed since the diagnosis of the other primary malignancy
3. Patients deemed unsuitable by the investigator for treatment of chemo-Lorlatinib combination
4. Presence of toxicities contraindicating the continuation of therapy with Lorlatinib
5. Concomitant use of potent CYP3A4/5 inducers

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. PFS defined as the time from randomization to the first documented disease progression or death due to any cause, whichever occurs first

Secondary endpoints 4

1. intracranial PFS defined as time from randomization until CNS disease progression or death from any cause
2. OS is defined as the time from randomization until death from any cause
3. Frequency and severity of adverse events graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
4. Patient reported NSCLC specific QoL as measured by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire: - Core 30 (QLQ-C30): Questionnaire consisting of 30 measuring subjects’ general cancer symptoms and functioning - 13-item Lung Cancer (QLQ-LC13) module: A complementary questionnaire measuring lung cancer symptoms and side-effects from conventional chemo- and radiotherapy

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Auxiliary 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centro Di Riferimento Oncologico Di Aviano

Sponsor organisation

Centro Di Riferimento Oncologico Di Aviano

Address

Via Franco Gallini 2

City

Aviano

Postcode

33081

Country

Italy

Scientific contact point

Organisation

Centro Di Riferimento Oncologico Di Aviano

Contact name

Alessandra Bearz

Public contact point

Organisation

Centro Di Riferimento Oncologico Di Aviano

Contact name

Alessandra Bearz

Locations

1 EU/EEA country · 14 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 15 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications