Clinical trial NCT05740943: Induction Lorlatinib in Stage III Non-small Cell Lung Cancer
Official title: Induction Lorlatinib for ALK Fusion Locally Advanced Non-small Cell Lung Cancer: A Prospective, Single Arm, Open-label Phase 2 Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Stage III NSCLC
Surgery
Keywords: ALK fusion
Induction Treatment
Multidisciplinary
ctDNA
Lorlatinib
Lead sponsor: Guangdong Provincial People's Hospital
Sponsor class: OTHER
First posted: 2023-02-23
Enrollment: 48
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: A Simon two-stage design was applied. Primary endpoint for this study was pCR. The unacceptable response rate for pCR was less than 20% and desirable response rate was 40%. The error rate for alpha was set as 0.05 and 0.2 for beta. The Optimal assay was chosen and 43 patients were to be enrolled to meet adequate statical power. 13 patients would be enrolled in stage I and at least 3 patients achieved pCR were required to proceed stage II enrollment. Overall, if 12 patients achieved pCR, the study would be determined as positive. 10% drop-off rate should be considered and at least 48 patients should be enrolled.
Primary purpose: TREATMENT

Brief summary: A prospective, single-arm, open-label phase 2 study that evaluates the efficacy and safety of induction Lorlatinib in stage III non-small cell lung cancer and explores the clinical feasibility of dynamic ctDNA and multidisciplinary assessment in guiding local treatments.

Detailed description: Simon two-stage was applied to estimate the required sample size for the study. Overall an estimated 43 patients were required and at least 12 patients achieved pathological complete response would be deemed as positive result. Patients will be provided 3 cycles induction Lorlatinib 100mg and then assessed whether patients would be eligible for radical surgery or local radiotherapy through multidisciplinary evaluation. After local intervention, patients could choose consolidation treatment of Lorlatinib for up to 2 years or adjuvant doublet chemotherapy for up to 4 cycles. Dynamic blood samples will be collected before and after induction Lorlatinib as well as consolidation treatment. The primary endpoints is pCR for patients who received radical surgery.

Eligibility criteria: Inclusion Criteria:

* Age :18 Years to 75 Years;
* ECOG physical score 0-2 points; expected survival time ≥ 1 year;
* Pathologically confirmed diagnosis with Stage III NSCLC which harbored ALK fusion detected by next generation sequencing (NGS) or immunohistochemistry (IHC) with or without FISH. Suspected N2 (station 2/4/7) for stage III disease should be confirmed by either mediastinoscopy or EBUS.
* At least one measurable target lesion according to the RECIST 1.1 standard;
* The main organ function meets the following criteria: 1) blood routine: absolute value of neutrophils ≥ 1.5 × 109 / L, platelets ≥ 75 × 109 / L, hemoglobin ≥ 80 g / L; 2) blood biochemistry: total bilirubin ≤ 1.5 times the upper limit of normal value, aspartate aminotransferase and alanine aminotransferase ≤ 2.5 times the upper limit of normal value (if liver metastasis, ≤ upper limit of normal value 5 times), serum creatinine ≤ 1.5 times the upper limit of normal;
* Subjects voluntarily joined the study and signed informed consent, with good compliance to follow-up.

Exclusion Criteria:

* Stage I, stage II and metastatic stage IV NSCLC;
* Histologically confirmed small cell lung cancer (including lung cancer mixed with small cell lung cancer and non-small cell lung cancer);
* Patients who have previously used any other anti-tumor drugs or received surgery/radiotherapy;
* Patients with any underlying disease that investigators consider it may affect patient's prognosis including sever cardiovascular, pulmonary disease or serious infections.
* Clinically obvious gastrointestinal abnormalities, which may affect the intake, transport or absorption of drugs (such as inability to swallow, chronic diarrhea, intestinal obstruction, etc.), or patients with total gastrectomy;
* Pregnant or lactating women; those who have fertility are unwilling or unable to take effective contraceptive measures;
* Patients with low compliance or willingness to take the drugs and surveillance.

Primary outcomes:
measure: Pathological Complete Response (pCR)
timeFrame: After surgery (approximately 2 weeks)
Secondary outcomes:
measure: Progression-free Survival (PFS)
timeFrame: From date of induction treatment till the date of first documented disease progression or death, whichever came first, assessed up to 48 months
measure: Objective Response Rate (ORR)
timeFrame: After last dose of induction treatment (approximately 1 week)
measure: Event-free Survival (EFS)
timeFrame: From date of radical surgery till the date of first documented disease relapse, assessed up to 48 months
measure: Dynamic ctDNA alteration
timeFrame: From induction treatment till completion of consolidation lorlatinib (approximately 2.5 years)
measure: Overall Survival (OS)
timeFrame: From date of induction treatment till the date of death from any cause, assessed up to 60 months.
measure: Adverse Events (AEs)
timeFrame: From Initiation of induction treatment till treatment discontinuation, assessed up to 24 months.
Other outcomes:
Locations:
city: Guangzhou
country: China
facility: Guangdong Provincial People's Hospital
state: Guangdong
Study officials:
affiliation: Guangdong Provincial People's Hospital
name: Wen-Zhao Zhong, MD.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Zhang C, Li SL, Nie Q, Dong S, Shao Y, Yang XN, Wu YL, Yang Y, Zhong WZ. Neoadjuvant Crizotinib in Resectable Locally Advanced Non-Small Cell Lung Cancer with ALK Rearrangement. J Thorac Oncol. 2019 Apr;14(4):726-731. doi: 10.1016/j.jtho.2018.10.161. Epub 2018 Nov 5.
citation: Leonetti A, Minari R, Boni L, Gnetti L, Verze M, Ventura L, Musini L, Tognetto M, Tiseo M. Phase II, Open-label, Single-arm, Multicenter Study to Assess the Activity and Safety of Alectinib as Neoadjuvant Treatment in Surgically Resectable Stage III ALK-positive NSCLC: ALNEO Trial. Clin Lung Cancer. 2021 Sep;22(5):473-477. doi: 10.1016/j.cllc.2021.02.014. Epub 2021 Feb 24.
citation: Zhang C, Yan LX, Jiang BY, Wu YL, Zhong WZ. Feasibility and Safety of Neoadjuvant Alectinib in a Patient With ALK-Positive Locally Advanced NSCLC. J Thorac Oncol. 2020 Jun;15(6):e95-e99. doi: 10.1016/j.jtho.2019.12.133. No abstract available.
citation: Chaft JE, Dagogo-Jack I, Santini FC, Eng J, Yeap BY, Izar B, Chin E, Jones DR, Kris MG, Shaw AT, Gainor JF. Clinical outcomes of patients with resected, early-stage ALK-positive lung cancer. Lung Cancer. 2018 Aug;122:67-71. doi: 10.1016/j.lungcan.2018.05.020. Epub 2018 May 22.
citation: Shaw AT, Bauer TM, de Marinis F, Felip E, Goto Y, Liu G, Mazieres J, Kim DW, Mok T, Polli A, Thurm H, Calella AM, Peltz G, Solomon BJ; CROWN Trial Investigators. First-Line Lorlatinib or Crizotinib in Advanced ALK-Positive Lung Cancer. N Engl J Med. 2020 Nov 19;383(21):2018-2029. doi: 10.1056/NEJMoa2027187.