Alectinib Pharmacokinetic in Patients With NSCLC

Study Overview
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Brief Summary
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This interventional study aims to determine the pharmacokinetics of orally administered alectinib with dose escalation from 300 mg to 600 mg twice daily in Mexican patients with advanced ALK-positive NSCLC. The main question it aims to answer is: what will be the peak plasma concentrations of alectinib following sequential dose escalation (300, 450, and 600 mg BID) over nine weeks of pharmacokinetic evaluation (phase I) in Mexican patients with advanced ALK-rearranged NSCLC? In phase I (on days 0, 21, and 42), oral alectinib will be administered twice per day (BID) to patients with ALK-positive NSCLC; starting with 300 mg BID in 21-day cycles and dose escalation in 150 mg increments until 600 mg BID. Blood samples will be taken before and after administration of each dose (on days 1, 22, and 43). The primary endopoints in phase I will be dose-limiting toxicity (DLT) and PK parameters (Cmax. maximum plasma concentration; Tmax: time to reach maximum concentration: AUC 1-12: area under plasma ocncentrations-time curve steady-state concentration). At the end of the last blood collection (at day 43), the evaluation of each cycle will be at 600 mg, and the participant will be discharged to continue their treatment on an outpatient basis. Phase one will finish on day 63 of the study. In phase II, the chosen BID dose based on the phase I portion will be administrated until disease progression, development of unacceptable side effects, or withdrawal of consent. The primary endpoint in phase 2 is the overall response rate (ORR) per RECIST V.1.1.

Detailed Description
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Alectinib will be administrated under fast conditions. The primary endpoint of the phase II part was ORR. Other secondary endpoints in phase II are progression-free survival (PFS), overall survival (OS), intracranial response (ICR), and duration of response (DOR). Exploratory endpoints in this follow-up analysis included the evaluation of the correlation between tumor shrinkage and PFS and chosen dose to relieve cancer symptoms.

Official Title
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A Phase I/II Open-label Clinical Trial to Evaluate the Pharmacokinetics of Alectinib With Sequential Dose Escalation in Patients Diagnosed With ALK-rearranged Advanced Non-small Cell Lung Cancer.

Conditions
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Non-small Cell Lung Cancer Stage IIIB, ALK Gene Mutation

Intervention / Treatment
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* Drug: Alectinib Oral Product


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Both sexes ≥ 18 years old Pathologically confirmed diagnosis of NSCLC Stage IIIB - IV by the American Joint Committee of Cancer Version 8. Recurrent disease (at least 180 days from curative intent treatment) ALK rearrangements tested by FDA-approved tests (IHQ or FISH) Karnofsky PS scale ≥ 70% Having received first-line treatment with anti-ALK inhibitors and one previous line of platinum-based chemotherapy. Measurable disease as referred by RECIST version 1.1 Symptomatic brain metastases could receive prior treatment with radiotherapy or surgery for at least two weeks before treatment initiation. Asymptomatic brain metastases could not receive local therapy before study inclusion. Negative highly sensitive pregnancy test (serum or urine) within 72 days before first dose intervention. Sexually active patients should use a contraceptive method with a failure rate of less than 1% per year. Signed written informed consent Adequate organ function (hematological, liver, and renal function) Life expectancy of at least 12 weeks Exclusion Criteria: Carcinomatous meningitis confirmed by a positive CRL cytology or highly suspicious brain MRI. Previous malignancies except for any carcinoma in-situ Treatment with other anti-cancer therapy Participating in other clinical trials in the former four weeks Any other serious condition or uncontrolled active infection, altered mental status, or psychiatric condition that, in the investigator´s opinion, would limit the ability of an individual to meet the requirements of the study or which affects the interpretability of the results. Active hepatitis virus infection (any serotype) or chronic infection with a potential risk of reactivation evaluated through a serological panel. Active HIV infection. Breastfeeding.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Patients (≥18 years), both sex, clinical stage IIIB and IV, ALK-rearranged NSCLC treated by Thoracic Oncology Department at Instituto Nacional de Cancerología (INCan).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Alectinib escalation dose<br>Alecensa 150 mg Roche | Drug: Alectinib Oral Product<br>* Alectinib is administered with a sequential dose escalation every 21 days from 300 to 600mg twice daily in the phase 1 portion. In phase 2, patients received an investigator-chosen dose based on the PK analysis.<br>* Other names: Alecensa 150 mg Roche;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC | The area under the curve (AUC). Pharmacokinetic behavior of the initial alectinib for each given dose (300, 450 and 600 mg). | Amount of drug concentration between 0 to 12 hours after first drug administration | 
| Cmax | Highest concentration of drug in blood (Serum) for each given dose (300, 450 and 600 mg). | From baseline control pre-dose, 0.50, 1.00, 2.00, 3.00, 4.00, 5.00, 6.00, 8.00, 10.00 and 11.90 hours | 
| Cmin | Lowest concentration of drug in blood (Serum) for each given dose (300, 450 and 600 mg). | From baseline control pre-dose, 0.50, 1.00, 2.00, 3.00, 4.00, 5.00, 6.00, 8.00, 10.00 and 11.90 hours | 
| Tmax | Time in witch Cmax is reached in each dose of the drug (300,450 and 600 mg) | From first dose administration through the following 12 hours (day 1) | 
| ORR | overall response rate is measured in phase two | From first dose administration up to disease progression by CT scan every 6 weeks, through study completion. | 
| Steady state | The amount of drug in the plasma has built up to a therapeutically effective concentration level, and as long as regular doses are administered to balance the amount of drug being cleared, the drug will continue to be active. | For phase two: between 2 and 4 months of treatment with investigators chosen dose. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events | Tolerance during drug escalation doses (300, 450, and 600 mg) in the phase one portion based on the PK analysis. | From date of first dose administration through 9 weeks. | 
| Drug toxicity | Adverse events under alectinib Administration a the chosen dose are measured in the phase two portion. | From date of starting phase 2 portion until the date of first documented progression date or death from any cause, whichever comes first, assessed up to 60 months. | 
| PFS | Progression-free survival | From date of first dose administration until the date of first documented progression date or death from any cause, whichever comes first, assessed up to 100 months. | 
| OS | overall survival | From date of first dose administration until the date of documented death from any cause or last follow-up, whichever comes first, assessed up to 120 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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alectinib, positive-ALK, non small cell lung cancer