Phase 3 Randomized Trial of Ensartinib Versus Crizotinib in ALK-Positive Non-Small Cell Lung Cancer Patients with Prior Chemotherapy and No ALK TKI Treatment
- Trial ID
- 2024-513454-29-00
- Protocol
- X396-CLI-301
- Sponsor
- Xcovery Holding Co. LLC
Trial statistics
Objectives
The primary objective of this study is to evaluate the **efficacy** and **safety** of ensartinib compared to crizotinib in patients with Anaplastic Lymphoma Kinase (ALK)-positive Non-Small Cell Lung Cancer (NSCLC) who have received up to one prior chemotherapy regimen and no prior ALK tyrosine kinase inhibitor (TKI). This is clinically relevant as it aims to determine the potential benefits and risks of ensartinib, a newer therapeutic option, in a specific patient population, potentially offering an alternative to existing treatments.
Secondary objectives include:
- To obtain additional pharmacokinetic (PK) data on ensartinib from sparse PK sampling from patients at selected sites.
- To compare the quality of life (QoL) in patients receiving ensartinib versus crizotinib.
- To evaluate the status of exploratory biomarkers and correlate with clinical outcome.
- To obtain germline DNA samples for possible pharmacogenetic analysis in the event that outliers with respect to efficacy, tolerability/safety, or exposure are identified.
Participants
The clinical trial involves a total of **241 participants** diagnosed with **Non-Small Cell Lung Cancer (NSCLC)**. The study population includes both male and female subjects, aged 18 years and older, who have been confirmed to have advanced or recurrent ALK-positive NSCLC. Participants were selected based on their ability to comply with trial procedures and their measurable disease status per RECIST v. 1.1. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 to 2, indicating a relatively stable general health status. Participants must have a life expectancy of at least 12 weeks and adequate organ function. The trial population may include individuals with asymptomatic brain metastases, provided they meet specific criteria regarding corticosteroid use and prior treatment. Lifestyle considerations such as the ability to swallow oral medication and adherence to contraceptive measures are also relevant. The selection process ensures that participants have not received prior ALK tyrosine kinase inhibitor (TKI) treatment and have undergone no more than one prior chemotherapy regimen for metastatic disease. The trial includes a vulnerable population, reflecting the serious nature of the condition being studied.
Plans and Procedures
The clinical trial is a **randomized**, **controlled**, and **open-label** Phase 3 study designed to evaluate the efficacy and safety of ensartinib compared to **crizotinib** in patients with **Anaplastic Lymphoma Kinase (ALK)**-positive **Non-Small Cell Lung Cancer (NSCLC)**. The primary endpoint is progression-free survival (PFS) as assessed by independent radiology review based on RECIST v. 1.1 criteria. Secondary endpoints include overall survival, CNS response rate, time to CNS progression, and objective response rate, among others. The trial is expected to conclude by December 31, 2025, with recruitment having started on February 1, 2017.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed ALK-positive NSCLC, measurable disease, and adequate organ function. Randomization will occur after central confirmation of ALK positivity. The trial includes follow-up visits to monitor treatment response and safety, with assessments conducted at regular intervals. The end-of-study visit will evaluate the final outcomes and any long-term effects of the treatment.
The expected duration of participant involvement is up to 102 weeks, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, withdrawal of consent, or non-compliance with study procedures. Participants must be at least 18 years old, have a life expectancy of at least 12 weeks, and be able to swallow oral medication. The study requires participants to comply with contraceptive measures if applicable and to provide written informed consent.
Treatment
The clinical trial involves the administration of **XALKORI 200 mg hard capsules**, which contain the active substance **crizotinib**. This pharmaceutical form is a hard capsule, intended for **oral use**. The maximum daily dose is 500 mg, with a total dose not exceeding 1.55 kg. The treatment period is capped at 102 days. Crizotinib is a small molecule, chemically synthesized, and is not a paediatric formulation. The product is authorized in the EU under the marketing authorization number EU/1/12/793/001 and is manufactured by Pfizer Europe MA EEIG.
Another treatment in the study is **X-396 Capsules**, containing the active substance **X-396**. These capsules are also administered orally. The maximum daily dose for X-396 is 225 mg, with a total dose limit of 0.7 kg. The treatment duration is similarly limited to 102 days. X-396 is a small molecule, chemically derived, and is not formulated for paediatric use. The product is provided by Xcovery Holding Company, LLC.
The trial also includes **XALKORI 250 mg hard capsules**, which, like the 200 mg variant, contain **crizotinib** as the active ingredient. These capsules are administered orally, with a maximum daily dose of 500 mg and a total dose not exceeding 1.55 kg. The treatment period is restricted to 102 days. This formulation is also a small molecule, chemically synthesized, and not intended for paediatric use. It is authorized in the EU with the marketing authorization number EU/1/12/793/003, produced by Pfizer Europe MA EEIG.
Throughout the trial, participant compliance with the dosing schedule will be monitored to ensure adherence to the prescribed regimen. The study aims to compare the efficacy and safety of these treatments in patients with **Anaplastic Lymphoma Kinase (ALK) Positive Non-Small Cell Lung Cancer (NSCLC)** who have received up to one prior chemotherapy regimen and no prior ALK tyrosine kinase inhibitor (TKI).
Efficacy
The efficacy of the clinical trial will be assessed primarily through **Progression-Free Survival (PFS)**, as evaluated by an independent radiology review (IRR) using RECIST v. 1.1 criteria. This primary endpoint will provide a measure of the time during and after treatment in which the patient's disease does not worsen. Secondary efficacy endpoints include overall survival, central nervous system (CNS) response rate, time to CNS progression, objective response rate, time to response, and duration of response, all based on both IRR and investigator assessments. Additionally, patient-reported outcomes such as time to deterioration and health-related quality of life will be measured using the EORTC C30/LC13 Quality of Life questionnaire and the Lung Cancer Symptom Scale (LCSS).
Pharmacodynamic and potential pharmacogenetic assessments will be conducted, with biomarkers in blood or tissue samples being analyzed to evaluate their relation to efficacy. The schedule for these assessments will align with the trial's protocol, ensuring systematic data collection and analysis. The trial aims to compare the efficacy and safety of the ALK inhibitors ensartinib and crizotinib in patients with ALK-positive non-small cell lung cancer (NSCLC), who have received up to one prior chemotherapy regimen and no prior ALK tyrosine kinase inhibitor (TKI).
Inclusion and Exclusion Criteria
Inclusion Criteria
- Histologically or cytologically confirmed diagnosis of advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC that is ALK-positive by an FDA-approved assay, performed centrally. Patients must be ALK positive by local test prior to submitting tissue to the central lab. Randomization will occur after ALK positive confirmation is received from the central lab. Patients may have received up to 1 prior chemotherapy regimen for metastatic disease, which may also include maintenance therapy. Note that patients that have received adjuvant or neoadjuvant chemotherapy and developed metastatic disease within 6 months from the end of that therapy would be considered to have received 1 prior regimen for metastatic disease
- Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0 to 2. (see Appendix A)
- Life expectancy of at least 12 weeks.
- Ability to swallow and retain oral medication.
- Adequate organ system function, defined as follows: a. Absolute neutrophil count (ANC) ≥1.5 x 109/L b. Platelets ≥100 x 109/L c. Hemoglobin ≥9 g/dL (≥90 g/L). Note that transfusions are allowed to meet the required hemoglobin level d. Total bilirubin ≤1.5 times the upper limit of normal (ULN) e. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x ULN if no liver involvement or ≤5 x ULN with liver involvement. f. Creatinine ≤1.5 x ULN. If >1.5 x ULN, patient may still be eligible if calculated creatinine clearance ³50 mL/min (0.83 mL/s) as calculated by the Cockcroft-Gault method.
- Brain metastases allowed if asymptomatic at study baseline. Patients with untreated brain metastases must not be on corticosteroids. If patients have neurological symptoms or signs due to CNS metastases, patients need to complete whole brain radiation or focal treatment at least 14 days before start of study treatment and be asymptomatic on stable or decreasing doses of corticosteroids at baseline.
- Men with partners of childbearing potential willing to use adequate contraceptive measures during the study and for 90 days after the last dose of study medication.
- Women who are not of child-bearing potential, and women of child-bearing potential who agree to use adequate contraceptive measures during the study and for 90 days after the last dose of study medication, and who have a negative serum or urine pregnancy test within 1 week prior to initial trial treatment.
- Patients must be ≥18 years of age.
- Patients must have measurable disease per RECIST v. 1.1.
- Willingness and ability to comply with the trial and follow-up procedures.
- Ability to understand the nature of this trial and give written informed consent. Note the following pertains to patients enrolled in France
- Specific to France: Subjects will be eligible for inclusion in this study only affiliated to the French Social Security system, and currently benefit from the corresponding rights and cover.
Exclusion Criteria
- Patients that have previously received an ALK TKI or PD-1/PD-L1 therapy, and patients currently receiving cancer therapy (i.e., other targeted therapies, chemotherapy, radiation therapy, immunotherapy, biologic therapy, hormonal therapy, surgery and/or tumor embolization).
- Use of an investigational drug within 21 days prior to the first dose of study drug. Note that to be eligible, any drug-related toxicity should have recovered to Grade 1 or less, with the exception of alopecia.
- Any chemotherapy within 4 weeks, or major surgery or radiotherapy within the last 14 days.
- Patients with primary CNS tumors and leptomeningeal disease are ineligible.
- Patients with a previous malignancy within the past 3 years (other than curatively treated basal cell carcinoma of the skin, in situ carcinoma of the cervix, or any cancer that is considered to be cured and have no impact on PFS and OS for the current NSCLC).
- Concomitant systemic use of anticancer herbal medications. These should be stopped prior to study entry.
- Patients receiving: a. Strong CYP3A inhibitors (including, but not limited to, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole, grapefruit, grapefruit juice) b. Strong CYP3A inducers (including, but not limited to, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, St. John's Wort) c. CYP3A substrates with narrow therapeutic window (including, but not limited to, alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus).
- Women who are pregnant or breastfeeding.
- Presence of active gastrointestinal (GI) disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of study medications.
- Patients at risk for GI perforation.
- Clinically significant cardiovascular disease including: QTcF interval >450 ms for men and >470 ms for women, symptomatic bradycardia <45 beats per minute or other significant ECG abnormalities in the investigator’s opinion. Clinically uncontrolled hypertension in the investigator’s opinion (e.g., blood pressure >160/100 mmHg; note that isolated elevated readings considered to not be indicative of uncontrolled hypertension are allowed). The following within 6 months prior to Cycle 1 Day 1: Congestive heart failure (New York Heart Class III or IV (see Appendix D). Arrhythmia or conduction abnormality requiring medication. Note: patients with atrial fibrillation/flutter controlled by medication and arrhythmias controlled by pacemakers are eligible. Severe/unstable angina, coronary artery/peripheral bypass graft, or myocardial infarction. Cerebrovascular accident or transient ischemia.
- Patients who are immunosuppressed (including known HIV infection), have a serious active infection at the time of treatment, have interstitial lung disease/pneumonitis, or have any serious underlying medical condition that would impair the ability of the patient to receive protocol treatment. Patients with controlled hepatitis C, in the investigator’s opinion, are allowed. Patients with known hepatitis B must be HBeAg and HB viral DNA negative for enrollment. Note that, because of the high prevalence, all patients in the Asia-Pacific region (except Australia, New Zealand, and Japan) must be tested and, if HBsAg positive, must be HBeAg and HB viral DNA negative for enrollment.
- Known hypersensitivity to tartrazine, a dye used in the ensartinib 100 mg capsule.
- Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.
- Concurrent condition that in the investigator’s opinion would jeopardize compliance with the protocol or would impart excessive risk associated with study participation that would make it inappropriate for the patient to be enrolled.
- Inability or unwillingness to comply with study and/or follow-up procedures outlined in the protocol. Note the following pertains to patients enrolled in France.
- Specific to France: Subjects will not be eligible when under legal protection.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 01 Feb 2017 | 2 |
 Czechia | Not Recruiting | 01 Feb 2017 | 5 |
 France | Not Recruiting | 01 Feb 2017 | 9 |
 Italy | Not Recruiting | 01 Feb 2017 | 18 |
 The Netherlands | Not Recruiting | 01 Feb 2017 | — |
 Poland | Not Recruiting | 01 Feb 2017 | 3 |
 Spain | Not Recruiting | 01 Feb 2017 | 7 |
| Netherlands | — | — | 3 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
XALKORI 250 mg hard capsules | Comparator | HARD CAPSULES | ORAL USE | 500 | 102 | PRD672299 |
X-396 Capsules | Test | CAPSULES | ORAL USE | 225 | 102 | PRD6978378 |
XALKORI 200 mg hard capsules | Comparator | HARD CAPSULES | ORAL USE | 500 | 102 | PRD672298 |