eXalt3: Study Comparing X-396 (Ensartinib) to Crizotinib in ALK Positive Non-Small Cell Lung Cancer (NSCLC) Patients

NCT ID: NCT02767804

Last Updated: 2025-10-14

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 290 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-06-30
• Study Completion Date: 2025-12-31

Brief Summary

The primary purpose of this study is to evaluate the efficacy and safety of X-396 (ensartinib) vs. crizotinib in patients with ALK-positive non-small cell lung cancer that have received up to 1 prior chemotherapy regimen and no prior ALK inhibitor.

Detailed Description

To evaluate the efficacy and safety of X-396 (ensartinib) vs. crizotinib in patients with ALK-positive NSCLC that have received up to 1 prior chemotherapy regimen and no prior ALK tyrosine kinase inhibitor (TKI), to obtain additional pharmacokinetic (PK) data from sparse PK sampling, to compare the quality of life (QoL) in patients receiving X-396 vs. crizotinib, to evaluate the status of exploratory biomarkers and correlate with clinical outcome, and to obtain germline DNA samples for possible pharmacogenetic analysis in the event that outliers with respect to efficacy, tolerability/safety, or exposure are identified.

Conditions

Non-small Cell Lung Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

X-396 (ensartinib)

Eligible patients with ALK+ NSCLC will receive oral X-396 (ensartinib) at 225mg QD with or without food until progression or unacceptable toxicity develops

Group Type: EXPERIMENTAL

X-396 (ensartinib)

Intervention Type: DRUG

oral ALK inhibitor

crizotinib

Eligible patients with ALK+ NSCLC will receive oral crizotinib at 250mg BID with or without food until progression or unacceptable toxicity develops

Group Type: ACTIVE_COMPARATOR

crizotinib

Intervention Type: DRUG

oral ALK inhibitor

Interventions

X-396 (ensartinib)

oral ALK inhibitor

Intervention Type: DRUG

crizotinib

oral ALK inhibitor

Intervention Type: DRUG

Other Intervention Names

Xalkori

Eligibility Criteria

Inclusion Criteria

1. 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.

2. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0 to 2. (see Appendix A)

3. Life expectancy of at least 12 weeks.

4. Ability to swallow and retain oral medication.

5. Adequate organ system function, defined as follows:

1. Absolute neutrophil count (ANC) ≥1.5 x 109/L

2. Platelets ≥100 x 109/L

3. Hemoglobin ≥9 g/dL (≥90 g/L) Note that transfusions are allowed to meet the required hemoglobin level

4. Total bilirubin ≤1.5 times the upper limit of normal (ULN)

5. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x ULN if no liver involvement or ≤5 x ULN with liver involvement.

6. Creatinine < 1.5 x ULN. If >1.5 x ULN, patient may still be eligible if calculated creatinine clearance >50 mL/min (0.83mL/s) as calculated by the Cockcroft-Gault method.

6. 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.

7. 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.

8. 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.

9. Patients must be >18 years-of-age.

10. Patients must have measurable disease per RECIST v. 1.1.

11. Willingness and ability to comply with the trial and follow-up procedures.

12. Ability to understand the nature of this trial and give written informed consent.

Note the following pertains to patients enrolled in France

In France, a subject 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

1. 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).

2. 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.

3. Any chemotherapy within 4 weeks, or major surgery or radiotherapy within the last 14 days.

4. Patients with primary CNS tumors and leptomeningeal disease are ineligible.

5. 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).

6. Concomitant systemic use of anticancer herbal medications. These should be stopped prior to study entry.

7. Patients receiving

1. strong CYP3A inhibitors (including, but not limited to, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole, grapefruit, grapefruit juice)

2. strong CYP3A inducers (including, but not limited to, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, St. John's Wort)

3. CYP3A substrates with narrow therapeutic window (including, but not limited to, alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus).

8. Women who are pregnant or breastfeeding.

9. Presence of active gastrointestinal (GI) disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of study medications.

10. Patients at risk for GI perforation.

11. Clinically significant cardiovascular disease including:

1. 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.

2. 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:

1. Congestive heart failure (New York Heart Class III or IV).

2. Arrhythmia or conduction abnormality requiring medication. Note: patients with atrial fibrillation/flutter controlled by medication and arrhythmias controlled by pacemakers are eligible.

3. Severe/unstable angina, coronary artery/peripheral bypass graft, or myocardial infarction.

4. Cerebrovascular accident or transient ischemia.

12. 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.

13. Known hypersensitivity to tartrazine, a dye used in the ensartinib 100 mg capsule.

14. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.

15. 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.

16. 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

17. In France, a subject will not be eligible when under legal protection.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Xcovery Holdings, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Giovanni Selvaggi, MD

Role: STUDY_CHAIR

CEO

Locations

Moffitt Cancer Center

Tampa, Florida, United States

University Cancer & Blood Center

Athens, Georgia, United States

Washington University School of Medicine

St Louis, Missouri, United States

Providence Portland Medical Center

Portland, Oregon, United States

Sanatorio Parque S.A.

Rosario, , Argentina

Border Medical Oncology Research Unit

Albury, New South Wales, Australia

Chris O'Brien Lifehouse

Camperdown, New South Wales, Australia

Chris O Brien Lifehouse

Camperdown, , Australia

Catholic University of Louvain (UCL) - Site Mont Godinne

Yvoir, , Belgium

Instituto do Câncer do Estado de São Paulo

São Paulo, São Paulo, Brazil

Hospital de Câncer de Barretos - Fundação Pio XII

São Paulo, São Paulo, Brazil

Hospital Haroldo Juaçaba - Instituto do Cancêr do Ceará

Fortaleza, , Brazil

Fundacao do ABC Faculdade de Medicina do ABC

São Paulo, , Brazil

Infirmière recherche Clinique, IUCPQ

Québec, Quebec, Canada

Anhui Provincial Hospital

Hefei, Anhui, China

Beijing Chao Yang Hospital

Beijing, Beijing Municipality, China

Peking Union Medical College Hospital

Beijing, Beijing Municipality, China

Peking University Cancer Hospital

Beijing, Beijing Municipality, China

Beijing Chest Hospital,Capital Medical University

Beijing, Beijing Municipality, China

Fujian Provincial Cancer Hospital

Fuzhou, Fujian, China

Guangdong General Hospital

Guangzhou, Guangdong, China

Fourth Hospital of Hebei Medical University

Shijiazhuang, Hebei, China

Hunan Cancer Hospital

Changsha, Hu'nan, China

Union Hospital of Tongji Medical College of Huazhong Science and Techology University

Wuhan, Hubei, China

Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology

Wuhan, Hubei, China

Hubei Cancer Hospital

Wuhan, Hubei, China

Nanjing General Hospital

Nanjing, Jiangsu, China

The First Bethune Hospital of Jilin University

Changchun, Jilin, China

Jilin Cancer Hospital

Changchun, Jilin, China

The First Hospital of China Medical University

Shenyang, Liaoning, China

The Affiliated Hospital of Qingdao University

Qingdao, Shandong, China

Shanghai Chest Hospital

Shanghai, Shanghai Municipality, China

Zhejiang Cancer Hospital

Hangzhou, Zhejiang, China

Peking University Cancer Hospital

Beijing, , China

Zhejiang Cancer Hospital

Hangzhou, , China

Vítkovická Nemocnice , a.s.

Ostrava-Vitkovice, , Czechia

Krajská zdravotní, a.s., Masarykova nemocnice

Ústí nad Labem, , Czechia

CHRU Lille

Lille, , France

Hopital Arnaud de Villeneuve

Montpellier, , France

CHU de Rennes Hôpital Pontchaillou

Rennes, , France

Hopital Saint-Louis

Vellefaux, , France

Charite Campus Virchow-Klinikum

Berlin, , Germany

Lungen Clinic Grosshansdorf

Großhansdorf, , Germany

Prince of Wales Hospital

Hong Kong, , Hong Kong

Queen Elizabeth Hospital

Hong Kong, , Hong Kong

The University of Hong Kong/Queen Mary Hospital

Hong Kong, , Hong Kong

Prince of Wales Hospital

Shatin, , Hong Kong

Hadassah Medical Center

Jerusalem, , Israel

Rabin Medical Center Institute of Oncology, Davidoff Center

Petah Tikva, , Israel

IEO Istituto Europeo di Oncologia

Milan, , Italy

Centro Operativo Studi Clinici S.C.Oncologia Medica

Perugia, , Italy

Azienda Socio Sanitaria Territoriale (ASST) della Valtellina e dell'Alto Laria

Sondrio, , Italy

VU Medical Center

Amsterdam, , Netherlands

Maastricht University Medical Centre (MUMC)

Maastricht, , Netherlands

Medical University of Gdansk

Gdansk, , Poland

Federal State Budgetary Scientific Institution Russian Oncological Scientific Center named after N.N. Blokhin

Moscow, , Russia

LLC "Vitamed"

Moscow, , Russia

Moscow City Oncology Hospital #63

Moscow, , Russia

BIH of Omsk Region "Clinical Oncology Dispensary"

Omsk, , Russia

Pavlov First Medical University

Saint Petersburg, , Russia

Petrov Research Institute of Oncology

Saint Petersburg, , Russia

Seoul National University Hospital

Seoul, , South Korea

Asan Medical Center

Seoul, , South Korea

Hospital del Mar

Barcelona, , Spain

Hospital de la Santa Creu i Sant Pau

Barcelona, , Spain

Hospital Vall d'Hebrón

Barcelona, , Spain

Hospital Son Ltatzer

Palma de Mallorca, , Spain

Trakya University Balkan Oncology Hospital

Edirne, , Turkey (Türkiye)

Blackpool Victoria Hospital

Blackwood, , United Kingdom

Southmead Hospital

Bristol, , United Kingdom

The Clatterbridge Cancer Centre NHS Foundation Trust

Metropolitan Borough of Wirral, , United Kingdom

Kings Mill Hospital

Nottingham, , United Kingdom

Countries

United States; Argentina; Australia; Belgium; Brazil; Canada; China; Czechia; France; Germany; Hong Kong; Israel; Italy; Netherlands; Poland; Russia; South Korea; Spain; Turkey (Türkiye); United Kingdom

References

Horn L, Wang Z, Wu G, Poddubskaya E, Mok T, Reck M, Wakelee H, Chiappori AA, Lee DH, Breder V, Orlov S, Cicin I, Cheng Y, Liu Y, Fan Y, Whisenant JG, Zhou Y, Oertel V, Harrow K, Liang C, Mao L, Selvaggi G, Wu YL. Ensartinib vs Crizotinib for Patients With Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer: A Randomized Clinical Trial. JAMA Oncol. 2021 Nov 1;7(11):1617-1625. doi: 10.1001/jamaoncol.2021.3523.

Reference Type: DERIVED

PMID: 34473194 (View on PubMed)

Other Identifiers

X396-CLI-301

Identifier Type: -

Identifier Source: org_study_id