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

Non-small Cell Lung Cancer Clinical Trial

Official title:

Phase 3 Randomized Study Comparing X-396 (Ensartinib) to Crizotinib in Anaplastic Lymphoma Kinase (ALK) Positive Non-Small Cell Lung Cancer (NSCLC) Patients

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02767804
• Other study ID #: X396-CLI-301
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: June 2016
• Est. completion date: December 31, 2025

Study information

• Verified date: May 2024
• Source: Xcovery Holdings, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 290
• Est. completion date: December 31, 2025
• Est. primary completion date: June 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Non-small Cell Lung Cancer

Intervention

Drug:
• X-396 (ensartinib)
oral ALK inhibitor
• crizotinib
oral ALK inhibitor

Locations

Country	Name	City	State
Argentina	Sanatorio Parque S.A.	Rosario
Australia	Border Medical Oncology Research Unit	Albury	New South Wales
Australia	Chris O Brien Lifehouse	Camperdown
Australia	Chris O'Brien Lifehouse	Camperdown	New South Wales
Belgium	Catholic University of Louvain (UCL) - Site Mont Godinne	Yvoir
Brazil	Hospital Haroldo Juaçaba - Instituto do Cancêr do Ceará	Fortaleza
Brazil	Fundacao do ABC Faculdade de Medicina do ABC	São Paulo
Brazil	Hospital de Câncer de Barretos - Fundação Pio XII	São Paulo	SP
Brazil	Instituto do Câncer do Estado de São Paulo	São Paulo	SP
Canada	Infirmière recherche Clinique, IUCPQ	Quebec City	Quebec
China	Beijing Chao Yang Hospital	Beijing	Beijing
China	Beijing Chest Hospital,Capital Medical University	Beijing	Beijing
China	Peking Union Medical College Hospital	Beijing	Beijing
China	Peking University Cancer Hospital	Beijing	Beijing
China	Peking University Cancer Hospital	Beijing
China	Jilin Cancer Hospital	Changchun	Jilin
China	The First Bethune Hospital of Jilin University	Changchun	Jilin
China	Hunan Cancer Hospital	Changsha	Hunan
China	Fujian Provincial Cancer Hospital	Fuzhou	Fujian
China	Guangdong General Hospital	Guangzhou	Guangdong
China	Zhejiang Cancer Hospital	Hangzhou
China	Zhejiang Cancer Hospital	Hangzhou	Zhejiang
China	Anhui Provincial Hospital	Hefei	Anhui
China	Nanjing General Hospital	Nanjing	Jiangsu
China	The Affiliated Hospital of Qingdao University	Qingdao	Shandong
China	Shanghai Chest Hospital	Shanghai	Shanghai
China	The First Hospital of China Medical University	Shenyang	Liaoning
China	Fourth Hospital of Hebei Medical University	Shijiazhuang	Hebei
China	Hubei Cancer Hospital	Wuhan	Hubei
China	Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology	Wuhan	Hubei
China	Union Hospital of Tongji Medical College of Huazhong Science and Techology University	Wuhan	Hubei
Czechia	Vítkovická Nemocnice , a.s.	Ostrava-Vitkovice
Czechia	Krajská zdravotní, a.s., Masarykova nemocnice	Usti nad Labem
France	CHRU Lille	Lille
France	Hopital Arnaud de Villeneuve	Montpellier
France	CHU de Rennes Hôpital Pontchaillou	Rennes
France	Hopital Saint-Louis	Vellefaux
Germany	Charite Campus Virchow-Klinikum	Berlin
Germany	Lungen Clinic Grosshansdorf	Grosshansdorf
Hong Kong	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	Sha Tin
Israel	Hadassah Medical Center	Jerusalem
Israel	Rabin Medical Center Institute of Oncology, Davidoff Center	Petah Tiqva
Italy	IEO Istituto Europeo di Oncologia	Milano
Italy	Centro Operativo Studi Clinici S.C.Oncologia Medica	Perugia
Italy	Azienda Socio Sanitaria Territoriale (ASST) della Valtellina e dell'Alto Laria	Sondrio
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Netherlands	VU Medical Center	Amsterdam
Netherlands	Maastricht University Medical Centre (MUMC)	Maastricht
Poland	Medical University of Gdansk	Gdansk
Russian Federation	Federal State Budgetary Scientific Institution Russian Oncological Scientific Center named after N.N. Blokhin	Moscow
Russian Federation	LLC "Vitamed"	Moscow
Russian Federation	Moscow City Oncology Hospital #63	Moscow
Russian Federation	BIH of Omsk Region "Clinical Oncology Dispensary"	Omsk
Russian Federation	Pavlov First Medical University	Saint Petersburg
Russian Federation	Petrov Research Institute of Oncology	Saint Petersburg
Spain	Hospital de la Santa Creu i Sant Pau	Barcelona
Spain	Hospital del Mar	Barcelona
Spain	Hospital Vall d'Hebrón	Barcelona
Spain	Hospital Son Ltatzer	Palma de Mallorca
Turkey	Trakya University Balkan Oncology Hospital	Edirne
United Kingdom	Blackpool Victoria Hospital	Blackwood
United Kingdom	Southmead Hospital	Bristol
United Kingdom	Kings Mill Hospital	Nottingham
United Kingdom	The Clatterbridge Cancer Centre NHS Foundation Trust	Wirral
United States	University Cancer & Blood Center	Athens	Georgia
United States	Providence Portland Medical Center	Portland	Oregon
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Moffitt Cancer Center	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Xcovery Holdings, Inc.

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Belgium,  Brazil,  Canada,  China,  Czechia,  France,  Germany,  Hong Kong,  Israel,  Italy,  Korea, Republic of,  Netherlands,  Poland,  Russian Federation,  Spain,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free survival (PFS)	as assessed by independent radiology review based on RECIST v. 1.1 criteria	36 months
Secondary	Overall survival (OS)	Time in months from date of randomization to death due to any cause	48 months
Secondary	CNS response rate	Based on IRR, time to CNS progression (based on IRR), objective response rate (based on IRR)	36 months
Secondary	ORR based on independent radiology review	The proportion of patients in ITT who have an objective response (i.e., those who achieve a best response of CR or PR) per RECIST 1.1 criteria	36 months