Clinical trial NCT02767804: eXalt3: Study Comparing X-396 (Ensartinib) to Crizotinib in ALK Positive Non-Small Cell Lung Cancer (NSCLC) Patients
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Non-small Cell Lung Cancer
Keywords: ALK-positive NSCLC
Lead sponsor: Xcovery Holdings, Inc.
Sponsor class: INDUSTRY
First posted: 2016-05-10
Enrollment: 290
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Progression-free survival (PFS)
timeFrame: 36 months
Secondary outcomes:
measure: Overall survival (OS)
timeFrame: 48 months
measure: CNS response rate
timeFrame: 36 months
measure: ORR based on independent radiology review
timeFrame: 36 months
Other outcomes:
Locations:
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Athens
country: United States
facility: University Cancer & Blood Center
state: Georgia
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Portland
country: United States
facility: Providence Portland Medical Center
state: Oregon
city: Rosario
country: Argentina
facility: Sanatorio Parque S.A.
city: Albury
country: Australia
facility: Border Medical Oncology Research Unit
state: New South Wales
city: Camperdown
country: Australia
facility: Chris O'Brien Lifehouse
state: New South Wales
city: Camperdown
country: Australia
facility: Chris O Brien Lifehouse
city: Yvoir
country: Belgium
facility: Catholic University of Louvain (UCL) - Site Mont Godinne
city: São Paulo
country: Brazil
facility: Instituto do Câncer do Estado de São Paulo
state: SP
city: São Paulo
country: Brazil
facility: Hospital de Câncer de Barretos - Fundação Pio XII
state: SP
city: Fortaleza
country: Brazil
facility: Hospital Haroldo Juaçaba - Instituto do Cancêr do Ceará
city: São Paulo
country: Brazil
facility: Fundacao do ABC Faculdade de Medicina do ABC
city: Quebec City
country: Canada
facility: Infirmière recherche Clinique, IUCPQ
state: Quebec
city: Hefei
country: China
facility: Anhui Provincial Hospital
state: Anhui
city: Beijing
country: China
facility: Beijing Chao Yang Hospital
state: Beijing
city: Beijing
country: China
facility: Peking Union Medical College Hospital
state: Beijing
city: Beijing
country: China
facility: Peking University Cancer Hospital
state: Beijing
city: Beijing
country: China
facility: Beijing Chest Hospital,Capital Medical University
state: Beijing
city: Fuzhou
country: China
facility: Fujian Provincial Cancer Hospital
state: Fujian
city: Guangzhou
country: China
facility: Guangdong General Hospital
state: Guangdong
city: Shijiazhuang
country: China
facility: Fourth Hospital of Hebei Medical University
state: Hebei
city: Wuhan
country: China
facility: Union Hospital of Tongji Medical College of Huazhong Science and Techology University
state: Hubei
city: Wuhan
country: China
facility: Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology
state: Hubei
city: Wuhan
country: China
facility: Hubei Cancer Hospital
state: Hubei
city: Changsha
country: China
facility: Hunan Cancer Hospital
state: Hunan
city: Nanjing
country: China
facility: Nanjing General Hospital
state: Jiangsu
city: Changchun
country: China
facility: The First Bethune Hospital of Jilin University
state: Jilin
city: Changchun
country: China
facility: Jilin Cancer Hospital
state: Jilin
city: Shenyang
country: China
facility: The First Hospital of China Medical University
state: Liaoning
city: Qingdao
country: China
facility: The Affiliated Hospital of Qingdao University
state: Shandong
city: Shanghai
country: China
facility: Shanghai Chest Hospital
state: Shanghai
city: Hangzhou
country: China
facility: Zhejiang Cancer Hospital
state: Zhejiang
city: Beijing
country: China
facility: Peking University Cancer Hospital
city: Hangzhou
country: China
facility: Zhejiang Cancer Hospital
city: Ostrava-Vitkovice
country: Czechia
facility: Vítkovická Nemocnice , a.s.
city: Usti nad Labem
country: Czechia
facility: Krajská zdravotní, a.s., Masarykova nemocnice
city: Lille
country: France
facility: CHRU Lille
city: Montpellier
country: France
facility: Hopital Arnaud de Villeneuve
city: Rennes
country: France
facility: CHU de Rennes Hôpital Pontchaillou
city: Vellefaux
country: France
facility: Hopital Saint-Louis
city: Berlin
country: Germany
facility: Charite Campus Virchow-Klinikum
city: Grosshansdorf
country: Germany
facility: Lungen Clinic Grosshansdorf
city: Hong Kong
country: Hong Kong
facility: Prince of Wales Hospital
city: Hong Kong
country: Hong Kong
facility: Queen Elizabeth Hospital
city: Hong Kong
country: Hong Kong
facility: The University of Hong Kong/Queen Mary Hospital
city: Sha Tin
country: Hong Kong
facility: Prince of Wales Hospital
city: Jerusalem
country: Israel
facility: Hadassah Medical Center
city: Petah Tiqva
country: Israel
facility: Rabin Medical Center Institute of Oncology, Davidoff Center
city: Milano
country: Italy
facility: IEO Istituto Europeo di Oncologia
city: Perugia
country: Italy
facility: Centro Operativo Studi Clinici S.C.Oncologia Medica
city: Sondrio
country: Italy
facility: Azienda Socio Sanitaria Territoriale (ASST) della Valtellina e dell'Alto Laria
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Amsterdam
country: Netherlands
facility: VU Medical Center
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Centre (MUMC)
city: Gdańsk
country: Poland
facility: Medical University of Gdansk
city: Moscow
country: Russian Federation
facility: Federal State Budgetary Scientific Institution Russian Oncological Scientific Center named after N.N. Blokhin
city: Moscow
country: Russian Federation
facility: LLC "Vitamed"
city: Moscow
country: Russian Federation
facility: Moscow City Oncology Hospital #63
city: Omsk
country: Russian Federation
facility: BIH of Omsk Region "Clinical Oncology Dispensary"
city: Saint Petersburg
country: Russian Federation
facility: Pavlov First Medical University
city: Saint Petersburg
country: Russian Federation
facility: Petrov Research Institute of Oncology
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Barcelona
country: Spain
facility: Hospital Vall d'Hebrón
city: Palma de Mallorca
country: Spain
facility: Hospital Son Ltatzer
city: Edirne
country: Turkey
facility: Trakya University Balkan Oncology Hospital
city: Blackwood
country: United Kingdom
facility: Blackpool Victoria Hospital
city: Bristol
country: United Kingdom
facility: Southmead Hospital
city: Nottingham
country: United Kingdom
facility: Kings Mill Hospital
city: Wirral
country: United Kingdom
facility: The Clatterbridge Cancer Centre NHS Foundation Trust
Study officials:
affiliation: CEO
name: Giovanni Selvaggi, MD
role: STUDY_CHAIR
References:
citation: 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.