REVOL858R trial

JRCT ID: jRCTs051200142

Registered date:02/03/2021

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: Advanced/recurrent non-squamous non-small cell lung cancer harboring EGFR exon 21 L858R mutation pre
• Date of first enrollment: 24/03/2021
• Target sample size: 230
• Study type: Interventional

Intervention(s)

Group A: Osimertinib monotherapy
Osimertinib orally administered daily at 80 mg/day.

Group B: Erlotinib + ramucirumab combination therapy
Erlotinib orally administered daily at 150 mg/day and ramucirumab administered intravenously at 10 mg/kg biweekly. When T790M mutation is detected, the protocol treatment is to be continued with osimertinib being orally administered daily at a dose of 80 mg/day,

Outcome(s)

• Primary Outcome: The time to failure of strategy (TFS: the time from randomization until disease progression with osimertinib, the time from randomization until disease progression of the primary treatment in the experimental arm when osimertinib is not administered, or death)
• Secondary Outcome: Overall survival (OS), progression-free survival 1 (PFS1: the time from randomization until disease progression of the primary treatments or death), PFS2 (the time from randomization until the second disease progression or death), objective response rate, time to treatment failure (TTF), time to discontinuation of any EGFR-tyrosine kinase inhibitor (TKI; TD-TKI), and safety

Key inclusion & exclusion criteria

• Age minimum: >= 20age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

[IC, age]
1) Prior to the start of the study, subjects were given a thorough explanation of the content and gave their informed consent.
2) All subjects were aged 20 or over when consent was acquired.
[Tissue types, markers]
3) All subjects were either histologically or cytologically diagnosed with non-squamous cell non-small cell lung cancer.
4) EGFR mutations (exon 21 L858R point mutation) were confirmed using tumor tissue or cell diagnostic specimens (cases with other genetic mutations such as G719X combined were eligible, with the exception of T790M and exon 20 insertion mutation positive cases).
[Spread of lesions, disease condition]
5) Stage IIIB, stage IIIC, stage IV, or recurrent post-surgery for which definitive radiotherapy is impossible.
6) An imaging test for disease staging was conducted as scheduled prior to registration.
Chest and upper abdomen CT imaging (within 28 days prior to registration)
Contrast-enhanced brain CT scan or MRI (within 28 days prior to registration)
Bone scintigraphy or PET-CT (within 42 days prior to registration)
Simple testing is tolerated if contract agent cannot be used for any reason.
7) No symptomatic brain metastases. However, patients with asymptomatic or symptomatic brain metastases who are considered neurologically recovered following radiation therapy or surgical treatment (CTCAE v5.0 grade 0-1) were considered eligible.
8) Patients with evaluable lesions (regardless of whether lesions can be measured using RECIST version 1.1).
[Pre-treatment]
9) All cases will be lung cancer untreated with chemotherapy. Both pre-operative and post-operative chemotherapy without EGFR-TKI cases were accepted, provided the last administration was 6 months or more prior to the start of the study.
[Physical condition, clinical examinations]
10) ECOG performance status (PS) score of either 0 or 1.
11) No severe impediments in main organs.
12) Eligible patients of reproductive potential (both sexes) must agree to use adequate contraceptive methods (hormonal or barrier methods) during the study period and for at least 12 weeks after the last dose of study therapy. Eligible female patients of childbearing potential must have a negative serum pregnancy test with in 7 days prior to first dose of treatment.

Exclude criteria

[Multiple cancers]
1) Having multiple active cancers.*1
*1: Multiple cancers refers to simultaneous occurrence of multiple cancers or a disease-free period of 3 years or less with asynchronous multiple cancers. Carcinoma in situ judged locally cured and cancerous lesions within the mucous membranes are not considered multiple active cancers.
[Complications: Bleeding]
2) History of pulmonary hemorrhaging (bleeding of 2.5 mL or more from the respiratory organs per instance) or bloody phlegm complications within 2 months prior to first dose of protocol therapy.
a) Continuous presentation of bloody phlegm (for one week or more).
b) Bloody sputum with a history of continuous administration of oral hemostatic agents within the last month, or requiring their continuous administration.
c) Bloody phlegm requiring the administration of injectable hemostatic agents.
3) Patients with any of the following risk factors.
a) Imaging clearly shows tumor infiltration of large thoracic vessels.
b) Tumor is directly exposed to the trachea or bronchi.
c) Imaging shows clear cavitation of the lung lesion.
4) Clear deep vein thrombosis or pulmonary artery thrombosis occurs within 3 months of registration.
5) Requiring administration of anticoagulants (with the exception of anti-platelet drugs such as low-dose aspirin) within the last 14 days or requires their administration during the trial period. However, cases of anti-platelet drugs such as low-dose aspirin, direct oral anticoagulants (DOAC), or low molecular weight heparin administered at a stable dose for 14 days or more, PT-INR adjusted to 3 or less using warfarin are eligible.
6) Hemorrhaging of grade 3 or higher observed within 3 months of registration.
[Complications: Infection]
7) Having an active systemic infection or a local infection requiring surgical treatment.
8) Have active hepatitis B or C (even if various antigens and antibodies are positive, patients are eligible as long as there is no active hepatitis).
[Complications: Cardiovascular system]
9) Any arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular event, or transient ischemic attack, and congestive heart failure Class II or above in the New York Heart Association (NYHA) classification, with in 6 months prior to enrollment. Severe arrhythmia receiving continuous treatment.
10) Continuous hypertension for a period of 4 weeks or more (systolic blood pressure 160 mmHg or diastolic blood pressure 100 mmHg or more) despite management with antihypertensive agents.
[Complications: Other]
11) Nausea, vomiting, or absorption impediments causing difficulty with administration of the trial drug.
12) Child-Pugh category B score (or more severe) cirrhosis, history of hepatic encephalopathy, or cirrhosis with ascites which is clinically problematic (regardless of severity).
13) Clear interstitial lung disease identified in a CT scan.
14) Spinal cord compression.
15) Having a history of severe hypersensitivity or hypersensitivity to the components and additives of osimertinib and erlotinib.
16) Clinically problematic mental disorder judged to make registration in this study difficult.
17) A prior history of GI perforation/fistula (within 6 months of first dose of protocol therapy) or risk factors for perforation.
18) A serious or nonhealing wound, ulcer, or bone fracture within 28 days prior to first dose of protocol therapy.
19) The patient has elective or planned major surgery to be performed during the course of the clinical trial.
[Pregnancy]
20) Pregnant women, lactating women, women who may be pregnant at present or female patients who do not intend to use contraception.
[Concomitant drugs]
21) Calculated based on prednisone, requiring continuous full-body administration of high-dosage steroids over 10 mg/day (orally or IV) or currently using other immunosuppressant drugs. Patients taking oral steroids equivalent to less than 10 mg/day of prednisone are eligible.
22) Requiring oral administration of drugs which induce CYP3A4.
23) Chronic antiplatelet therapy, including dipyridamole or clopidogrel, or similar agents. Once-daily aspirin use (maximum dose 325 mg/day) is permitted.
[Preceding treatment]
24) At the time of registration, any of the following preceding treatments have not been completed, or the specified time period has not yet elapsed. (Same day of the week registration possible.)
a)Surgery (including exploratory thoracotomy, examination thoracotomy, and VATS surgery): 4 weeks
b)Palliative radiotherapy: 2 weeks
Administration of blood transfusion or hematopoietic factor preparations: 2 weeks
25) Other patients determined unfit by an attending physician will also be excluded.

Related Information

• Primary Sponsor: Hayashi Hidetoshi
• Secondary Sponsor: Seto Takashi,Haratake Naoki
• Source(s) of Monetary Support: Eli Lilly Japan K.K.