Ramucirumab and Erlotinib for NSCLC Patients with Brain Metastases

JRCT ID: jRCTs051220059

Registered date:28/06/2022

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: non-small Cell Lung Cancer
• Date of first enrollment: 08/11/2022
• Target sample size: 32
• Study type: Interventional

Intervention(s)

Ramucirumab:i.v.,once in 2 weeks
Erlotinib:oral,once daily for consecutive days
Treatment with regimen is continued until the rating of PD (progressive disease) or satisfaction of the protocol treatment discontinuation criteria.

Outcome(s)

• Primary Outcome: Intracranial overall response rate (iORR)

Secondary Outcome

Intracranial disease control rate (iDCR)
Intracranial progression-free survival (iPFS)
Extracranial ORR (eORR)
Extracranial progression-free survival (ePFS)
Overall response rate (ORR)
Overall progression-free survival (PFS)
Overall survival (OS)
Safety

Key inclusion & exclusion criteria

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

Include criteria

1)Patients revealed by head MRI (contrast-enhanced MRI as far as possible) within 28 days before registration (28-day earlier on the same day of the week is acceptable) to have treatment-naive brain metastasis (major axis double the slice thickness or more and 5 mm or more). Symptom-free patients and patients with mild symptoms (remaining controlled for one week or more by anti-brain edema therapy with steroid at dose levels not exceeding 40 mg when converted into prednisolone dose level) are eligible. Patients having undergone stereotactic radiotherapy are eligible if their clinical symptoms are stable and they have recovered from all treatment-related adverse events by the time of registration. Patients planned to receive radiotherapy for brain metastasis must have at least one lesion not covered by irradiation.
2)Patients rated histologically or cytologically to have non-small cell lung carcinoma.
3)Carcinoma at stage IV or postoperative recurrence not amenable to radical treatment.
4)Having received no chemotherapy for the cancer covered by this study. Patients having received preoperative or postoperative chemotherapy are eligible if the final chemotherapy dose is given 6 months or more before the date of registration with this study. Provided patients having received EGFR-TKI during preoperative or postoperative chemotherapy are not eligible.
5)EGFR mutation positive (excluding patients confirmed to have T790M mutation).
6)Patients able to take oral-dose drugs.
7)Age of 20 years old or older at the time of consent obtainment.
8)ECOG performance status(PS)of 0-2.
9)Patients free of severe disorder of major organs (bone marrow, heart, lungs, liver) and satisfying the criteria given below (the latest data collected within 14 days before registration are used for judgment of eligibility. The 14-day period is counted from the date of registration and includes the same day of the preceding week).
Neutrophils >=1,500 /mm3
Hemoglobin >=9.0 g/dL
Platelets >=100,000 /mm3
AST,ALT <=3.0xULN (upper limit of normal range)
(Patients with liver metastasis: <=5.0xULN)
Total bilirubin <=1.5xULN
Serum creatinine <=1.5xULN
or creatinine clearance >=40 mL/min
SpO2 (Room air) 90% or more
PT-INR<=1.5, and APTT longer by 5 seconds or less than the upper limit of normal range (unless receiving anticoagulant therapy)
*In patients receiving anticoagulant therapy, such as warfarin, the anticoagulant therapy should be replaced with low-molecular-weight heparin before starting the protocol treatment and then PT-INR<=3.0 should be confirmed.
Urinary protein<=1+(test paper method, or less than 1,000 mg/day in 24-hour pooled urine
10)No restriction about presence/absence of lesions other than brain lesions (no restriction about presence/absence of measurable lesions according to RECIST1.1). However, thoracic/abdominal CT performed within 28 days before registration is essential (28-day earlier on the same day of the week is acceptable).
11)Patients expected to survive for at least 3 months.
12)The absence of any of the prior treatments or procedures described below, or if any prior treatments or procedures had been done, the specified period of time has elapsed since the completion of the prior treatments or procedures before registration:
i)Stereotactic radiation/Gamma knife therapy for brain metastasis
Passage of 1 or more days from the final irradiation day.
ii)Surgery for brain metastasis
Passage of 7 or more days after surgery.
(The presence of untreated brain metastasis meeting the criterion 1) other than lesions treated in i)ii) is required.)
13)Restriction on other prior treatments (other than brain metastasis treatments)
i)Higher invasive surgery (open abdominal/thoracic surgery):One month or more has elapsed.
ii)Thoracic drainage: One week or more has elapsed after postoperative removal of sutures.
14)Obtainment of written consent from the patient himself/herself after sufficient explanation of the study content before registration in this study.

Exclude criteria

1)The patient has known to have T790M EGFR mutation
2)Having developed grade 3 or higher gastrointestinal bleeding within 3 months before registration or hemoptysis (defined as bright red blood or >= 1/2 teaspoon,regardless of grade) within 2 months before registration.
3)Patients with imaging findings suggestive of macrovascular tumor invasion, tumor encasement, or hollowing within the tumor.
4) Patients with tumor exposure in the central airway up to the segmental branch.
5)Patients having developed severe uncontrollable coagulation disorder or severe hemorrhagic complication within 6 months before registration.
6)Patients who have developed deep vein thrombus, pulmonary embolism within 3 months before registration.
7)Patients having undergone surgery within 4 weeks before registration.
Provided, skin tumor resection and endoscopic surgery are acceptable if one week or more has elapsed after surgery.
8) Active double cancer. Synchronous double cancer and metachronous double cancer with disease-free survival of within 2 years requiring treatment will be regarded as double cancer.
9)Patients confirmed by MRI or cerebrospinal fluid test to have meningeal dissemination
10)Patients having developed cerebrovascular or neurovascular disease (including myocardial infarction, cerebral infarction and transient ischemic attack) or other arterial thromboembolic events within 6 months before registration.
11) Patients judged to have developed gastrointestinal perforation within 6 months before registration or to have a risk for perforation (gastrointestinal invasion, metastasis).
12)Patients having poorly controlled hypertension (systolic blood pressure remaining 160 mmHg or higher and diastolic blood pressure remaining 100 mmHg or higher for 4 weeks or more).
13)Patients having unhealed wound or peptic ulcer.
14)Patients having developed fracture within 1 month before registration.
15) Patients with poorly controlled metabolic disease (diabetes mellitus) or other nonmalignant organ or systemic diseases or secondary effects of cancer that induce a high medical risk and/or make assessment of survival uncertain. Provided, patients on continued insulin use are eligible if the condition is rated as been well controlled.
16)Local infection or systemic active infection requiring surgical treatment, such as drainage.
17)Periodical users of non-steroidal anti-inflammatory drugs (NSAIDs:indomethacin, ibuprofen, naproxen or analogous drugs) or anti-platelet drugs (aspirin, dipyridamole, ticlopidine, clopidogrel or analogous drugs). Provided, low-dose aspirin (325 mg/day or less) is acceptable. NSAIDs are acceptable if 7 days or more have elapsed after switching to acetaminophen.
18)Patients rated as Child-Pugh B or severer liver cirrhosis or having hepatic encephalopathy or symptomatic hepatic ascites.
19)Active hepatitis B or hepatitis C (Patients testing positive for HBs antibody, HBc antibody or HBs antigen are eligible if the virus level is lower than the detection limit and hepatitis is inactive. Patients testing positive for HCV antibody are eligible if hepatitis is inactive).
20)Interstitial pulmonary disease evident on CT scan at the time of registration (positive history or organization of radiation pneumonitis is acceptable).
21)Patients judged to be difficult for registration with this study because of clinically significant psychiatric disease.
22)Complication by clinically significant ophthalmic disease [example: severe dry eye syndrome (including Sjoren syndrome), dry keratoconjunctivitis, keratitis].
23)Patients requiring oral treatment with CYP3A4-inducing drugs or inhibitors.
24)Hypersensitivity to any ingredient or additive in ramucirumab or erlotinib.
25)The patient has elective or planned major surgery to be performed during the course of the clinical trial.
26)Pregnant women, lactating women or women unwilling to take contraceptive measures.
Males desiring pregnancy of their partner. Because the teratogenicity of ramucirumab is not known, the patient, if sexually active, must be postmenopausal, surgically sterile, or using effective contraception (hormonal or barrier methods).
Female patients of childbearing potential must have a negative Qualitative urinary hCG test within 7 days prior to first dose of protocol therapy.
27)Other patients judged by the clinical investigator to be inappropriate for the study.

Related Information

• Primary Sponsor: Takayama Koichi
• Source(s) of Monetary Support: Eli Lilly Japan K.K.