A prospective, open-label, multicenter, randomized phase II trial: Sequential therapy with BEvacizumab, RAd001 (everolimus) and AxiTinib in metastatic kidney cancer (BERAT study)
- Conditions
- metastatic renal cell carcinoma (mRCC)MedDRA version: 18.0Level: LLTClassification code 10050076Term: Metastatic renal carcinomaSystem Organ Class: 100000004864Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2011-005939-78-DE
- Lead Sponsor
- CESAR Central European Society for Anticancer Drug Research-EWIV
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- Not specified
Inclusion Criteria
(1)Signed Informed Consent
(2)Documented progressive disease prior to study inclusion.
(3)Adult males and females: = 18 years of age.
(4)Metastatic or locally advanced RCC, not amendable to surgery with curative intention.
(5)ECOG performance status 0-1.
(6)Patients with measurable disease (at least one uni-dimensionally measurable target lesion by CT-scan or MRI) according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) If prior palliative radiotherapy to metastatic lesions: = 1 measurable lesion that has not been irradiated. Patients with bone lesions as the only measurable lesion are eligible, provided that lesions consist of soft tissue, which is assessed via CT or MRI.
(7)Prior radiotherapy and surgery are allowed if completed 4 weeks (for minor surgery 2 weeks) prior to start of treatment and patient recovered from toxic effects.
(8)Modified MSKCC risk (according to Heng): good or intermediate.
(9)White blood cell count (WBC) = 4x10*9/L with neutrophils = 1.5 x 10*9/L, platelet count = 100x10*9/L, hemoglobin = 9 g/dL.
(10)Total bilirubin = 2 x upper limit of normal.
(11)AST and ALT = 2.5 x upper limit of normal, or = 5 x upper limit of normal in case of liver metastases.
(12)Serum creatinine = 2 x upper limit of normal or calculated creatinine clearance >30 ml/min.
(13)International Normalized Ratio (INR) =1.5 except for patients on stable anticoagulant therapy. Activated partial thromboplastin time (aPTT) =1.5 times upper limit of normal (ULN) or greater than the lower limit of the therapeutic range. Note: The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR or aPTT is within therapeutic limits (according to the medical standard in the institution) and the patient has been on a stable dose of anticoagulants for at least two weeks at the treatment start.
(14)Adequate cardiac function (left ventricular ejection fraction =50% as assessed by ECHO)
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 13
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 9
Exclusion Criteria
(15)Any investigational drug within the 30 days before inclusion.
(16)Known or suspected allergy or hypersensitivity reaction to any of the components of study treatments or their exipients.
(17)Pregnancy (absence to be confirmed by beta-hCG test) or lactation period.
(18)Men or women of child-bearing potential who are sexually active and unwilling to use a highly effective method of contraception (Pearl index < 1%) during the trial. Oral contraceptives are acceptable if a barrier method is applied in conjunction.
(19)Clinically symptomatic brain or meningeal metastasis (known or suspected), unless completion of local therapy for at least 3 months with discontinuation of steroids prior to start of treatment.
(20)Cardiac arrhythmias requiring anti-arhythmics (excluding beta blockers, digoxin or digitoxin).
(21)History of any of the following cardiac events within the past 6 months:
•myocardial infarction (including severe/unstable angina),
•coronary/peripheral artery bypass graft,
•congestive heart failure (CHF) (NYHA Class III, or IV),
•cerebrovascular accident,
•transient ischemic attack,
•pulmonary embolism, abdominal or tracheo-oesophageal fistula, gastrointestinal perforation, or intra-abdominal abscess
(22)Hemorrhage = grade 3 or clinically significant hemoptysis within the past 4 weeks
(23)Uncontrolled severe hypertension (failure of diastolic blood pressure to fall below 90 mm Hg despite the use of = 3 anti-hypertensive drugs).
(24)History of relevant pulmonary hypertension or interstitial lung disease or severely impaired lung function.
(25)Acute or sub-acute intestinal occlusion or history of inflammatory bowel disease or chronic diarrhea.
(26)Previous malignancy (other than renal cell cancer) in the last 3 years, except basal cell cancer of the skin, pre-invasive cancer of the cervix, T1a prostate carcinoma or superficial bladder tumor [Ta, Tis and T1].
(27)History of organ allograft.
(28)Significant disease which, in the investigator’s opinion would exclude the patient from the study.
(29)Medication that is known to interfere with any of the agents applied in the trial.
(30)Patients with a serious non-healing wound, ulcer or bone fracture.
(31)Patients with a history of seizure(s) not controlled with standard medical therapy.
(32)Patients receiving chronic systemic treatment with corticosteroids (dose of > 20 mg/day methylprednisone equivalent) or another immune-suppressive agent. Inhaled and topical steroids are acceptable.
(33)Legal incapacity or limited legal capacity.
(34)Medical or psychological conditions that would not permit the patient to complete the study or sign informed consent.
(35)Significant vascular disease (e.g. aortic aneurysm, aortic dissection), or symptomatic peripheral vascular disease.
(36)Evidence or history of recurrent thromboembolism (>1 episode of deep venous thrombosis/peripheral embolism = CTCAE Grade 3) during the past 2 years, bleeding diathesis or coagulopathy.
(37)Poorly controlled diabetes as defined by fasting serum glucose > 2.0 x ULN.
(38)Active (acute or chronic) or uncontrolled infection of bacterial, mycotic or viral genesis.
(39)Liver disease such as chronic active hepatitis or chronic persistent hepatitis.
(40)Patients with a known history of HIV seropositivity.
(41)QT prolongation (QTc > 450 msec).
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: progression free survival (PFS) rate of 2nd line treatment at 6 months after randomisation;Secondary Objective: progression free survival (PFS) for 2nd line treatment,<br>cumulative PFS for each sequence,<br>PFS and objective response rate (ORR) for each treatment given, <br>overall survival (OS), <br>safety, <br>quality of life;Primary end point(s): The primary endpoint is progression free survival (PFS) rate at 6 months for the 2nd line therapy, defined as the number of patients surviving for longer than 6 months without progression divided by the total number of patients.;Timepoint(s) of evaluation of this end point: all patients ended treatment in 2nd line
- Secondary Outcome Measures
Name Time Method Secondary end point(s): -Progression-free Survival (PFS) for 2nd line treatment <br>-cumulative PFS for each sequence (Arm A: Everolimus followed by TKI, and Arm B: TKI followed by Everolimus)<br>-PFS and ORR for each treatment given, <br>-overall survival (OS)<br>-safety assessed using CTCAE v4.0<br>-quality-of-life<br>;Timepoint(s) of evaluation of this end point: all patients ended treatment