Sequential Therapy With Bevacizumab, RAd001 (Everolimus) and Tyrosinekinase Inhibitors (TKI) in Metastatic Renal Cell Carinoma (mRCC) (BERAT)

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2012 by Central European Society for Anticancer Drug Research
Sponsor:
Information provided by (Responsible Party):
Central European Society for Anticancer Drug Research
ClinicalTrials.gov Identifier:
NCT01731158
First received: September 28, 2012
Last updated: November 21, 2012
Last verified: November 2012
  Purpose

This will be a prospective, open label, randomized multicenter phase-II study to evaluate progression free survival (PFS) in 2nd line treatment in patients with locally advanced or metastatic clear-cell renal cell cancer (cc-RCC) receiving everolimus (arm A) in comparison to a tyrosine-kinase inhibitor (TKI) (arm B). Following 2nd line treatment, patients will be switched to a TKI in arm A and everolimus in arm B. All patients will receive bevacizumab as standardized first-line treatment.

Another key element of the study is the analysis of predictive biomarkers, which will be performed in serum and tumor tissue, respectively. Serum samples will be collected at prespecified timepoints throughout the study and analysed by SELDI-TOF-MS and DIGE. Candidate proteins are thought to predict therapeutic outcome and candidates are subject for target validation by Western Blot or ELISA. In addition, formalin-fixed paraffin-embedded (FFPE) tumor tissue will be collected prospectively and analysed for micro RNA (miRNA). Candidate miRNAs that predict therapeutic outcome will be validated by quantitative RT-PCR. Furthermore, circulating tumor cells (CTCs) will be generated from blood drawings during routine visits. The primary objective is to correlate the marker profile defined from the FFPE tissue with the profile obtained from CTCs in order to validate expression based markers ant their change during different treatment lines.


Condition Intervention Phase
Metastatic Renal Cell Carcinoma
Drug: Avastin in combination with Roferon-A
Drug: Afinitor
Drug: Sutent, Nexavar or Votrient
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Prospective, Open-label, Multicenter, Randomized Phase II Trial: Sequential Therapy With BEvacizumab, RAd001 (Everolimus) and Tyrosinekinase Inhibitors (TKI) in Metastatic Renal Cell Carcinoma (mRCC) (BERAT Study)

Resource links provided by NLM:


Further study details as provided by Central European Society for Anticancer Drug Research:

Primary Outcome Measures:
  • PFS rate of 2nd line treatment at 6 months after randomisation [ Time Frame: 6 months after randomisation ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • PFS for 2nd line treatment [ Time Frame: after completion of second-line treatment (expected median treatment 1st and 2nd line: 16 months) ] [ Designated as safety issue: No ]
  • PFS for each treatment given [ Time Frame: after completion of each treatment line (expected median treatment duration 1st line: 11 months, 2nd line: 5 months, 3rd line: 6 months) ] [ Designated as safety issue: No ]
  • Overall Survival [ Time Frame: after death of patient ] [ Designated as safety issue: No ]
  • number and severity (CTCAE 4.0) adverse events [ Time Frame: continuously throughout trial ] [ Designated as safety issue: Yes ]
  • quality of life [ Time Frame: continuously throughout trial (baseline, week 5, week 11, every 12 weeks, end of treatment for all treatment lines via FKSI-10 questionnaire) ] [ Designated as safety issue: No ]
  • ORR for each treatment given [ Time Frame: after completion of each treatment line (expected median treatment duration 1st line: 11 months, 2nd line: 5 months, 3rd line: 6 months) ] [ Designated as safety issue: No ]

Estimated Enrollment: 100
Study Start Date: October 2012
Estimated Study Completion Date: May 2016
Estimated Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
arm A

sequential therapy with approved drugs

Avastin in combination with Roferon-A (first-line), Afinitor (second-line) and a TKI (third-line)

Drug: Avastin in combination with Roferon-A
Other Name: Bevacizumab in combination with Interfereon-alfa
Drug: Afinitor
Other Name: Everolimus
Drug: Sutent, Nexavar or Votrient
TKI
Other Name: Sunitinib, Sorafenib or Pazopanib
arm B

sequential therapy with approved drugs

Avastin in combination with Roferon-A (first-line), a TKI (second-line) and Afinitor (third-line)

Drug: Avastin in combination with Roferon-A
Other Name: Bevacizumab in combination with Interfereon-alfa
Drug: Afinitor
Other Name: Everolimus
Drug: Sutent, Nexavar or Votrient
TKI
Other Name: Sunitinib, Sorafenib or Pazopanib

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Signed Informed Consent
  • Documented progressive disease prior to study inclusion.
  • Adult males and females: ≥ 18 years of age.
  • Metastatic or locally advanced RCC, not amendable to surgery with curative intention.
  • ECOG performance status 0-1.
  • 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.
  • 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.
  • Modified MSKCC risk (according to Heng): good or intermediate.
  • 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.
  • Total bilirubin ≤ 2 x upper limit of normal.
  • AST and ALT ≤ 2.5 x upper limit of normal, or ≤ 5 x upper limit of normal in case of liver metastases.
  • Serum creatinine ≤ 2 x upper limit of normal or calculated creatinine clearance >30 ml/min.
  • 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.
  • Adequate cardiac function (left ventricular ejection fraction ≥50% as assessed by ECHO)

Exclusion Criteria:

  • Any investigational drug within the 30 days before inclusion.
  • Known or suspected allergy or hypersensitivity reaction to any of the components of study treatments or their excipients.
  • Pregnancy (absence to be confirmed by beta-hCG test) or lactation period.
  • 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.
  • 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.
  • Cardiac arrhythmias requiring anti-arrhythmics (excluding beta blockers, digoxin or digitoxin).
  • History of any of the following cardiac events within the past 6 months:

    1. myocardial infarction (including severe/unstable angina),
    2. coronary/peripheral artery bypass graft,
    3. congestive heart failure (CHF) (NYHA Class III, or IV),
    4. cerebrovascular accident,
    5. transient ischemic attack,
    6. pulmonary embolism, abdominal or tracheo-oesophageal fistula, gastrointestinal perforation, or intra-abdominal abscess
  • Hemorrhage ≥ grade 3 or clinically significant hemoptysis within the past 4 weeks
  • Uncontrolled severe hypertension (failure of diastolic blood pressure to fall below 90 mm Hg despite the use of ≥ 3 anti-hypertensive drugs).
  • History of relevant pulmonary hypertension or interstitial lung disease or severely impaired lung function.
  • Acute or sub-acute intestinal occlusion or history of inflammatory bowel disease or chronic diarrhea.
  • 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].
  • History of organ allograft.
  • Significant disease which, in the investigator's opinion would exclude the patient from the study.
  • Medication that is known to interfere with any of the agents applied in the trial.
  • Patients with a serious non-healing wound, ulcer or bone fracture.
  • Patients with a history of seizure(s) not controlled with standard medical therapy.
  • 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.
  • Legal incapacity or limited legal capacity.
  • Medical or psychological conditions that would not permit the patient to complete the study or sign informed consent.
  • Significant vascular disease (e.g. aortic aneurysm, aortic dissection), or symptomatic peripheral vascular disease.
  • 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.
  • Poorly controlled diabetes as defined by fasting serum glucose > 2.0 x ULN.
  • Active (acute or chronic) or uncontrolled infection of bacterial, mycotic or viral genesis.
  • Liver disease such as chronic active hepatitis or chronic persistent hepatitis.
  • Patients with a known history of HIV seropositivity.
  • QT prolongation (QTc > 450 msec).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01731158

Contacts
Contact: Berta Moritz, Ph.D. +43 1 522 30 93 ext 12 berta.moritz@cesar.or.at

Locations
Germany
Charité Berlin Recruiting
Berlin, Germany
University Hospital Bonn Not yet recruiting
Bonn, Germany
University Hospital Dresden Not yet recruiting
Dresden, Germany
University Hospital Düsseldorf Not yet recruiting
Düsseldorf, Germany
Waldkrankenhaus St. Marien Not yet recruiting
Erlangen, Germany
University Hospital Essen Recruiting
Essen, Germany
University Hospital Frankfurt Recruiting
Frankfurt, Germany
University Hospital Freiburg Recruiting
Freiburg, Germany
University Hospital Göttingen Not yet recruiting
Göttingen, Germany
University Hospital Hannover Recruiting
Hannover, Germany
Oncological Practice Hannover Not yet recruiting
Hannover, Germany
University Hospital Magdeburg Not yet recruiting
Magdeburg, Germany
University Hospital Tübingen Not yet recruiting
Tübingen, Germany
Sponsors and Collaborators
Central European Society for Anticancer Drug Research
Investigators
Study Chair: Viktor Grünwald, MD University Hospital Hannover, Germany
  More Information

No publications provided

Responsible Party: Central European Society for Anticancer Drug Research
ClinicalTrials.gov Identifier: NCT01731158     History of Changes
Other Study ID Numbers: C-II-008, 2011-005939-78
Study First Received: September 28, 2012
Last Updated: November 21, 2012
Health Authority: Germany: Federal Institute for Drugs and Medical Devices

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Renal Cell
Adenocarcinoma
Kidney Diseases
Kidney Neoplasms
Neoplasms
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Glandular and Epithelial
Urogenital Neoplasms
Urologic Diseases
Urologic Neoplasms
Bevacizumab
Everolimus
Interferon-alpha
Sirolimus
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Antineoplastic Agents
Antiviral Agents
Growth Inhibitors
Growth Substances
Immunologic Factors
Immunosuppressive Agents
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on October 20, 2014