Clinical trial NCT00536640: Inoperable Non-Squamous NSCLC Stage III/IV: A Randomised Phase II Study With Bevacizumab Plus Erlotinib Or Gemcitabine/Cisplatin Plus Bevacizumab
Official title: Inoperable Non-Squamous NSCLC Stage III/IV: A Randomised Phase II Study With Bevacizumab Plus Erlotinib Or Gemcitabin/Cisplatin Plus Bevacizumab
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Carcinoma, Non-Small-Cell Lung
Keywords: Non Small Cell Lung Carcinoma (NSCLC Stage III an IV)
Lead sponsor: Aktion Bronchialkarzinom e.V.
Sponsor class: OTHER
Collaborators: name: Roche Pharma AG
First posted: 2007-09-28
Enrollment: 224
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: This study wants to determine the activity of a non chemotherapy first line biological treatment with Erlotinib/Bevacizumab or Gemcitabine-Cisplatin/Bevacizumab in patients with the diagnosis of non-squamous advanced Non Small Lung Cancer.

Detailed description: Prospective, randomized multi-center, open label phase II study to determine the activity of a non-chemotherapy first line biological treatment with Erlotinib/Bevacizumab or Gemcitabine-Cisplatin/Bevacizumab in patients with the diagnosis of non-squamous advanced Non-Small-Lung-Cancer.

* Duration of treatment/patient: up to 1,5 years
* Follow Up: ≈ 6 month
* Planned number of patients: 220 treated patients (110 patients/arm)

Eligibility criteria: Inclusion Criteria:

* Histological confirmed Non-Small Cell Lung Cancer that can not be treated within a defined radiological field
* Tumor stage IIIB (pleural effusion or pericardial effusion included) or IV
* The following histological tumor types are eligible:

  * Adenocarcinoma (including adenocarcinomas with bronchioloalveolar differentiation)
  * Large Cell Carcinoma (including large cell carcinomas with neuroendocrine differentiation)
  * Mixed Cell Carcinoma without small cell fraction and without predominant squamous cell fraction (\< 50%)
  * undifferentiated non-small-cell-carcinoma
* No previous chemotherapy within the last five years
* At least 4 weeks since last major surgery
* Age ≥ 18 years
* ECOG \<= 2
* Adequate hematological laboratory parameters

  * Hemoglobin ≥ 10 g/dl
  * WBC ≥ 3.000/µl
  * Platelets ≥ 100.000/µl
* Adequate hepatic laboratory parameters

  * Bilirubin \<= 2,0 mg/dl
  * AST(GOT) \<= 2,5 x ULN in patients without liver metastases
  * AST(GOT) \<= 5 x UNL in patients with liver metastases
  * ALT(GPT) \<= 2,5 x ULN in patients without liver metastases
  * ALT(GPT) \<= 5 x UNL in patients with liver metastases
* Adequate renal laboratory parameters

  * Creatinine \<= 1,5 mg/dl
  * Creatinine Clearance \> 60 ml/min
* Adequate plasmatic blood coagulation - INR \<= 1,5 and PTT \<= 1,5 x ULN
* Normal cardiac function defined by LVEF \> 49% (echocardiography)
* Electrocardiogram without significant signs of cardiac arrhythmias
* Provision of informed consent according to local regulatory requirements prior to any protocol specific treatment
* Measurable lesion according to RECIST-Criteria's
* Negative pregnancy test for women of childbearing potential unless they are postmenopausal at baseline. (Postmenopausal women must have been amenorrheic at least for 12 months to be considered of non childbearing potential)
* Women of child bearing potential to must be willing to use an acceptable method to avoid pregnancy at least one month before study start. Examples: oral contraceptives (sole application of oral contraceptives is not sufficient), diaphragm pessary, intrauterine device (spiral), condom plus diaphragm pessary plus spermicide

Exclusion Criteria:

* Histologic confirmed squamous cell carcinoma
* Pregnancy or lactation period
* Tumor extension treatable with radiotherapy
* Current clinical signs or symptoms of brain and/or leptomeningeal metastases confirmed by CT or MRI brain scan
* Evidence of tumor invading or abutting major blood vessels
* Other co-existing malignancies or malignancies diagnosed within the last 5 years with the exception of a CIS of the cervix or non-melanomatous skin cancer. Patients curatively treated and free of disease for at least 5 years will be discussed with the Principal Investigator (LKP) before inclusion
* Any previous chemotherapy within the last five years
* Any radiotherapy with exception of the following situations:

  * concomitant small field radiotherapy in the case of solitary bone metastases or other solitary metastases
  * in case of large field radiotherapy or multi-radiation fields due to multiple bone metastases or other metastases. The application of study medication then must be delayed at least for 24 h (after last radiotherapy)
  * in case of radiotherapy of the primary tumor trial therapy can be employed if radiotherapy has ended at least 6 weeks ago and new tumor progression is clearly documented
* Treatment with an investigational new drug, currently or within the last 28 days, and/or participation in another clinical trial, currently or during the last 12 weeks, and/or previous participation in this study
* A history or presence of any CNS disorder or psychiatric disability judged by the Investigator to be clinically significant and/or interfering with compliance of oral drug intake
* Patients with any clinically significant disease that in the opinion of the investigator is likely to put the patient at risk or to interfere with the evaluation of the patient's safety and of the study outcome. This includes, but is not limited to:

  * Any known significant ophthalmologic abnormalities of the surface of the eye (the use of contact lenses is not recommended)
  * Immediate need for therapeutic intervention (e.g.: upper inflow congestion or poststenotic pneumonia)
  * Clinically significant cardiac disease (e.g. right-sided heart failure, symptomatic coronary artery disease and cardiac arrhythmias not well controlled with medication) or myocardial infarction within the last 6 months
  * pleural effusion or pericardial effusion with the need for intervention
* Uncontrolled hypertension
* Non healing wound, ulcer or bone fracture
* Fresh thrombosis under therapy with anticoagulants
* Hemorrhagic diathesis, Hemophilia A, Hemophilia B
* Implantation of a central vein catheter (Prot-Catheter) within 24 h prior to application of study medication
* Present hemoptysis of any CTC grade or history of hemoptysis of any CTC grade within 3 month prior to study start
* Peritoneal carcinomatosis
* History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 month prior to study start
* Interstitial pneumonia or extensive or symptomatic interstitial fibrosis of the lung
* Pleural effusion or ascites, which cause respiratory compromise
* Any other active or uncontrolled infection
* Organ allograft
* History of a mental disease or condition such as to interfere with the patient's ability to understand the requirements of the study and the intake of study medication according to study protocol
* Inability to swallow pills
* Current or recent (within 10 days of first dose of study medication) use of coumadin/warfarin or marcumar/phenprocoumon for therapeutic purposes Prophylactic use of low molecular weight heparins is allowed
* Current or recent (within 10 days of first dose of study medication) use of ASS - Dosage \> 325 mg/day
* Current or recent (within 10 days of first dose of study medication) use of Plavix/Clopidogrel
* Alcohol and drug abuse
* Known hypersensitivity to any of the study drugs
* Presence of a tracheobronchial fistula or fistulization in other organ systems like gastrointestinal fistulas or fistulization of urogenital tract

Primary outcomes:
measure: The main efficacy parameter is the progression free survival.
timeFrame: Recruitment 1 year, Follow up 2 years
Secondary outcomes:
measure: Overall survival
timeFrame: Recruitment 1 year, Follow up 2 years
measure: Quality of life
timeFrame: Screening, prior to next treatment cycle, treatment day 126, end of therapy
measure: Response rate
timeFrame: Screening, prior to treatment cycle 3, prior to treatment clycle 5, treatment day 126, every 6 weeks after treatment day 126, end of therapy
measure: Molecular investigations
timeFrame: Screening, prior to treatment cycle 3
Other outcomes:
Locations:
city: Bayreuth
country: Germany
facility: Klinikum Bayreuth GmbH
city: Berlin
country: Germany
facility: Charite´ Mitte
city: Berlin
country: Germany
facility: Gemeinschaftskrankenhaus Havelhöhe
city: Berlin
country: Germany
facility: Helios Klinikum Emil v. Behring
city: Bochum
country: Germany
facility: Augusta-Krankenanstalten
city: Bonn
country: Germany
facility: Johanniter-Krankenhaus Bonn
city: Borstel
country: Germany
facility: Forschungszentrum Borstel
city: Duisburg
country: Germany
facility: St. Johannes Hospital
city: Frankfurt am Main
country: Germany
facility: Krankenhaus Nordwest
city: Frankfurt Oder
country: Germany
facility: Klinikum Frankfurt (Oder)GmbH
city: Frankfurt
country: Germany
facility: Städtisches Krankenhaus Frankfurt-Höchst
city: Fulda
country: Germany
facility: Medizinisches Versorgungszentrum Osthessen
city: Greifswald
country: Germany
facility: Universitätsklinikum Greifswald
city: Großhansdorf
country: Germany
facility: Krankenhaus Großhansdorf
city: Göttingen
country: Germany
facility: Georg-August-Universität Göttingen
city: Halle
country: Germany
facility: Diakoniekrankenhaus Halle/S.
city: Hamburg
country: Germany
facility: Asklepios Klinik Harburg
city: Heidelberg
country: Germany
facility: Thoraxklinik Universitätsklinikum Heidelberg
city: Hemer
country: Germany
facility: Lungenklinik Hemer
city: Immenhausen
country: Germany
facility: Fachklinik für Lungenerkrankungen Immenhausen
city: Karlsruhe
country: Germany
facility: St. Vincentius-Kliniken Karlsruhe
city: Kassel
country: Germany
facility: Klinikum Kassel GmbH
city: Koblenz
country: Germany
facility: Katholisches Klinikum Haus Marienhof
city: Köln
country: Germany
facility: Malteser Krankenhaus St. Hildegardis
city: Leer
country: Germany
facility: Onkologische Schwerpunktpraxis Dr. Lothar Müller
city: Lemgo
country: Germany
facility: Klinikum Lippe-Lemgo
city: Ludwigshafen
country: Germany
facility: Klinikum Ludwigshafen
city: Löwenstein
country: Germany
facility: Klinik Löwenstein
city: Lübeck
country: Germany
facility: Universitätsklinikum Schleswig-Holstein
city: Mainz
country: Germany
facility: St. Hildegardis Krankenhaus
city: Marburg
country: Germany
facility: Universitätsklinikum Marburg
city: Minden
country: Germany
facility: Johannes Wesling Klinikum Minden
city: Regensburg
country: Germany
facility: Krankenhaus Barmherzige Brüder
city: Stralsund
country: Germany
facility: Hanse-Klinikum Stralsund
city: Velbert
country: Germany
facility: Onkologische Gemeinschaftspraxis Dr. Nusch
city: Wangen
country: Germany
facility: Fachkliniken Wangen
city: Wuppertal
country: Germany
facility: Helios Klinikum Wuppertal
Study officials:
affiliation: Aktion Bronchialkarzinom e.V.
name: Prof. Dr. Martin Wolf, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Thomas M, Fischer J, Andreas S, Kortsik C, Grah C, Serke M, von Eiff M, Witt C, Kollmeier J, Muller E, Schenk M, Schroder M, Villalobos M, Reinmuth N, Penzel R, Schnabel P, Acker T, Reuss A, Wolf M; ABC-Lung Cancer Group. Erlotinib and bevacizumab versus cisplatin, gemcitabine and bevacizumab in unselected nonsquamous nonsmall cell lung cancer. Eur Respir J. 2015 Jul;46(1):219-29. doi: 10.1183/09031936.00229014. Epub 2015 Mar 18.