Bevacizumab, Pemetrexed Disodium, and Cisplatin or Erlotinib Hydrochloride and Bevacizumab in Treating Patients With Stage IV Non-Small Cell Lung Cancer. A Multicenter Phase II Trial Including Biopsy at Progression (BIO-PRO Trial).

This study is currently recruiting participants.
Verified December 2013 by Swiss Group for Clinical Cancer Research
Sponsor:
Information provided by (Responsible Party):
Swiss Group for Clinical Cancer Research
ClinicalTrials.gov Identifier:
NCT01116219
First received: April 27, 2010
Last updated: December 8, 2013
Last verified: December 2013
  Purpose

RATIONALE: Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Drugs used in chemotherapy, such as pemetrexed disodium and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether bevacizumab given together with pemetrexed disodium and cisplatin is more effective than erlotinib hydrochloride given together with bevacizumab in treating patients with non-small cell lung cancer.

PURPOSE: This phase II trial is studying giving bevacizumab together with pemetrexed disodium and cisplatin to see how well it works compared with giving erlotinib hydrochloride together with bevacizumab in treating patients with stage IV non-small cell lung cancer.


Condition Intervention Phase
Lung Cancer
Biological: bevacizumab, erlotinib
Drug: bevacizumab, pemetrexed, cisplatin
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Bevacizumab, Pemetrexed and Cisplatin, or Erlotinib and Bevacizumab for Advanced Non-Squamous NSCLC Stratified by EGFR Mutation Status. A Multicenter Phase II Trial Including Biopsy at Progression (BIO-PRO Trial).

Resource links provided by NLM:


Further study details as provided by Swiss Group for Clinical Cancer Research:

Primary Outcome Measures:
  • Progression-free survival at 6 months in stratum wtEGFR cohort 1 [ Time Frame: at 6 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Progression-free survival [ Time Frame: at 6 months ] [ Designated as safety issue: No ]
  • Overall survival [ Time Frame: from registration until death ] [ Designated as safety issue: No ]
  • Best response (RECIST 1.1) [ Time Frame: up to disease progression or start of new treatment ] [ Designated as safety issue: No ]
  • Adverse events (CTCAE v4.0) [ Time Frame: n.a. ] [ Designated as safety issue: Yes ]
  • Molecular markers in tumor tissue and blood [ Time Frame: n.a. ] [ Designated as safety issue: No ]

Estimated Enrollment: 149
Study Start Date: June 2010
Estimated Study Completion Date: August 2015
Estimated Primary Completion Date: August 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Stratum mut EGFR
  • Bevacizumab 7.5 mg/kg i.v. every 3 weeks and
  • Erlotinib 150 mg p.o. daily until progression.
Biological: bevacizumab, erlotinib
  • Bevacizumab 7.5 mg/kg i.v. every 3 weeks and
  • Erlotinib 150 mg p.o. daily until progression.
Other Names:
  • bevacizumab (Avastin)
  • erlotinib (Tarceva)
Active Comparator: Stratum wtEGFR

Cohort 1:

Induction chemotherapy with

  • Bevacizumab 7.5 mg/kg i.v. and
  • Pemetrexed 500 mg/m2 i.v. and
  • Cisplatin* 75 mg/m2 i.v. every 3 weeks for a maximum of 4 cycles or until progression.

Followed by maintenance therapy in patients without disease progression with

  • Bevacizumab 7.5 mg/kg i.v. and
  • Pemetrexed 500 mg/m2 i.v. every 3 weeks until progression.

Cohort 2:

Induction chemotherapy with

  • Pemetrexed 500 mg/m2 i.v. and
  • Cisplatin* 75 mg/m2 i.v. every 3 weeks for a maximum of 4 cycles or until progression.

Followed by maintenance therapy in patients without disease progression with

o Pemetrexed 500 mg/m2 i.v. every 3 weeks until progression.

Drug: bevacizumab, pemetrexed, cisplatin

Induction chemotherapy with

  • Bevacizumab 7.5 mg/kg i.v. and
  • Pemetrexed 500 mg/m2 i.v. and
  • Cisplatin* 75 mg/m2 i.v. every 3 weeks for a maximum of 4 cycles or until progression. Followed by maintenance therapy in patients without disease progression with
  • Bevacizumab 7.5 mg/kg i.v. and
  • Pemetrexed 500 mg/m2 i.v. every 3 weeks until progression.
Other Names:
  • Bevacizumab (Avastin)
  • pemetrexed (Alimta)

Detailed Description:

OBJECTIVES:

Primary

  • To demonstrate that tailored therapy, according to tumor histology and EGFR-mutation status, and the introduction of novel drug combinations in the frontline treatment of patients with stage IV non-squamous non-small cell lung cancer, is promising for further investigation.

Secondary

  • To prospectively explore molecular markers of clinical outcomes.

OUTLINE: This is a multicenter study. Patients are stratified according to EGFR(epidermal growth factor receptor)-mutation status (mutated vs wildtype). Patients are assigned to 1 of 2 groups.

  • mutEGFR (mutated epidermal growth factor receptor) group: Patients receive bevacizumab IV over 30-90 minutes on day 1 and oral erlotinib hydrochloride once daily on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • wtEGFR (wildtype epidermal growth factor receptor) group cohort 1:

    • Induction chemotherapy: Patients receive bevacizumab IV over 30-90 minutes, pemetrexed disodium IV over 10 minutes, and cisplatin IV over 60 minutes on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
    • Maintenance therapy: Patients without progressive disease receive bevacizumab IV over 30-90 minutes and pemetrexed disodium IV over 10 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression.

Blood and tissue specimens are collected for EGFR and molecular markers analysis, including gene expression, mutation, and pharmacogenomic analyses.

After completion of study treatment, patients are followed every 3 months.

  • wtEGFR (wildtype epidermal growth factor receptor) group cohort 2:

    • Induction chemotherapy: Patients receive pemetrexed disodium IV over 10 minutes, and cisplatin IV over 60 minutes on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
    • Maintenance therapy: Patients without progressive disease receive pemetrexed disodium IV over 10 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression.

Blood and tissue specimens are collected for EGFR and molecular markers analysis, including gene expression, mutation, and pharmacogenomic analyses.

After completion of study treatment, patients are followed every 3 months.

PROJECTED ACCRUAL: A total of 129 evaluable patients (77 in cohort 1 and 52 in cohort 2) with wtEGFR status and 20 patients with mutEGFR status will be accrued for this study.

  Eligibility

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

DISEASE CHARACTERISTICS:

  • Histologically confirmed non-small cell lung cancer of the following non-squamous subtypes:

    • Adenocarcinoma
    • Bronchioloalveolar carcinoma
    • Large cell carcinoma
  • Stage IV disease including any of the following:

    • M1a (separate tumor nodule in a contralateral lobe, tumor with pleural nodules, or malignant pleural or pericardial effusion)
    • M1b (distant metastasis)
  • Measurable disease, defined as ≥ 1 lesion (outside of irradiated areas) that can be measured in ≥ 1 dimension as ≥ 10 mm (≥ 15 mm in case of lymph nodes) according to RECIST 1.1
  • Paraffin-embedded or formalin-fixed diagnostic biopsy collected in the past 2 months must be available
  • Must have EGFR-mutation status (mutated or wild type) confirmed by the central pathologist in Basel
  • Must consent to tumor biopsy at progression
  • No intrathoracic tumors invading or abutting major blood vessels
  • No CNS metastases by mandatory CT scan (MRI within the past 3 weeks is acceptable)

PATIENT CHARACTERISTICS:

  • WHO performance status 0-1
  • Hemoglobin ≥ 100 g/L
  • ANC ≥ 1,500/mm³
  • Platelet count ≥ 100,000/mm³
  • Bilirubin ≤ 1.5 times upper limit of normal (ULN)
  • ALT ≤ 3 times ULN (≤ 5 times ULN if liver metastases are present)
  • Alkaline phosphatase ≤ 3 times ULN (≤ 5 times ULN if liver metastases are present)
  • Calculated creatinine clearance ≥ 60 mL/min
  • Urine dipstick for proteinuria < 2+
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception during and for 12 months after completion of study therapy
  • Must be compliant and have geographic proximity to allow proper staging and follow-up
  • No active bleeding, including hemoptysis ≥ grade 2 (defined as bright red blood of ≥ 5 mL per episode within the past 4 weeks)

    • Minor hemoptysis is allowed
  • No prior malignancy within the past 5 years, except adequately treated cervical carcinoma in situ or localized non-melanoma skin cancer
  • No psychiatric disorder precluding understanding of information on trial-related topics, giving informed consent, or interfering with compliance for oral drug intake
  • No other medical condition that would impair the ability of the patient to participate in the trial or might preclude therapy with trial drugs, including any of the following:

    • Unstable or uncompensated respiratory, cardiac, hepatic, or renal disease
    • Active infection
    • Uncontrolled diabetes mellitus
    • Uncontrolled arterial hypertension (i.e., BP ≥ 150/100 mm Hg despite optimal medical therapy)
    • History of myocardial infarction in the last 3 months
    • History of hemorrhagic disorders
    • Non-healing wound, ulcer, or bone fracture
    • Significant traumatic injury within the past 28 days
  • No known hypersensitivity to trial drugs or to any other component of the trial drugs

PRIOR CONCURRENT THERAPY:

  • See Disease Characteristics
  • No prior chemotherapy or molecular-targeted therapy for metastatic disease (neoadjuvant or adjuvant chemotherapy allowed if terminated > 6 months ago)
  • No prior radiotherapy to lesion(s) selected for measurement
  • At least 30 days since prior yellow fever vaccination
  • At least 30 days since prior experimental drugs, anticancer therapy, or treatment in a clinical trial
  • More than 28 days since major surgical procedure or open biopsy
  • No concurrent full-dose oral, intravenous, or subcutaneous anticoagulants (low-dose heparin or aspirin [≤ 325 mg p.o. daily] allowed)
  • No concurrent herbal extracts or drugs contraindicated for use with trial drugs
  • No concurrent investigational agents
  • No other concurrent anti-neoplastic or anti-tumor agents, including chemotherapy, immunotherapy, or hormonal anticancer therapy
  • No concurrent Asasantin® (acetylsalicylic acid and dipyridamole) or Plavix® (clopidogrel bisulfate)

Inclusion criteria

  • Before registration, patient must give written informed consent for participation in the trial including tumor biopsy at progression.
  • Patient must have the capability to understand informed consent and information given by the investigator on the trial.
  • Non-small cell lung cancer (NSCLC), predominant non-squamous subtype (adenocarcinoma, bronchioloalveolar carcinoma, and large cell carcinoma) confirmed by the central pathologist in Basel.
  • NSCLC stage IV according to the 7th edition of the TNM classification, including M1a (separate tumor nodule in a contralateral lobe, tumor with pleural nodules or malignant pleural or pericardial effusion) and/or M1b (distant metastasis).
  • Most recent diagnostic biopsy paraffin-embedded or only formalin-fixed and sufficient for further molecular analysis as determined by central pathologist in Basel.
  • EGFR mutation status determined by local or central pathologist in Basel.
  • EDTA blood samples (2 x 5 mL) for translational research projects will be taken before treatment start.
  • WHO performance status 0-1 (see Appendix 4).
  • Age ≥ 18 years and legally competent person.
  • Measurable disease, defined as at least one lesion (outside of irradiated areas) that can be measured in at least one dimension as ≥ 10 mm (≥ 15 mm in case of lymph nodes)according to RECIST v1.1
  • Adequate hematological values: Hemoglobin ≥ 100 g/L, neutrophils ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L
  • Adequate hepatic function: Bilirubin ≤ 1.5 x ULN, ALT and AP ≤ 3 x ULN (≤ 5 x ULN in case of liver metastases)
  • Adequate renal function: Calculated creatinine clearance ≥ 60 mL/min (according to the formula of Cockroft-Gault)
  • Urine dipstick for proteinuria < 2+
  • Women are not breastfeeding. Women with child-bearing potential are using effective contraception (see 9.2.4 and 9.3.5), are not pregnant and agree not to become pregnant during participation in the trial and during the 12 months thereafter. A negative pregnancy test before inclusion into the trial is required for all women with childbearing potential. Men agree not to father a child during participation in the trial or during the 12 months thereafter.
  • Patient compliance and geographic proximity allow proper staging and follow-up.

Exclusion criteria

  • Diagnosis of SCLC, predominantly squamous NSCLC (>50% by central pathology review) or combined SCLC-NSCLC.
  • Patients with intrathoracic tumors invading or abutting major blood vessels.
  • Prior chemotherapy or molecular targeted therapy for metastatic disease, with the exception of neoadjuvant or adjuvant chemotherapy if terminated 6 months before registration. Prior radiotherapy to lesion(s) selected for measurement.
  • CNS metastases by mandatory CT-scan (MRI is acceptable).
  • Anticoagulation, with the exception of low dose heparin or aspirin (≤ 325 mg p.o. daily).
  • Active bleeding, including hemoptysis ≥ grade 2 (defined as bright red blood of at least 5 mL per episode within the last 4 weeks of registration). Minor hemoptysis is allowed.
  • Yellow fever vaccination within the 30 days prior to registration.
  • Previous malignancy within 5 years with the exception of adequately treated cervical carcinoma in situ or localized non-melanoma skin cancer.
  • Psychiatric disorder precluding understanding of information on trial related topics, giving informed consent, or interfering with compliance for oral drug intake.
  • Concurrent treatment with other experimental drugs or other anti-cancer therapy, treatment in a clinical trial within 30 days prior to trial entry.
  • Evidence of other medical condition which would impair the ability of the patient to participate in the trial or might preclude therapy with trial drugs (e.g. unstable or uncompensated respiratory, cardiac, hepatic or renal disease, active infection, uncontrolled diabetes mellitus; uncontrolled arterial hypertension ≥ 150/100 mmHg, history of myocardial infarction in the last 3 months, history of hemorrhagic disorders, non healing wound, ulcer or bone fracture)
  • Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to registration
  • Known hypersensitivity to trial drugs or hypersensitivity to any other component of the trial drugs.
  • Any concomitant drugs contraindicated for use with the trial drugs according to the Swissmedic-approved product information.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01116219

Contacts
Contact: Oliver Gautschi, PD MD +41 41 205 58 60 oliver.gautschi@luks.ch

Locations
Switzerland
Kantonsspital Aarau Recruiting
Aarau, Switzerland, CH-5001
Contact: Christoph Mamot, MD    +41 62 838 60 64    christoph.mamot@ksa.ch   
Principal Investigator: Christoph Mamot, MD         
Kantonsspital Baden Recruiting
Baden, Switzerland, 5404
Contact: Clemens Caspar, MD    +41 56 486 25 11    clemens.caspar@ksb.ch   
Principal Investigator: Caspar Clemens, MD         
Clinical Cancer Research Center at University Hospital Basel Recruiting
Basel, Switzerland, CH-4031
Contact: Alfred Zippelius, Prof.    +41 61 265 50 74    AZippelius@uhbs.ch   
Principal Investigator: Alfred Zippelius, MD         
Saint Claraspital AG Recruiting
Basel, Switzerland, CH-4016
Contact: Christian U. Ludwig, MD    41-61-685-8470    christian.ludwig@claraspital.ch   
Principal Investigator: Christian U. Ludwig, MD         
Istituto Oncologico della Svizzera Italiana - Ospedale San Giovanni Recruiting
Bellinzona, Switzerland, CH-6500
Contact: Patrizia Froesch, MD    +41 91 811 48 40    patrizia.froesch@eoc.ch   
Principal Investigator: Patrizia Froesch, MD         
Inselspital Bern Recruiting
Bern, Switzerland, CH-3010
Contact: Adrian Ochsenbein, Prof.    +41 31 632 81 69    adrian.ochsenbein@sec.insel.ch   
Principal Investigator: Adrian Ochsenbein, MD         
Spitalzentrum Biel Recruiting
Biel, Switzerland, CH-2501
Contact: Markus Borner, MD    41-32-324-3714    markus.borner@spital-biel.ch   
Principal Investigator: Markus Borner, MD         
Kantonsspital Bruderholz Recruiting
Bruderholz, Switzerland, CH-4101
Contact: Lorenz M. Jost, MD    41-61-436-3636    lorenz.jost@ksbh.ch   
Principal Investigator: Lorenz M. Jost, MD         
Kantonsspital Graubuenden Recruiting
Chur, Switzerland, CH-7000
Contact: Richard Cathomas, MD    +41 81 256 66 95    richard.cathomas@ksgr.ch   
Principal Investigator: Richard Cathomas, MD         
Kantonsspital Freiburg Recruiting
Freiburg, Switzerland, 1700
Contact: Daniel Betticher, MD    +41 26 426 72 40    betticherd@h-fr.ch   
Principal Investigator: Daniel Betticher, MD         
Hopital Cantonal Universitaire de Geneve Recruiting
Geneva, Switzerland, CH-1211
Contact: Nicolas Mach    41-22-372-9858    nicolas.mach@hcuge.ch   
Principal Investigator: Nicolas Mach, MD         
Centre Pluridisciplinaire d' Oncologie Recruiting
Lausanne, Switzerland, 1011
Contact: Solange Peters    41-21-314-0737    solange.peters@chuv.ch   
Principal Investigator: Solange Peters, MD         
Kantonsspital Liestal Recruiting
Liestal, Switzerland, CH-4410
Contact: Andreas Lohri, MD    41-61-925-2710    andreas.lohri@ksli.ch   
Principal Investigator: Andreas Lohri, MD         
Kantonsspital Luzern Recruiting
Luzerne, Switzerland, CH-6000
Contact: Oliver Gautschi, PD MD    +41 41 205 58 60    oliver.gautschi@luks.ch   
Principal Investigator: Oliver Gautschi, MD         
Kantonsspital Olten Recruiting
Olten, Switzerland, 4600
Contact: Catrina Uhlmann Nussbaum, MD    +41 62 311 42 41    cuhlmann_ol@spital.ktso.ch   
Principal Investigator: Catrina Uhlmann Nussbaum, MD         
Kantonsspital - St. Gallen Recruiting
St. Gallen, Switzerland, CH-9007
Contact: Martin Früh, MD    +41 71 494 10 68    martin.frueh@kssg.ch   
Principal Investigator: Martin Früh, MD         
Regionalspital Recruiting
Thun, Switzerland, 3600
Contact: Daniel Rauch, MD    +41 33 226 26 45    daniel.rauch@spitalstsag.ch   
Principal Investigator: Daniel Rauch, MD         
Spital Uster Recruiting
Uster, Switzerland, 8610
Contact: Georg Tscherry, MD    +41 44 911 11 11    georg.tscherry@spitaluster.ch   
Principal Investigator: Georg Tscherry, MD         
Kantonsspital Winterthur Recruiting
Winterthur, Switzerland, CH-8401
Contact: Miklos Pless, MD    41-52-266-4520    miklos.pless@ksw.ch   
Principal Investigator: Miklos Pless, MD         
City Hospital Triemli Recruiting
Zurich, Switzerland, CH-8063
Contact: Daniel Reding, MD    +41 44 466 11 11    daniel.reding@triemli.stzh.ch   
Principal Investigator: Daniel Reding, MD         
UniversitaetsSpital Zuerich Recruiting
Zurich, Switzerland, CH-8044
Contact: Rolf A. Stahel, Prof.    +41 44 634 28 71    rolf.stahel@usz.ch   
Principal Investigator: Rolf A. Stahel, MD         
Onkozentrum Hirslanden Recruiting
Zürich, Switzerland, 8008
Contact: Thomas von Briel, MD    +41 44 387 21 11    vonbriel@onkozentrum.ch   
Principal Investigator: Thomas von Briel, MD         
Sponsors and Collaborators
Swiss Group for Clinical Cancer Research
Investigators
Study Chair: Oliver Gautschi, MD Luzerner Kantonsspital
Principal Investigator: Adrian Ochsenbein, MD University Hospital Inselspital, Berne
Principal Investigator: Nicolas Mach, MD Hopital Cantonal Universitaire de Geneve HUG
Principal Investigator: Sacha Rothschild, MD University Hospital, Basel, Switzerland
  More Information

Additional Information:
No publications provided

Responsible Party: Swiss Group for Clinical Cancer Research
ClinicalTrials.gov Identifier: NCT01116219     History of Changes
Other Study ID Numbers: SAKK 19/09, SWS-SAKK-19-09, EU-21026
Study First Received: April 27, 2010
Last Updated: December 8, 2013
Health Authority: Switzerland: Swissmedic

Keywords provided by Swiss Group for Clinical Cancer Research:
adenocarcinoma of the lung
bronchoalveolar cell lung cancer
large cell lung cancer
stage IV non-small cell lung cancer
recurrent non-small cell lung cancer

Additional relevant MeSH terms:
Carcinoma, Non-Small-Cell Lung
Lung Neoplasms
Carcinoma, Bronchogenic
Bronchial Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Pemetrexed
Bevacizumab
Cisplatin
Erlotinib
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Radiation-Sensitizing Agents
Physiological Effects of Drugs
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Folic Acid Antagonists
Antimetabolites, Antineoplastic
Antimetabolites
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors
Protein Kinase Inhibitors

ClinicalTrials.gov processed this record on April 14, 2014