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).

NCT ID: NCT01116219

Last Updated: 2019-05-15

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 149 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-06-30
• Study Completion Date: 2016-05-31

Brief Summary

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.

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.

Conditions

Lung Cancer

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Stratum mut EGFR

• Bevacizumab 7.5 mg/kg i.v. every 3 weeks and
• Erlotinib 150 mg p.o. daily until progression.

Group Type: ACTIVE_COMPARATOR

bevacizumab, erlotinib

Intervention Type: BIOLOGICAL

• Bevacizumab 7.5 mg/kg i.v. every 3 weeks and
• Erlotinib 150 mg p.o. daily until progression.

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.

Group Type: ACTIVE_COMPARATOR

bevacizumab, pemetrexed, cisplatin

Intervention Type: DRUG

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.

Interventions

bevacizumab, erlotinib

• Bevacizumab 7.5 mg/kg i.v. every 3 weeks and
• Erlotinib 150 mg p.o. daily until progression.

Intervention Type: BIOLOGICAL

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.

Intervention Type: DRUG

Other Intervention Names

bevacizumab (Avastin); erlotinib (Tarceva); Bevacizumab (Avastin); pemetrexed (Alimta)

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Swiss Cancer Institute

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Oliver Gautschi, MD

Role: STUDY_CHAIR

Luzerner Kantonsspital

Adrian Ochsenbein, MD

Role: PRINCIPAL_INVESTIGATOR

Insel Gruppe AG, University Hospital Bern

Nicolas Mach, MD

Role: PRINCIPAL_INVESTIGATOR

Hopital Cantonal Universitaire de Geneve HUG

Sacha Rothschild, MD

Role: PRINCIPAL_INVESTIGATOR

University Hospital, Basel, Switzerland

Locations

Kantonsspital Aarau

Aarau, , Switzerland

Kantonsspital Baden

Baden, , Switzerland

Saint Claraspital AG

Basel, , Switzerland

Clinical Cancer Research Center at University Hospital Basel

Basel, , Switzerland

Istituto Oncologico della Svizzera Italiana - Ospedale San Giovanni

Bellinzona, , Switzerland

Inselspital Bern

Bern, , Switzerland

Spitalzentrum Biel

Biel, , Switzerland

Kantonsspital Bruderholz

Bruderholz, , Switzerland

Kantonsspital Graubuenden

Chur, , Switzerland

Kantonsspital Freiburg

Fribourg, , Switzerland

Hopital Cantonal Universitaire de Geneve

Geneva, , Switzerland

Centre Pluridisciplinaire d' Oncologie

Lausanne, , Switzerland

Kantonsspital Liestal

Liestal, , Switzerland

Kantonsspital Luzern

Luzerne, , Switzerland

Kantonsspital Olten

Olten, , Switzerland

Kantonsspital - St. Gallen

Sankt Gallen, , Switzerland

Regionalspital

Thun, , Switzerland

Spital Uster

Uster, , Switzerland

Kantonsspital Winterthur

Winterthur, , Switzerland

Onkozentrum Hirslanden

Zurich, , Switzerland

UniversitaetsSpital Zuerich

Zurich, , Switzerland

City Hospital Triemli

Zurich, , Switzerland

Countries

Switzerland

References

Gautschi O, Rothschild SI, Li Q, Matter-Walstra K, Zippelius A, Betticher DC, Fruh M, Stahel RA, Cathomas R, Rauch D, Pless M, Peters S, Froesch P, Zander T, Schneider M, Biaggi C, Mach N, Ochsenbein AF; Swiss Group for Clinical Cancer Research. Bevacizumab Plus Pemetrexed Versus Pemetrexed Alone as Maintenance Therapy for Patients With Advanced Nonsquamous Non-Small-cell Lung Cancer: Update From the Swiss Group for Clinical Cancer Research (SAKK) 19/09 Trial. Clin Lung Cancer. 2017 May;18(3):303-309. doi: 10.1016/j.cllc.2016.11.007. Epub 2016 Nov 23.

Reference Type: RESULT

PMID: 27993482 (View on PubMed)

Other Identifiers

SWS-SAKK-19-09

Identifier Type: -

Identifier Source: secondary_id

EU-21026

Identifier Type: -

Identifier Source: secondary_id

SAKK 19/09

Identifier Type: -

Identifier Source: org_study_id