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Bevacizumab or Pemetrexed Dis...

Bevacizumab or Pemetrexed Disodium Alone or In Combination After Induction Therapy in Treating Patients With Advanced Non-Squamous Non-Small Cell Lung Cancer

Last Updated: 2023-07-07

Study Results

Results available

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE3

Total Enrollment

1516 participants

Study Classification

INTERVENTIONAL

Study Start Date

2010-10-25

Study Completion Date

2021-08-17

Brief Summary

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RATIONALE: Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. 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. Bevacizumab may also stop the growth of non-small cell lung cancer by blocking blood flow to the tumor. Pemetrexed disodium may stop the growth of tumor cells by blocking some enzymes needed for cell growth. It is not yet known whether giving bevacizumab or pemetrexed disodium alone or in combination is more effective in treating non-squamous non-small cell lung cancer.

PURPOSE: This randomized phase III trial is studying bevacizumab and pemetrexed disodium alone or in combination after induction therapy to see how well they work in treating patients with advanced non-squamous non-small cell lung cancer.

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Detailed Description

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OBJECTIVES:

Primary

* To compare the overall survival (OS) of patients with advanced non-squamous non-small cell lung cancer (NSCLC) treated with maintenance therapy with bevacizumab vs pemetrexed disodium vs bevacizumab and pemetrexed disodium following induction therapy.

Secondary

* To determine the response rate in patients treated with these regimens.
* To evaluate the progression-free survival (PFS) of patients treated with these regimens.
* To define the toxicity of these regimens in these patients.
* To determine the frequency of polymorphisms in VEGF 3578 AA, 1154 AA, ABCB1 G2677TT/AA, and ERCC-118 TT in patients treated with induction therapy comprising paclitaxel, carboplatin and bevacizumab and determine the association between genotypes and response rate.
* To determine the association between bevacizumab and pemetrexed disodium population pharmacokinetics and patient-specific covariate with bevacizumab or pemetrexed disodium toxicity.
* To determine the frequency of TSER\*3 polymorphisms in NSCLC and the association between TSER polymorphisms and benefit from pemetrexed disodium.
* To evaluate TS and ERCC1 expression by RT-PCR and MTAP mutations in existing tumor specimens as a predictor of pemetrexed disodium response.
* To evaluate polymorphisms within CYPs 2C8, 3A4, 3A5 and/or the UGT1A1 collectively or monogenically as markers for variation in efficacious and/or toxic response of individuals to treatment with taxanes.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to gender (male vs female), stage of disease (IIIB-T4Nx \[with nodule in ipsilateral lung lobe and not candidate for combined chemotherapy and radiation\] and IV M1a vs IV M1b vs recurrent), best response to first-time therapy (complete response/partial response vs stable disease), and smoking status (never vs smoker).

* Induction therapy (Arm I): Patients receive paclitaxel IV over 3 hours, carboplatin IV over 15-30 minutes, and bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
* Maintenance Therapy: Patients achieving complete response, partial response or stable disease following induction therapy are randomized to 1 of 3 treatment arms. Treatment begins within 6 weeks of the last day of induction chemotherapy administration.

* Arm A: Patients receive bevacizumab IV over 30-90 minutes on day 1.
* Arm B: Patients receive pemetrexed disodium IV over 10 minutes on day 1.
* Arm C: Patients receive bevacizumab as in arm A and pemetrexed as in arm B. In all arms, courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Some patients undergo blood sample collection at baseline and periodically during study for correlative studies.

After completion of study therapy, patients are followed up every 3 months for 2 years and then every 6 months for 2-5 years.

Conditions

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Lung Cancer

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Arm A (Induction then Maintenance with Bevacizumab)

Induction Therapy:

Patients receive paclitaxel IV over 3 hours, carboplatin IV over 15-30 minutes, and bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

Maintenance Therapy:

Patients achieving complete response, partial response or stable disease following induction therapy are randomized to 1 of 3 treatment arms. Patients in arm A receive bevacizumab IV over 30-90 minutes on day 1 of every cycle until progression or unacceptable toxicity.

Group Type EXPERIMENTAL

Paclitaxel

Intervention Type DRUG

Given IV

Carboplatin

Intervention Type DRUG

Given IV

Bevacizumab

Intervention Type BIOLOGICAL

Given IV

Arm B (Induction then Maintenance with Pemetrexed)

Induction Therapy:

Patients receive paclitaxel IV over 3 hours, carboplatin IV over 15-30 minutes, and bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

Maintenance Therapy:

Patients achieving complete response, partial response or stable disease following induction therapy are randomized to 1 of 3 treatment arms. Patients in arm B receive pemetrexed IV over 10 minutes on day 1 of every cycle until progression or unacceptable toxicity.

Group Type EXPERIMENTAL

Paclitaxel

Intervention Type DRUG

Given IV

Carboplatin

Intervention Type DRUG

Given IV

Bevacizumab

Intervention Type BIOLOGICAL

Given IV

Pemetrexed Disodium Heptahydrate

Intervention Type DRUG

Given IV

Arm C (Induction then Maintenance with Bevacizumab & Pemetrexed)

Induction Therapy:

Patients receive paclitaxel IV over 3 hours, carboplatin IV over 15-30 minutes, and bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

Maintenance Therapy:

Patients achieving complete response, partial response or stable disease following induction therapy are randomized to 1 of 3 treatment arms. Patients in arm C receive bevacizumab as in arm A and pemetrexed as in arm B.

Group Type EXPERIMENTAL

Paclitaxel

Intervention Type DRUG

Given IV

Carboplatin

Intervention Type DRUG

Given IV

Bevacizumab

Intervention Type BIOLOGICAL

Given IV

Pemetrexed Disodium Heptahydrate

Intervention Type DRUG

Given IV

Interventions

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Paclitaxel

Given IV

Intervention Type DRUG

Carboplatin

Given IV

Intervention Type DRUG

Bevacizumab

Given IV

Intervention Type BIOLOGICAL

Pemetrexed Disodium Heptahydrate

Given IV

Intervention Type DRUG

Other Intervention Names

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Taxol NSC 673089 carboplatin for injection or platinum diamine [1,1-cyclobutane-decarbozxylate (2-0,0')-,(SP-4-2)] NSC 704865 RhuMAb VEGF Recombinant Humanized Monoclonal Anti-VEGF Antibody L-Glutamic acid N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]- disodium salt heptahydrate

Eligibility Criteria

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Inclusion Criteria

* Cytologically or histologically confirmed non-small cell lung cancer (NSCLC)
* Predominant non-squamous histology (NSCLC not otherwise specified allowed). Mixed tumors are categorized by the predominant cell type.
* Stage IV disease including M1a or M1b stages or recurrent disease
* Stage IIIB (T4NX) disease with ipsilateral lung lobe allowed provided patients are not candidates for combined chemotherapy or radiotherapy
* At least 12 months since prior adjuvant chemotherapy
* At least 2 weeks since prior radiotherapy
* Prior carboplatin allowed provided it was given as part of adjuvant chemotherapy
* Patients with brain metastasis must have received local therapy to the brain and have no evidence of progression in the brain for at least 2 weeks from the time of completion of local therapy, prior to registration
* ECOG (Eastern Cooperative Oncology Group) performance status 0-1
* Leukocytes ≥ 3,000/mm\^3
* Absolute neutrophil count ≥ 1,500/mm\^3
* Platelet count ≥ 100,000/mm\^3
* Total bilirubin ≤ institutional upper limit of normal (ULN)
* AST and ALT ≤ 3 times ULN
* Creatinine ≤ institutional ULN OR creatinine clearance ≥ 60 mL/min
* Urine protein:urine dipstick ≤ 0-1+ (if \> 1+, urine protein creatinine ratio must be \< 1)
* Measurable or non-measurable disease as defined by RECIST (Response Evaluation Criteria in Solid Tumours) criteria
* Patients with hypertension must be adequately controlled (BP \< 150/100 mm Hg) with appropriate anti-hypertensive therapy or diet
* Concurrent therapeutic anti-coagulation allowed
* Fertile patients must agree to abstain from sexual intercourse or to use adequate contraceptive methods during and for at least 6 months after completion of study therapy

* Patient must have an overall stable or better response after 4 courses of induction therapy
* ECOG (Eastern Cooperative Oncology Group) performance status 0-1
* Patients must be registered to Step 2 within 6 weeks of the last day of chemotherapy administration on Step 1
* Acceptable bone marrow, renal and hepatic function within 2 weeks of registration

Exclusion Criteria

* Prior malignancy within the past 3 years except superficial melanoma, basal cell carcinoma, or carcinoma in situ
* Prior systemic chemotherapy for advanced stage lung cancer
* Prior use of paclitaxel, pemetrexed disodium, or bevacizumab
* Major hemoptysis within the past 4 weeks
* Uncontrolled intercurrent illness including, but not limited to, active infection, symptomatic congestive heart failure, unstable angina pectoris, serious cardiac arrhythmia, psychiatric illness/social situations that would limit compliance with study requirements
* History of arterial thrombotic events or major bleeding within the past 12 months
* Major surgery such as thoracotomy, laparotomy, craniotomy, or significant traumatic injury within 6 weeks prior to registration. Biopsy procedures and chest tube insertion are not considered major surgery for the purpose of this protocol.
* Core biopsy within 7 days of registration
* Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within the past 6 months
* Clinically significant cardiovascular disease
* Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months
* History of serious non-healing wounds, ulcers, or bone fractures
* Cavitary lesions in the lungs
* Pregnant or nursing
* Concurrent anti-retroviral therapy in patients with HIV infection

Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Suresh Ramalingam, MD

Role: STUDY_CHAIR

Emory University

Locations

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Regional Medical Center

Anniston, Alabama, United States

Site Status

Fairbanks Cancer Treatment Center at Fairbanks Memorial Hospital

Fairbanks, Alaska, United States

Site Status

North Bay Cancer Center

Fairfield, California, United States

Site Status

Todd Cancer Institute at Long Beach Memorial Medical Center

Long Beach, California, United States

Site Status

Community Hospital of the Monterey Peninsula Comprehensive Cancer Center

Monterey, California, United States

Site Status

Veterans Affairs Medical Center - Palo Alto

Palo Alto, California, United States

Site Status

Feather River Hospital Cancer Center

Paradise, California, United States

Site Status

Sutter Cancer Center at Roseville Medical Center

Roseville, California, United States

Site Status

Sutter Cancer Center

Sacramento, California, United States

Site Status

Salinas Valley Memorial Hospital

Salinas, California, United States

Site Status

Stanford Cancer Center

Stanford, California, United States

Site Status

Aurora Presbyterian Hospital

Aurora, Colorado, United States

Site Status

Boulder Community Hospital

Boulder, Colorado, United States

Site Status

Penrose Cancer Center at Penrose Hospital

Colorado Springs, Colorado, United States

Site Status

St. Anthony Central Hospital

Denver, Colorado, United States

Site Status

Kaiser Permanente - Denver

Denver, Colorado, United States

Site Status

Porter Adventist Hospital

Denver, Colorado, United States

Site Status

Presbyterian - St. Luke's Medical Center

Denver, Colorado, United States

Site Status

St. Joseph Hospital

Denver, Colorado, United States

Site Status

Rose Medical Center

Denver, Colorado, United States

Site Status

CCOP - Colorado Cancer Research Program

Denver, Colorado, United States

Site Status

Swedish Medical Center

Englewood, Colorado, United States

Site Status

Poudre Valley Hospital

Fort Collins, Colorado, United States

Site Status

Front Range Cancer Specialists

Fort Collins, Colorado, United States

Site Status

North Colorado Medical Center

Greeley, Colorado, United States

Site Status

Kaiser Permanente - Lafayette

Lafayette, Colorado, United States

Site Status

Littleton Adventist Hospital

Littleton, Colorado, United States

Site Status

Sky Ridge Medical Center

Lone Tree, Colorado, United States

Site Status

Hope Cancer Care Center at Longmont United Hospital

Longmont, Colorado, United States

Site Status

McKee Medical Center

Loveland, Colorado, United States

Site Status

Parker Adventist Hospital

Parker, Colorado, United States

Site Status

St. Mary - Corwin Regional Medical Center

Pueblo, Colorado, United States

Site Status

North Suburban Medical Center

Thornton, Colorado, United States

Site Status

Exempla Lutheran Medical Center

Wheat Ridge, Colorado, United States

Site Status

Praxair Cancer Center at Danbury Hospital

Danbury, Connecticut, United States

Site Status

Helen and Harry Gray Cancer Center at Hartford Hospital

Hartford, Connecticut, United States

Site Status

Saint Francis/Mount Sinai Regional Cancer Center at Saint Francis Hospital and Medical Center

Hartford, Connecticut, United States

Site Status

George Bray Cancer Center at the Hospital of Central Connecticut - New Britain Campus

New Britain, Connecticut, United States

Site Status

Kaiser Permanente at Capitol Hill Medical Center

Washington D.C., District of Columbia, United States

Site Status

Sibley Memorial Hospital

Washington D.C., District of Columbia, United States

Site Status

Veterans Affairs Medical Center - Washington, DC

Washington D.C., District of Columbia, United States

Site Status

North Broward Medical Center

Deerfield Beach, Florida, United States

Site Status

Michael and Dianne Bienes Comprehensive Cancer Center at Holy Cross Hospital

Fort Lauderdale, Florida, United States

Site Status

Broward General Medical Center Cancer Center

Fort Lauderdale, Florida, United States

Site Status

Memorial Cancer Institute at Memorial Regional Hospital

Hollywood, Florida, United States

Site Status

Ella Milbank Foshay Cancer Center at Jupiter Medical Center

Jupiter, Florida, United States

Site Status

CCOP - Mount Sinai Medical Center

Miami Beach, Florida, United States

Site Status

Florida Hospital Cancer Institute at Florida Hospital Orlando

Orlando, Florida, United States

Site Status

Sacred Heart Cancer Center at Sacred Heart Hospital

Pensacola, Florida, United States

Site Status

Sacred Heart Medical Oncology

Pensacola, Florida, United States

Site Status

Cleveland Clinic Florida - Weston

Weston, Florida, United States

Site Status

Phoebe Cancer Center at Phoebe Putney Memorial Hospital

Albany, Georgia, United States

Site Status

Winship Cancer Institute of Emory University

Atlanta, Georgia, United States

Site Status

Veterans Affairs Medical Center - Atlanta (Decatur)

Decatur, Georgia, United States

Site Status

Nancy N. and J. C. Lewis Cancer and Research Pavilion at St. Joseph's/Candler

Savannah, Georgia, United States

Site Status

Pearlman Comprehensive Cancer Center at South Georgia Medical Center

Valdosta, Georgia, United States

Site Status

Saint Alphonsus Cancer Care Center at Saint Alphonsus Regional Medical Center

Boise, Idaho, United States

Site Status

Mountain States Tumor Institute at St. Luke's Regional Medical Center

Boise, Idaho, United States

Site Status

Saint Luke's Mountain States Tumor Institute - Fruitland

Fruitland, Idaho, United States

Site Status

St. Joseph Regional Medical Center

Lewiston, Idaho, United States

Site Status

Mountain States Tumor Institute - Meridian

Meridian, Idaho, United States

Site Status

Saint Luke's Mountain States Tumor Institute

Nampa, Idaho, United States

Site Status

Mountain States Tumor Institute at St. Luke's

Twin Falls, Idaho, United States

Site Status