Pemetrexed, Carboplatin, and Bevacizumab as First-Line Therapy in Treating Older Patients With Stage IIIB or Stage IV Non-Small Cell Lung Cancer

OBJECTIVES:

Primary

- To estimate the progression-free survival at 6 months in elderly patients with advanced
nonsquamous cell non-small cell lung cancer treated with pemetrexed disodium,
carboplatin, and bevacizumab as first-line therapy.

Secondary

- To assess the adverse events profile and safety of this regimen in these patients.

- To estimate the confirmed antitumor response rate, as defined by RECIST criteria, and
the overall survival of these patients.

- To compare the quality of life (QOL) of patients treated with this regimen vs the QOL
of younger patients.

- To correlate QOL with toxicities, as defined by NCI CTCAE v3.0 criteria.

Tertiary

- To evaluate polymorphisms in the genes that encode proteins involved in the cellular
transport, activation, and cytotoxic activity of pemetrexed disodium and evaluate their
relationship with treatment toxicity/efficacy and patient QOL.

- To evaluate polymorphisms in the genes involved in blood pressure regulation and their
relationship with susceptibility to hypertension induced by anti-VEGF therapy.

OUTLINE: This is a multicenter study.

Patients receive pemetrexed disodium IV over 10 minutes, carboplatin IV over 30 minutes, and
bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for up to 6
courses in the absence of disease progression or unacceptable toxicity. Patients with stable
disease or partial or complete response after 6 courses may continue to receive pemetrexed
disodium and bevacizumab every 21 days in the absence of disease progression or unacceptable
toxicity.

Tissue and blood samples are collected at baseline for pharmacogenetic analysis. Blood
samples are used to evaluate functionally relevant polymorphisms in the genes that encode
proteins involved in the transport and activation of pemetrexed disodium and in the genes
that encode proteins involved in susceptibility to hypertension induced by bevacizumab.
Tissue samples are used to evaluate expression and polymorphisms in pemetrexed disodium
target genes (TS, DHFR, and GARFT).

Quality of life is assessed at baseline and periodically during study.

After completion of study therapy, patients are followed periodically for up to 5 years.

DISEASE CHARACTERISTICS:

- Histologically or cytologically confirmed nonsquamous cell non-small cell lung cancer
(NSCLC)

- Stage IIIB (with pleural effusion) or IV disease

- Squamous cell carcinomas not allowed

- Adenosquamous histology allowed

- Clinically significant effusion (e.g., symptomatic pleural effusion or ascites)
allowed provided it is drained before study treatment

- No symptomatic pleural and/or peritoneal effusion (≥ grade 2 dyspnea, as defined
by NCI CTCAE v3.0 criteria) that is not amenable to drainage

- If effusion produces clinically significant measurable objective changes, such
as hypoxia or estimated volume > 500 mL, effusion should be drained even if
asymptomatic

- Measurable disease, defined as ≥ 1 lesion with longest diameter ≥ 2.0 cm by
conventional techniques or ≥ 1.0 cm by spiral CT scan

- If the sole site of disease is in a previously irradiated field, must have
evidence of disease progression/recurrence within the irradiated field OR
presence of a new lesion outside the irradiated field

- No symptomatic, untreated, or uncontrolled CNS metastases

- CNS metastases that were previously treated with whole brain radiotherapy (WBRT)
allowed

- Willing to enroll in NCCTG-N0392

PATIENT CHARACTERISTICS:

- ECOG performance status 0-1

- Life expectancy ≥ 12 weeks

- ANC ≥ 1,500/mm³

- Platelet count ≥ 100,000/mm³

- Hemoglobin ≥ 9 g/dL

- Total bilirubin ≤ 1.5 times upper limit of normal (ULN) OR direct bilirubin normal

- AST and ALT ≤ 3 times ULN (≤ 5 times ULN if liver has tumor involvement)

- Creatinine clearance ≥ 45 mL/min

- Not pregnant or nursing

- Fertile patients must use effective contraception during and for 3 months after
completion of study treatment

- Able to take folic acid, vitamin B_12 supplementation, or dexamethasone

- Able to complete questionnaire(s) alone or with assistance

- Willing to provide biologic specimens as required by the study

- Willing to return to NCCTG participating center for follow-up

- No clinically significant infection

- No serious, nonhealing wounds, ulcers, or bone fractures

- No seizure disorder

- No second primary malignancy within the past 5 years, except for any of the
following:

- Carcinoma in situ of the cervix

- Nonmelanomatous skin cancer

- History of melanoma allowed only if diagnosed and definitively treated ≥ 5
years ago with no subsequent evidence of recurrence

- Low-grade (Gleason score ≤ 6) localized prostate cancer (no nodal involvement)

- Previously treated stage I breast cancer

- No concurrent severe and/or uncontrolled medical condition, including any of the
following:

- Hypertension, labile hypertension, or history of poor compliance with
antihypertensive medication

- Angina pectoris

- Congestive heart failure within the past 3 months, unless ejection fraction >
40%

- Myocardial infarction within the past 6 months

- Cardiac arrhythmia

- Diabetes mellitus

- Interstitial pneumonia or extensive, symptomatic interstitial fibrosis of the
lung

- Active or recent history of hemoptysis > ½ teaspoon per event

- Ongoing or active infection

- Psychiatric illness/social situation that would limit compliance with study
requirements

- No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within
the past 12 months

- No diverticulitis within the past 12 months

- No stroke within the past 6 months

- No significant traumatic injury within the past 8 weeks

- Not at greater than normal risk of bleeding

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- No prior radiotherapy to > 25% of bone marrow

- More than 2 weeks since prior radiotherapy and recovered (alopecia allowed)

- At least 2 weeks since prior WBRT

- At least 3 days since prior gamma knife radiosurgery (without WBRT) for brain
metastases

- More than 4 weeks since prior administration of live or attenuated viral vaccine

- More than 8 weeks since prior major surgery (e.g., laparotomy) or open biopsy (> 4
weeks since minor surgery)

- Insertion of a vascular access device allowed

- No prior chemotherapy or systemic therapy for advanced lung cancer, except
neoadjuvant or adjuvant chemotherapy

- No NSAID's 2 days prior to (5 days for long-acting NSAID's), the day of, and 2 days
following protocol treatment

- More than 12 months since prior neoadjuvant therapy, adjuvant therapy, systemic
chemotherapy, chemoradiotherapy, immunotherapy, or biologic therapy

- No concurrent anticoagulants

- Low-dose warfarin or heparin for deep venous thrombosis prophylaxis allowed