Phase II Study Alimta and Gemzar + Avastin as First Line Chemotherapy for Elderly Patients With Stage IIIB/IV NSCLC

• Time to Progression (TTP) [ Time Frame: TTP was measured from day 1 of treatment until time of progression (assessed every 8 weeks), assessed up to 15 months. ] [ Designated as safety issue: No ]
  Time to progression is defined as the time from treatment start until objective tumor progression. Progression is defined per RECIST criteria v1.0 as a measurable increase in the smallest diameter of any target lesion, progression of existing non-target lesions, or the appearance of 1 or more new lesions. The median time to progression is the parameter used to describe TTP.
• Overall Survival (OS) [ Time Frame: OS was measured from day 1 of treatment until time of death, assessed up to 20 months. ] [ Designated as safety issue: No ]
  Overall survival is defined as the time from treatment start until death from any cause. The median overall survival time is used to measure OS.
• Overall Response [ Time Frame: Response to treatment was assessed after every 8 weeks of treatment, up to 50 weeks. ] [ Designated as safety issue: No ]
  Response was evaluated via changes from baseline in radiological tumor measurements performed after every 4th treatment cycle and at the end of treatment or time of progression. Response was evaluated using RECIST version 1.0 guidelines, where complete response (CR) is the disappearance of all target lesions; partial response (PR) is >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD) is neither sufficient shrinkage in sum of LD of target lesions to be PR nor increase of >=20%; Progressive Disease (PD) is the increase in existing lesions or new lesions.

The primary objective is to determine the progression free survival with pemetrexed, and gemcitabine plus bevacizumab as first-line chemotherapy in elderly patients with Stage IIIB/IV non-small cell lung cancer (NSCLC).

The secondary objectives are to determine the overall response rate; overall survival; chemotherapy induced toxicity profile of this combination; time to progression; and patient reported symptom burden.

Inclusion Criteria:

• Patient provides voluntary written informed consent before performance of any study-related procedure not part of normal medical care.
• Patient ≥ 65 years of age with ECOG of 0 to 1
• Patient must have histologically/cytologically confirmed Stage IIIB/IV NSCLC.
• Patient has measurable disease defined as at least 1 lesion that can be accurately measured in at least 1 dimension (by CT or MRI) & used to assess response as defined by RECIST criteria. Tumors within a previously irradiated field will be designated nontarget lesions.
• Patient has not received radiotherapy within 2 weeks(4 weeks required for brain metastases radiotherapy)of initial chemotherapy dosing for this study, and all acute toxicities due to prior radiotherapy have resolved prior to initial chemotherapy dosing.
• Patient has a negative serum pregnancy test or has undergone hysterectomy at time of enrollment.
• Greater than 12 weeks life expectancy.
• Patient has recovered from any recent surgery for at least 30 days & is free of active infection requiring antibiotics.
• Patient must be willing/able to discontinue use of NSAIDS prior to study drug dosing.
• Patient must be able to take folic acid, Vitamin B12, & dexamethasone per protocol.
• Patient must exhibit no greater than Grade 1 peripheral neuropathy.

Exclusion Criteria:

• Prior systemic or other concurrent chemo for metastatic NSCLC(Prior Tarceva is not allowed).Prior adjuvant chemo acceptable as long as > 12 months since completion and no prior pemetrexed, gemcitabine or bevacizumab.
• Lung carcinoma of squamous cell histology(mixed tumors will be categorized by the predominant cell type unless small cell elements are present, in which case the patient is ineligible; sputum cytology alone is acceptable.Patients with extrathoracic-only squamous cell NSCLC are eligible.Patients with only peripheral lung lesions (of any NSCLC histology) will also be eligible(a peripheral lesion is defined as a lesion in which the epicenter of the tumor is ≤ 2 cm from the costal or diaphragmatic pleura in a three-dimensional orientation based on each lobe of the lung and is > 2 cm from the trachea, main, and lobar bronchi).
• Hemoptysis within 1 month prior to study enrollment
• Ongoing treatment with full-dose warfarin or its equivalent i.e., unfractionated and/or low molecular weight heparin.(Low dose warfarin 1 mg given for prophylaxis is allowed).
• Hypersensitivity to any component of Alimta, gemcitabine &/or bevacizumab, &/or cannot tolerate folic acid, corticosteroids or Vitamin B12 supplements.
• Currently/have recently taken long-acting NSAID (Ibuprofen ≤ 400 mg QID acceptable) or aspirin (>325mg/day) within 5 days of initial pemetrexed administration.
• Clinically significant pericardial/pleural effusion or ascites unless able to be drained before study entry.
• Presence of third space fluid which cannot be controlled by drainage.
• Core biopsy/other minor surgical procedure(excluding placement of a vascular access device)within 7 days prior to study enrollment.
• Active infection or fever ≥ 38.5°C within 3 days of first scheduled day of protocol treatment.
• Serious, non-healing wound, ulcer, or untreated bone fracture.
• NYHA Grade II or greater CHF
• Inadequately controlled hypertension (defined as systolic blood pressure > 150 &/or diastolic blood pressure > 100mmHg on antihypertensive meds)
• Any prior history of hypertensive crisis or hypertensive encephalopathy.
• History of MI, CVA, TIA, or unstable angina within 6 months of study enrollment.
• Significant vascular disease (aortic aneurysm, aortic dissection or recent peripheral arterial thrombosis.)
• Symptomatic peripheral vascular disease
• Known bleeding diathesis or coagulopathy
• Presence of CNS(central nervous system) except for treated brain metastases. Treated brain metastases are defined as having no evidence of progression or hemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging(MRI or CT)during the screening period.Anticonvulsants(stable dose)are allowed.Treatment for brain metastases may include whole brain radiotherapy(WBRT),radiosurgery(RS;Gamma Knife,LINAC,or equivalent)or a combination as deemed appropriate by the treating physician.Radiotherapy must be completed at least 4 weeks prior to study enrollment and all acute radiotherapy toxicities resolved.Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to Day 1 will be excluded.
• A major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1 or anticipation of need for major surgical procedure during the course of the study.
• Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to enrollment.
• History of prior malignancy within the past 5 years except for curatively treated basal cell carcinoma of the skin, cervical intra-epithelial neoplasia, or localized prostate cancer with a current prostate specific antigen of < 1.0 mg/dL on 2 successive evaluations, at least 3 months apart, with the most recent evaluation no more than 4 weeks prior to entry.
• Have received radiotherapy to more than 25% of their bone marrow.
• Receiving concurrent investigational therapy or has received investigational therapy within 30 days of the first scheduled day of protocol treatment
• Pregnant/lactating.
• Any other medical condition deemed by the Investigator to be likely to interfere with a patient's ability to sign informed consent, cooperate/participate in the study, or interfere with interpretation of the results.
• History of allogeneic transplant.
• Known HIV infection or Hepatitis B or C.

• Eli Lilly and Company
• Genentech, Inc.