• Toxicity (Phase I)
• Overall Survival (phase II) [ Time Frame: One year ]

• Dose Limiting Toxicity (Phase I) [ Time Frame: Start of therapy to initiation of first consolidation chemotherapy cycle ]
• Response Rate (RECIST)
• Time to disease progression
• Progression free survival [ Time Frame: 1, 2 and 3 years ]
• Site of first failure
• Local control [ Time Frame: 1, 2 and 3 years ]
• Overall survival [ Time Frame: 2 and 3 years ]

The purpose of this study is to determine the safety and efficacy of the combination of pemetrexed and cisplatin given concurrently with high dose radiation treatment in patients with unresectable but potentially curable stage IIIA/B non-small cell lung cancer.

Concurrent chemoradiation is the accepted standard of care for most patients with unresectable stage III A/B non-small cell lung cancer (NSCLC) but no standard chemotherapy regimen or schedule has yet been established.

Cisplatin, combined with a third generation agent, provides the greatest activity in advanced NSCLC but, to date, no third generation agent has been shown to be tolerable at full dose in combination with radiotherapy (RT) and cisplatin. Pemetrexed/cisplatin (PemC) has shown promising activity in the advanced disease setting and full dose pemetrexed combined with RT or RT/carboplatin appears tolerable. This study was therefore designed to find the maximum tolerable dose of concurrent pemetrexed and cisplatin delivered concurrently with radiation, determine the recommended phase II dose of this regimen and then assess its efficacy in a phase II trial.

• Procedure: Radiotherapy
• Drug: Pemetrexed
• Drug: Cisplatinum

Inclusion Criteria:

1. Histologically or cytologically non-small cell lung cancer (adenocarcinoma, non-lobar and non-diffuse bronchioloalveolar cell carcinoma, large cell carcinoma, or squamous cell carcinoma) by mediastinoscopic or cytology. Patients must be inoperable stage IIIA/B, except those IIIB patients with malignant pleural/pericardial effusions (who are excluded). Stage III status should be based on mediastinoscopy (preferable) or enlarged (≥ 1.5 cm) mediastinal nodes on CT or appropriate imaging (CT/MR) for the delineation of T4 disease.
2. ECOG performance status 0 to 1 <5% weight loss over the preceding 3 months.
3. Evaluable disease
4. Age >18 years.
5. Deemed fit for full dose concurrent PC/RT based on participating medical and radiation oncologist assessment.
6. Patients must not have disease that is currently amenable to surgery.
7. Exploratory thoracotomy, mediastinoscopy, excisional biopsy or similar surgery for determining diagnosis, stage, or potential resectability of newly diagnosed lung tumor is allowed.
8. Forced expiratory volume in one second (FEV1) ≥ 1.3 L. Patients with FEV1 between 1.0 and 1.3 L may be entered in this trial following discussion with one of the principal investigators.

9. Patients must have blood tests done within 14 days of the first cycle of chemotherapy indicating normal organ and marrow function as defined below (ULN = upper limit of normal based on institutional policy):

   • Leukocytes ≥ 3.0 x 10^9/L
   • absolute neutrophil count ≥ 1.5 x 10^9/L
   • platelets ≥ 100 x 10^9/L
   • hemoglobin > 100 g/L
   • calcium < 1.2 x ULN
   • bilirubin < 1.5 x ULN
   • liver transaminases < 1.5 x ULN
   • calculated creatinine clearance ≥ 45mL/min as determined by the Cockroft-Gault formula
10. Signed informed consent from the patient or legal representative.

11. Women must be surgically sterile or postmenopausal, or use a medically approved contraceptive regimen during and for 3 months after treatment. Women of childbearing potential must have a negative serum pregnancy test within 14 days of initial chemotherapy and must not be lactating.

    Exclusion Criteria:

12. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
13. Patients may not be receiving any other investigational agents concurrently or within 30 days of study entry.
14. Previous thoracic radiation therapy.
15. Any prior chemotherapy.

16. Concurrent cancer from another primary site requiring treatment of any kind within the past 5 years.

    Patients cannot have had either breast cancer or melanoma even if more than 5 years previously. Curatively treated non-melanoma skin cancer or in situ carcinoma of the cervix are allowed.

17. Pregnant, breast feeding or unwilling to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation.
18. Because patients with immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy, HIV-positive patients are excluded from the study.
19. Unable to interrupt nonsteroidal anti-inflammatory drugs for at least 2 days (5 days for long-acting agents [e.g., piroxicam]) before, during, and for at least 2 days after administration of pemetrexed. Patients may use low to moderate doses of acetylsalicylic acid (up to 325 mg orally every 6 hours).
20. Unable/unwilling to take folic acid, vitamin B12 or dexamethasone.
21. Unable to understand or unwilling to sign a written informed consent document
22. Patients who, in the opinion of the investigator, are unsuitable in any other way to participate in the study.