Slow accrual and evidence from other studies showing benefit of early initiation of pemetrexed after first-line therapy

The purpose of the study is to determine in patients with Non Small Cell Lung Cancer refractory to previous chemotherapy whether concomitant treatment with cetuximab and pemetrexed improves progression-free survival compared with cetuximab monotherapy.

While EGFR inhibitors have demonstrated activity against NSCLC [their integration into first-line therapy in combination with standard agents has yielded disappointing results]. There are many potential reasons for the disappointing results in these first-line studies [ A single-arm Phase I trial of cetuximab in combination with docetaxel suggested better efficacy in second-line therapy for NSCLC than docetaxel alone but this comes at the expense of some increased toxicity]. Preliminary data indicate that cetuximab has single agent activity in this setting. The confidence intervals for this activity overlap the median time to progression of the current second-line cytotoxic therapy options compared in the Hanna study [A clinically relevant question is- does concurrent cetuximab and pemetrexed significantly improve upon outcomes of cetuximab monotherapy followed by pemetrexed monotherapy?].

Many patients who receive EGFR inhibitors develop an acneiform rash and the severity of the rash is associated with good outcomes from treatment. Several of these studies have demonstrated no correlation between the intensity or percentage of tumor cells staining for EFUR expression and response to therapy. However, a Phase II study, at the University of Colorado, of cetuximab added to standard first-line treatment of NSCLC revealed 6/10 responders developed the rash within 2 weeks of initiating treatment (Personal Communication, Dugan, et al. BMS). Therefore, early development of rash may be a clinically useful marker of subsequent response and novel approaches to the identification of biological markers for this phenotype prior to initiation of therapy may be helpful in subsequent determination of which patients will most likely benefit from EGFR inhibitor therapy.

To address these issues we propose a phase I randomized study of concurrent pemetrexed/cetuximab compared to sequential cetuximab/pemetrexed therapy for the second-line treatment of advanced NSCLC. Patients will be randomized at study entry. Regarding prospective analysis of the rapid-rash forming phenotype, all patients will receive 2 weeks of initial treatment with cetuximab and undergo formal rash evaluation, serum and skin collection. According to the initial randomization, half of the study subjects will continue with cetuximab monotherapy while the remainder will receive concurrent cetuximab and pemetrexed. The primary study endpoint of freedom from progression and secondary endpoint of objective response rate will be based on the comparison of patients in (he concurrent therapy group with patients treated with cetuximab monotherapy with Day-14 (first receipt of cetuximab) as the reference treatment start date. Overall survival will be analyzed as a secondary endpoint to assess the efficacy of concomitant treatment with cetuximab and pemetrexed compared to sequential treatment with cetuximab followed by pemetrexed upon disease progression. As patients in both treatment arms receive cetuximab, correlative studies will be performed on all enrolled patients. For serum proteomic studies designed to identify a serum polypeptide signature associated with response to cetuximab-based therapy, serum samples shall be collected at enrollment, and just prior to receiving the third dose of cetuximab therapy. To provide the opportunity to perform retrospective pharmacogenomic studies, whole blood DNA will be collected from each patient at enrollment and subsequently analyzed for candidate gene polymorphisms once outcome data is available. Finally, an alternative approach to identification of markers for responsiveness to EGFR inhibition already in progress at the University of Chicago entails collection of skin biopsies before and after treatment with an EGFR inhibitor.

As in ongoing collaborations with the University of Chicago Section of Dermatology, patients in this proposed study will undergo skin biopsies at enrollment and after 2 weeks of cetuximab therapy. The investigators will extract mRNA from the fresh frozen skin specimens and perform microarray studies to test the utility of mRNA expression patterns associated with rash and responsiveness to EOFR inhibitors in currently ongoing investigations at the University of Chicago. Therefore we expect this study: 1) to identify any significant improvement of concurrent cetuximab/pemetrexed therapy for second-line treatment of NSCLC over sequential monotherapy, 2) through timely minimally invasive collection of serum and exposed skin, to provide the opportunity to test previously identified biomarkers for individual responsiveness to cetuximab therapy, and 3) to confirm prospectively whether early development of rash on cetuximab treatment predicts responsiveness to either concurrent or sequential therapy.

Inclusion Criteria:

• Diagnosis of locally advanced or metastatic (Stage III or IV at entry) non-small cell lung cancer (NSCLC) that is not amenable to curative therapy.
• ECOG performance status 0-2
• Patients must have been previously treated with one platinum-containing or taxane-containing chemotherapy regimen for locally advanced or metastatic disease. Patients are also eligible if they have received one platinum-based chemotherapy regimen as neoadjuvant or adjuvant chemotherapy, but must have received an additional chemotherapy regimen upon recurrence.
• No more than two prior systemic anti-cancer therapies will be allowed.
• Prior radiation therapy is allowed to <25% of the bone marrow. Prior radiation to the whole pelvis is not allowed, Prior radiotherapy must be completed at least 2 weeks before study enrollment, and the patient must have recovered from the acute toxic effects of the treatment prior to study enrollment.
• Patients must have signed an approved informed consent.
• Male and female patients with reproductive potential must use an approved contraceptive method if appropriate (eg, intrauterine device, birth control pills, or barrier device) during and for 3 months after the study. Female patients must either not be of child bearing potential or have a negative pregnancy test within 7 days of treatment. Patients are considered not of child bearing potential if they are surgically sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are postmenopausal.
• Age>18
• Measurable disease in accord with RECIST criteria
• Bone marrow Function: absolute neutrophil count (ANC)>/=1,500/ul, platelets >/=l00,000, hemoglobin> 9g/dL
• Renal function: creatinine clearance (calculated by Cockcroft and Gault method) >/= 45mL/min
• Hepatic function: bilirubin </=1.5 x ULN; ALT/AST ,/= 2.5 x ULN; Albumin >/=2.5 g/dL

Exclusion Criteria:

• Prior treatment with pemetrexed
• Prior therapy that targets the EGF pathway.
• Active or uncontrolled infection.
• Significant history of uncontrolled cardiac disease; i.e., uncontrolled hypertension, unstable angina, and congestive heart failure.
• Pleural or pericardial effusions that cannot be completely evacuated prior to pemetrexed therapy.
• Acute hepatitis or known HIV.
• Prior severe infusion reaction to a monoclonal antibody.
• Any concurrent chemotherapy not indicated in the study protocol or any other investigational agent(s).
• Pregnancy or Breast-feeding.
• Second primary malignancy that is clinically detectable at the time of consideration for study enrollment.
• Inability to interrupt aspirin, or other nonsteroidal anti-inflammatory agents for a 5-day period.
• Inability or unwillingness to take folic acid or vitamin B12 supplementation.

Includes evaluable patients (those that received at least 3 doses of cetuximab)

up to 5 years

Serious adverse events of any grade are reported. For all other adverse events, only those grade 3 or higher were collected during the study. Adverse events are reported for the evaluable patients who received at least 3 doses of Cetuximab