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A Randomized Phase II Trial Comparing Cetuximab With Concurrent Pemetrexed/Cetuximab Therapy for Non-Small Cell Lung Cancer Refractory to Primary Treatment

Phase 2
18 Years
Not Enrolling
Non-small Cell Lung Cancer

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Trial Information

A Randomized Phase II Trial Comparing Cetuximab With Concurrent Pemetrexed/Cetuximab Therapy for Non-Small Cell Lung Cancer Refractory to Primary Treatment

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

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

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) >/=

- Hepatic function: bilirubin /=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.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To determine in patients with NSCLC refractory to previous chemotherapy whether concomitant treatment with cetuximab and pemetrexed improves progression-free survival compared with cetuximab monotherapy.

Outcome Time Frame:

8 weeks, 11 weeks, 14 weeks, 20 weeks, every 6-8 weeks thereafter

Safety Issue:


Principal Investigator

Michael Maitland, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Chicago


United States: Institutional Review Board

Study ID:




Start Date:

March 2005

Completion Date:

November 2009

Related Keywords:

  • Non-Small Cell Lung Cancer
  • Non-small cell lung cancer
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms



The University of ChicagoChicago, Illinois  60637