Welcome to the October edition of OncoFacts. I am going to be discussing lung cancer protocols as we continue in our series of emerging and important ongoing clinical trials in the United States for different major cancer types.

Lung Cancer Protocols

The American Cancer Society's most recent estimates for lung cancer in the United States for 2009 are:

• 219,440 new cases of lung cancer (both small cell and non-small cell)
• 159,390 deaths from lung cancer

In this presentation for the October 2009 OncoFacts, I will discuss 4 different clinical trials in front-line treatment for patients with stage IIIB and IV non-small cell lung cancer (NSCLC). Following a discussion of these 4 trials, I will be discussing 2 ongoing trials in the adjuvant setting.

Each presentation is formatted to present the reasons behind the initiation of each of the trials, their eligibility criteria, the statistical objectives of the trials, the study schema, and an internet link for further information regarding the trials and locations of institutions conducting the trials.

Reference:
American Cancer Society. Cancer Facts and Figures 2009. Atlanta, GA: American Cancer Society Inc.;2009. Available from: http://www.cancer.org/downloads/STT/500809web.pdf. Accessed October 5, 2009.

First-line treatment for stage IIIb/IV NSCLC

A phase III, randomized, double-blind, placebo-controlled multi-center study of ASA404 in combination with paclitaxel and carboplatin as first-line treatment for locally advanced or metastatic (stage IIIb/IV) NSCLC

Why is this trial being done? ASA404 is a novel tumor-vascular disrupting agent (VDA) that induces irreversible tumor vascular collapse, hemorrhagic necrosis of the tumor core, and cytokine production while enhancing cell-mediated cytotoxicity. ASA404 exhibits synergistic qualities when combined with a carboplatin and paclitaxel chemotherapy regimen in patients with NSCLC. Recently, a randomized phase II trial was conducted to determine ASA404 safety, tolerability, and efficacy in combination with paclitaxel and carboplatin in patients with stage IIIb/IV NSCLC. Seventy-six patients were randomized to receive 1200 mg/m² of ASA404 (N = 36) or placebo (N = 37), and an additional cohort of 31 patients were treated at 1800 mg/m² of ASA404. The best overall response observed as per an independent review was partial response (PR [31%]) compared to standard chemotherapy alone (22%).

Among the patients receiving 1800mg/m², 48% of the patients achieved PR (independent assessment). Median survival time was 14.0 months for the 1200 mg/m² ASA404 group and 8.8 months for the standard chemotherapy group (hazard ratio = 0.73, 95% CI = 0.39 - 1.38). The 1800mg/m² plus standard therapy in 31 patients has shown median OS of 14.9 months (AS1404-201).

This phase III trial is being conducted worldwide in order to demonstrate the safety and efficacy of ASA404 in combination with paclitaxel/carboplatin chemotherapy in the treatment of patients with stage IIIb/IV NSCLC who are eligible for first-line chemotherapy. The study population will consist of patients with NSCLC of all histologies eligible for first-line therapy.

Primary Objective: To compare the overall survival (OS) of patients receiving ASA404 or placebo in combination with paclitaxel and carboplatin for first-line treatment of stage IIIb/IV NSCLC.

Key Secondary Objectives: To compare the OS of patients with nonsquamous NSCLC receiving ASA404 or placebo in combination with paclitaxel and carboplatin and to compare the OS of patients with squamous NSCLC receiving ASA404 or placebo in combination with paclitaxel and carboplatin.

Who is eligible? Patients with newly diagnosed, histologically confirmed, stage IIIb or stage IV non-small cell carcinoma of the lung. No prior systemic antineoplastic treatment is allowed unless as adjuvant or neoadjuvant therapy for stage I/II NSCLC if greater than 12 months from entry onto this trial. Patients are excluded if they have central nervous system (CNS) metastases. Patients must have controlled blood pressure and no recent hemoptysis.

Study Schema: Paclitaxel 200 mg/m² and carboplatin area under the curve (AUC) 6 IV every 3 weeks
Paclitaxel 200 mg/m² and carboplatin AUC 6 IV every 3 weeks plus ASA404 at 1800 mg/m²
Patients will receive a maximum of 6 cycles or until disease progression. After completion of the chemotherapy, patients who have not progressed will continue to receive blinded study drug as maintenance treatment until disease progression.

Statistical Outcomes: In this trial, 1200 patients will be enrolled with the estimated primary completion date being December 2010.

For more information about this trial, please visit ClinicalTrials.gov. Available from: http://www.clinicaltrials.gov/ct2/show/NCT00662597?term=ASA404&rank=3. Accessed October 5, 2009.

Reference:
von Pawel J, Reck M, McKeage M, et al. Update on survival in a phase Ib/II study of DMXAA combined with carboplatin and paclitaxel in non-small cell lung cancer (NSCLC). Eur J Cancer. 2006;4(12):16. Abstract 40 and poster presentation at: 18th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics; Nov 7-10, 2006; Prague, Czech Republic.

Randomized, open-label, phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous NSCLC

Why is this trial being done? American Society of Clinical Oncology (ASCO) guidelines suggest that patients with inoperable NSCLC with a good performance status should be offered induction chemotherapy consisting of 4 to 6 cycles of a platinum-based doublet. A previously published Eastern Cooperative Oncology Group (ECOG) randomized trial comparing 4 platinum doublets concluded that there was no difference in OS and that carboplatin and paclitaxel could be considered a standard upon which to compare new regimens. Subsequently, the addition of bevacizumab to paclitaxel and carboplatin received US Food and Drug Administration (FDA) approval based on an improvement in OS in the front-line setting.

Pemetrexed has been studied as a single agent in the second-line treatment of NSCLC and has also been studied in the front-line in combination with cisplatin for nonsquamous histologies compared to cisplatin and gemcitabine, and a superior OS was again found. Other trials that have been reported and inform this current clinical trial are a phase III trial evaluating the use of pemetrexed as a maintenance therapy following 4 cycles of a non-pemetrexed platinum doublet, and a phase II study of the combination of pemetrexed/carboplatin/bevacizumab followed by pemetrexed and bevacizumab maintenance therapy. Thus, this trial will compare the induction regimens of pemetrexed/carboplatin/bevacizumab to the standard paclitaxel/carboplatin/bevacizumab for patients with advanced nonsquamous NSCLC. Maintenance therapy will also be given in both arms of the study and will compare pemetrexed and bevacizumab in the pemetrexed arm to bevacizumab alone in the paclitaxel arm.

Primary objective: The primary study objective is to compare the OS between the 2 regimens. Secondary objectives include the following: Efficacy including overall response rate, disease control rate (complete response [CR] + partial response [PR] + stable disease [SD]), progression-free survival (PFS), and time to progressive disease. Other secondary objectives include safety, quality of life, pharmacokinetics, and translational research investigating biomarkers relevant to therapy, disease state and clinical outcome.

Who is eligible? Patients must have stage IIIB or stage IV nonsquamous NSCLC. Patients must have received no prior treatment for any stage of this NSCLC. The disease must be measurable or nonmeasurable as defined by RECIST criteria. There are extensive exclusion criteria related to uncontrolled third-space fluid collections, surgery within 28 days, bleeding or coagulopathy.

Study Schema: Patients are randomly assigned to 1 of 2 arms:

Statistical Outcome: The study will enroll approximately 900 patients with the final analysis of OS being performed after 676 deaths. The estimated primary completion date for final data collection for OS is January 2012.

For more information about this trial, please visit ClinicalTrials.gov. Available from: http://www.clinicaltrials.gov/ct2/show/NCT00762034?term=
lung+cancer+and+jmhd&rank=1. Accessed October 5, 2009.

Reference
Patel JD, Bonomi P, Socinski MA, et al. Treatment rationale and study design for the pointbreak study: a randomized, open-label phase III study of pemetrexed/carboplatin/bevacizumab followed by maintenance pemetrexed/bevacizumab versus paclitaxel/carboplatin/bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. Clin Lung Cancer. 2009;10(4):252-256.

Carboplatin and paclitaxel with or without CP-751,871 (an IFG-1R Inhibitor) for advanced NSCLC of squamous, large cell and adenosquamous carcinoma histology

Why is this trial being done? Figitumumab (CP-751,871) is a selective fully humanized IgG2 monoclonal antibody against the insulin-like growth factor 1 receptor (IGF-1R) pathway. The IGF pathway is a fundamental mechanism of cell survival. The pathway is activated by the binding of IGF-1 to IGF-1R and triggers a complex signaling cascade that stimulates cell growth and survival. The IGF-1R is frequently overexpressed in human tumors including NSCLC. Figitumumab inhibits the IGF-1 pathway, and thus may block the signal transduction that occurs in lung cancers. A phase II randomized, non-comparative study showed a 54% response rate in treatment-naïve patients with NSCLC receiving paclitaxel/carboplatin plus figitumumab. The response rate for those patients treated with chemotherapy alone was 41%. Also noted was that 78% of a subset of patients with squamous cell carcinoma (n = 23) and 57% of patients with adenocarcinoma (n = 28) experienced and objective response with the combination. As a result, a phase III clinical trial has been initiated for figitumumab in NSCLC. The following trials are currently open and enrolling:

ADVIGO 1016: Randomized, open label, phase III trial of figitumumab (CP-751,871) in combination with paclitaxel and carboplatin versus paclitaxel and carboplatin in patients with NSCLC

ADVIGO 1018: Randomized, open label, phase III trial of erlotinib alone or in combination with CP-751,871 in patients with advanced NSCLC of non-adenocarcinoma histology.

Primary objective: The primary objective of this trial is an improvement in OS between the 2 regimens. Secondary objectives include overall objective response rate, PFS, safety, pharmacokinetics, and change in serum IGF-1 levels.

Who is eligible? Patients must have histologically confirmed, stage IIIB (with pleural effusion) or stage IV NSCLC with a primary histology of predominantly squamous cell, large cell, or adenosquamous carcinoma. Patients may not have had prior systemic treatment for NSCLC, except for adjuvant chemotherapy which must have been completed >12 months prior to randomization. Patients may not be on chronic steroids, and may not have uncontrolled diabetes.

Study schema:

Statistical Outcome: Approximately 820 patients will be accrued to the trial with the estimated primary completion date for the final data collection for survival in July 2011.

For more information about this trial, please visit ClinicalTrials.gov. Available from: http://www.clinicaltrials.gov/ct2/show/NCT00596830?term=CP-751%2C+871&rank=12. Accessed October 5, 2009.

Reference
Karp DD, Paz-Ares LG, Novello S, et al. High activity of the anti-IGF-IR antibody CP-751,871 in combination with paclitaxel and carboplatin in squamous NSCLC. J Clin Oncol. 2008;26(May 20 suppl). Abstract 8015 and oral presentation at: American Society of Clinical Oncology; May 30 – June 3, 2008; Chicago, IL.

Carboplatin and paclitaxel with or without bevacizumab and/or cetuximab in treating patients with stage IV or recurrent NSCLC

Why is this trial being done? As mentioned earlier, ASCO guidelines suggest that patients with inoperable NSCLC with a good performance status should be offered induction chemotherapy consisting of 4 to 6 cycles of a platinum-based doublet. A previously published ECOG randomized trial comparing 4 platinum doublets concluded that there was no difference in OS and that carboplatin and paclitaxel could be considered a standard upon which to compare new regimens. Subsequently, the addition of bevacizumab to paclitaxel and carboplatin received FDA approval based on an improvement in OS in the front-line. However, patients with squamous cell carcinoma were excluded from this trial. In a completely different phase III trial, FLEX, 1125 patients with all histologies of NSCLC were assigned to receive platinum-based chemotherapy with or without cetuximab. The trial met its statistical endpoint of improvement in OS with the addition of cetuximab. In addition, the benefit was seen in all histologic types including adenocarcinoma and squamous cell carcinoma. This current trial is being performed to compare how well paclitaxel and carboplatin work with or without bevacizumab and/or cetuximab in treating patients with stage IV or recurrent NSCLC.

Primary Objective: The primary objective of this trial is an improvement in OS among the regimens and PFS of epidermal growth factor receptor (EGFR) fluorescent in situ hybridization (FISH)–positive patients by institutional review.

Secondary objectives: The secondary objectives of this trial are OS and PFS of EGFR FISH–positive patients by centralized review; PFS of the entire study population; overall response rate; and correlation of KRAS mutations with response and outcome.

Who is Eligible? Patients with histologically confirmed NSCLC including any of the following types: adenocarcinoma, large cell carcinoma, squamous cell carcinoma, and unspecified. Patients must have newly diagnosed stage IV disease or recurrent disease after prior surgery and/or radiation. Patients must have measurable or non-measurable disease documented by computed tomography (CT) scan or magnetic resonance imaging (MRI).

Study Schema: This is a multi-center study. Patients are stratified according to bevacizumab-appropriate status (yes or no), smoking status (current or former versus never), and stage (M1a versus M1b). Patients are randomized to 1 of 2 treatment arms:

Arm I: Patients receive carboplatin IV and paclitaxel IV with or without bevacizumab on day 1 every 21 days for up to 6 courses of therapy. After completion of 6 courses, patients receiving bevacizumab may continue to receive bevacizumab in the absence of disease progression or unacceptable toxicity.

Arm II: Patients receive carboplatin and paclitaxel with or without bevacizumab as in arm I. Patients also receive cetuximab IV over 1 to 2 hours on days 1, 8, and 15. Treatment repeats every 21 days for up to 6 courses of therapy. After completion of 6 courses, patients may continue to receive cetuximab with or without bevacizumab (as above) in the absence of disease progression or unacceptable toxicity.

Statistical Outcome: Approximately 1546 patients will be accrued to the trial with the estimated primary completion date for the final data collection for survival in June 2012.

For more information about this trial, please visit ClincialTrials.gov. Available from: http://www.clinicaltrials.gov/ct2/show/NCT00946712?term= lung+cancer+and+cetuximab&rank=14. Accessed October 5, 2009.

Reference
Pirker R, Szczesna A, von Pawel J, et al. FLEX: A randomized, multicenter, phase III study of cetuximab in combination with cisplatin/vinorelbine (CV) versus CV alone in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2008;26(May 20 suppl). Abstract 3.

OncoFacts™ Editor:

Christy Russell, MD

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