Archive for October, 2008

Stimuvax Lung Cancer Vaccine Study Continues at CORT

October 30, 2008

CORT opened and enrolled in 2007 the first patient worldwide to the START Study (Stimulating Targeted Antigenic Responses To NSCLC), assessing the efficacy and safety of Stimuvax (BLP25 liposome vaccine) as a potential treatment for patients with unresectable stage III non-small cell lung cancer (NSCLC).  Our accrual to the study continues. 

Enrollment in the study, which will enroll more than 1,300 patients in approximately 30 countries, is continuing at CORT.  Currently, there are no approved maintenance therapies for patients responding to first-line treatment for unresectable stage III NSCLC.

“Patients with advanced lung cancer are in need of new therapies that effectively target cancer cells while providing better safety and tolerability,” said Dr. Frances Shepherd, Director of Medical Oncology at Princess Margaret Hospital in Toronto, Ontario and lead investigator of the START study. “Novel therapeutic vaccines such as Stimuvax may help the body’s immune system identify and destroy cancer cells without targeting normal, healthy cells.”

Lung cancer is the leading cause of cancer-related deaths in both men and women worldwide with approximately 80 percent of cases classified as NSCLC. Further, only about 15 percent of people diagnosed with NSCLC survive this disease after five years.(1) For most patients with NSCLC, current treatments provide limited success.

“The START study is the first Phase III program to evaluate a cancer vaccine in unresectable stage III non-small cell lung cancer,” said Dr. Wolfgang Wein, Senior Executive Vice President, Oncology, Merck Serono. “Our continued investment in research reflects our confidence in Stimuvax and commitment to developing innovative targeted therapies to advance treatment options for patients with cancer.”

The START study is a randomized, double-blind, placebo-controlled study that will evaluate patients with documented unresectable stage III NSCLC who have had a response or stable disease after at least two cycles of platinum-based chemo-radiotherapy. The study has been designed considering scientific advice from the European Medicines Agency (EMEA/CHMP) and has been agreed upon with the U.S. Food and Drug Administration (FDA) through a Special Protocol Assessment (SPA). Data from a randomized phase IIb study encouraged the initiation of the Phase III program.

For more information on the START study, or to find a participating center and eligibility criteria, go to http://www.nsclcstudy.com. The study is also listed on http://www.clinicaltrials.gov.   For patients interested in this study in the Dallas, Texas area, go to our website, www.cortpa.com, or call and speak with a Research Coordinator at: 972-566-5588.

About Stimuvax

Stimuvax is an innovative cancer vaccine designed to induce an immune response to cancer cells that express MUC1, a protein antigen widely expressed on common cancers. MUC1 is over expressed on many cancers such as lung cancer, breast cancer and colorectal cancer. Stimuvax is thought to work by stimulating the body’s immune system to identify and destroy cancer cells expressing MUC1.

A randomized Phase IIb study was conducted in 171 patients with stage IIIb and IV NSCLC with response or stable disease after first line therapy. While the overall study results were not statistically significant, in the randomization stratum of patients with stage IIIb locoregional disease, Stimuvax showed a median survival of 30.6 months versus 13.3 months in the control group — an improvement of 17.3 months. In the Phase IIb study, side effects were primarily limited to mild-to-moderate flu-like symptoms, GI disturbances, and mild injection site reactions.

Erbitux (Cetuximab) in First-Line Treatment Colorectal Cancer Mangement

October 30, 2008

CORT has conducted research and treatment studies with the monoclonal anti-EGFR (anti-epidermal growth factor) antibody cetuximab (Erbitux) since 2002.  Early cetuximab studies focused on treatment of disease that was refractory (resistant) to other available chemotherapy agent.  Those agents included fluropyrimidines (5FU), oxaliplatin (Eloxatin), and irinotecan (Camptosar).  Responses to Erbitux monotherapy were seen in 11.6% of patients, with a median duration of response of 4.2 months.  The median progression free survival was 1.5 months, and the median overall survival was 6.6 months. 

The CORT data on response predictors was reported at the same time several other major cancer centers released their results.  Certain baseline clinical characteristics (performance status, number of metastatic sites) and the appearance of skin rash after therapy were strong predictors of response and outcome.  Interestingly, the intensity of tumor tissue staining for EGFR protein did not correlate to response to cetuximab.  CORT data demonstrated that 25% of such refractory patients treated with cetuximab monotherapy had stable disease for longer than 6 months.  Certain patients had exceptional responses, including complete responses (CR).  One heavily pre-treated patient at CORT had a CR and continued maintenance cetuximab for 18 months, then continued in unmaintained remission for over one year.  This patient relapsed and again entered CR with cetuximab monotherapy retreatment, again lasting one year.  The patient stopped therapy, relapsed a third time, and then had only partial response to cetuximab therapy for a third time.  She continues to be alive on other investigational therapy.  Additional studies in patients refractory to irinotecan therapy demonstrated that cetuximab therapy combined with irinotecan was superior to cetuximab therapy alone (BOND-1), and cetuximab + irinotecan + bevacizumab (Avastin) was superior to cetuximab + irinotecan (BOND-2).  It must be noted that in BOND-2, these patients had not previously received bevacizumab in any earlier line of therapy. 

Multiple investigators have reported that mutated k-ras protein confers resistance to cetuximab therapy.  This is mechanistically explained by the activation of intracellular signaling “downstream” of the EGFR protein.   Commercial testing for k-ras protein mutation status is now available, and clinical use of this response prediction test is being widely adopted. 

Based on such promising data seen in the refractory colorectal patient population, cetuximab has been studied in first line treatment of metastatic colorectal cancer.  The 1198 patient Crystal Study was a randomized comparison of the FOLFIRI (irinotecan, 5-FU, leucovorin) and FOLFIRI-cetuximab.  The results were initially reported in 2007.  The study met its primary endpoint of increasing progression-free survival (PFS) (15% improvment: 8.9 months vs. 8.0 months, p=0.048). The study also demonstrated a 21% improvement in the response rate (46.9% vs. 38.7%, p=0.004).

In the analysis of the total treatment population, not sorted by k-ras status, the study did not demonstrate a statistically significant prolongation of overall survival (OS), compared to chemotherapy alone. The OS of all ERBITUX-treated patients was 19.9 months compared to 18.6 months for FOLFIRI alone (Hazard Ratio [HR]=0.931, p=0.305).

However, the study results were further analyzed by k-ras mutational status. 540 of the patients had tumor samples evaluable for k-ras. The k-rase mutation was detected in 192 of those patients (36%). Patients with k-Ras wild-type (non-mutated) tumors had the greatest benefit from cetuximab treatment. The OS for patients with the non-mutated, or “wild-type,” form of the K-Ras oncogene, which is noted in about 65% of patients with mCRC, was 24.9 months, 4 months difference, compared to 21 months for FOLFIRI alone (HR=0.844, p=0.217). These survival times are among the longest seen in first line treatment studies.

Furthermore, for patients with k-ras wild-type tumors, there was a 32% decrease in risk of progression (9.9 months vs. 8.7 months, HR=0.68, p=0.017) and a significant increase in response rate up to 59% (59.3% vs. 35%, p=0.003).

How will these results change therapy?  Until recently, oxaliplatin-based regimens with bevacizumab (Avastin) have been the most widely utilized first line treatments.  In April, 2008, a large study evaluating oxaliplatin-containing therapies (either Xelox or FOLFOX) with or without bevacizumab was reported in the Journal of Clinical Oncology.  This study of 1401 patients showed that the PFS was 9.4 months in the bevacizumab + chemotherapy group, versus 8.0 months in the placebo + chemotherapy group (harzard ratio (HR) 0.83; 97.5% CL: 0.72-0.95, p=0.00213).  The OS for the bevacizumab + chemotherapy group was 21.3 months, versus 19.9 months in the placebo + chemotherapy group (HR) 0.89; 97.5% CL, 0.76-1.03, p=0.077).   The response rates were similar in both arms.  Therefore, despite the significant longer progression time, the response rate and overall survival was not significantly improved by the addition of bevacizumab.  k-ras is not a factor that predicts bevacizumab response. 

The treatment paradigm for first line treatment of metastatic colorectal cancer is shifting based on the Crystal results.  FOLFIRI-cetuximab first-line treatment is expanding (in k-ras wild type patients).  In addition, the benefit of adding bevacizumab to oxaliplatin-based regimens appears to have limited benefits.  Another factor in reduced use of oxaliplatin regimens in the first line metastatic setting is the increased use of oxaliplatin-based adjuvant therapy.  For patients who received prior oxaliplatin-based adjuvant therapy, the risk of developing peripheral neuropathy with oxaliplatin regimens for relapsed disease is increased.  Cumulative marrow suppression of oxaliplatin (e.g, thrombocytopenia) is also problematic.  These toxicities limit retreatment with oxaliplatin regimens.  In addition, retreatment with oxaliplatin regimens after pior oxaliplatin adjuvant therapy may be less effective in some patients, becasue of disease resistance.  FOLFIRI is well tolerated, and neuropathy is not an expected toxicity of this regimen.

Cetuximab is also being studied in the colon cancer adjuvant therapy setting.  The NCCTG N0147 Study is comparing oxaliplatin-based therapy alone to oxaliplatin-based therapy wtih cetuximab for patients with Stage III disease. This study is opening at CORT.  

CORT is conducting other colon cancer studies, including the ECOG E5202 Study that evaluates adjuvant therapy for Stage II patients with bevacizumab + oxaliplatin-based therapy in tumor defined by high risk tumor genetic characteristics.  The role of adjuvant bevacizumab + oxaliplatin-based therapy versus oxaliplatin-based therapy alone for Stage III patients has been studied in the NSABP C-08 study, also conducted at CORT. That study has completed accrual, and results are eagerly anticipated. 

For consultation requests or more information about colon cancer treatment studies at CORT, visit our website at www.cortpa.com, or call and speak with a Research Coordinator at: 972-566-5588 (Dallas), or 972-981-4012 (Plano). 

Most Important Factor in Considering a Trial?

October 18, 2008

Your Interest in Cancer Clinical Trials

October 18, 2008

Multiple Myeloma: Will Molecular and Genetic Studies Assist in Selection Treatment?

October 18, 2008

Treatment of multiple myeloma has improved considerably in the past decade, with integration of high dose therapy (with autologous bone marrow transplant) and/or new drug therapies such as thalidomide (Thalomid), lenalidomide (Revlimid), and bortezomib (Velcade).  Of course, because the disease and the patients are very heterogeneous, no single treatment strategy is appropriate for all patients.   Researchers have been studying patient and disease characteristics that predict survival (prognostic factors) or predict outcome of specific therapy (predictive factors).  The hope is that patient’s disease can be better understood prior to therapy, and the patients can be offered the most effective treatment option available. 

Traditional factors based on the patient’s boney destruction, anemia, and thrombocytopenia (reflections of the myeloma marrow disease burden) and kidney function are encompassed in the Durie-Salmon staging system.  The International Staging System uses a combination of serum beta-2-microglobulin level and serum albumin to predict prognosis.  Neither of these systems incorporates new information about molecular or genetic subtypes or features of myeloma.  The prognosis (and perhaps treatment response) of such subtypes may be considerably different.

Genetic studies have identified that certain myeloma patients have disease with increased risk of shortened survival (high risk).  The Mayo stratification of myeloma and risk-adapted therapy (sMART) classification identifies the following features as high risk (25% of all myeloma patients): FISH (fluorescent in situ hybridization) detection of deletion of the short arm of chromosome 17 (17p-), translocations: t(4,14) and t(14,16), cytogenetic detection of deletion of chromosome 13, cytogenetic hypodiploidy (numerically reduced chromosomal number), and increased plasma cell labeling index (PCLI >=3%).  Chromosome 13 deletion is associated with diminished regulatory function of the Rb protein.  This may be a key factor in promoting clonal expansion. The sMART classification identifies patients (75% of all myeloma patients) as having standard risk, with hyperdiploidy, t(11,14), and t(6,14).   Certain additional genetic events may confer a negative effect on survival.  Deletion of the short arm of chromosome 17 (del 17p13) results in loss of the tumor suppressor gene p53. This deletion has been associated with short duration of response to high dose therapy, increased risk for CNS involvement, extramedullary disease, and occurrence of plasma cell leukemia.  K-ras mutations, chromosome 1 abnormalities, and NF-kB (nuclear factor-kB) activation may also have adverse effects on prognosis.  

As yet, a specific factor (or combination of factors) that might predict the best initial therapy for newly diagnosed patients have not been fully defined.   However, the t(4,14)(q16;q32) has an unequivocal negative influence on the prognosis of patients treated with melphalan-based chemotherapy.  Investigators have interpreted these findings and suggested that bortezomib (Velcade) therapy be introduced early in such high risk patients.  Guidelines in the form of algorithms for treatment selection have been developed, and these may be found at www.mSMART.org

CORT is conducting a clinical trial for patients who are not eligible for high dose therapy and transplant.  This study is the Millenium Oncology UPFRONT study, which randomly compares three treatments that contain borezomib (Velcade):

  • Velcade-Melphalan-Prednisone (VMP)
  • Velcade-Thalidomide-Dexamethasone (VTD)
  • Velcade-Dexamethasone (VD)

For more information about the UPFRONT study, or other treatments for multiple myeloma, contact a CORT research coordinator at 972-566-5588, or visit the CORT website: www.CORTPA.com.