Archive for the ‘Lung Cancer’ Category

Lung Cancer Study of Novel Oral Drug Sapacitabine at CORT

January 28, 2009

CORT has opened a phase I-II study of sapacitabine for second-line therapy of unresectable advanced or metastatic non-small cell lung cancer (NSCLC). Sapacitabine is an oral nucleoside analog prodrug that acts through a dual mechanism. The compound interferes with DNA synthesis by causing single-strand DNA breaks and induces arrest of the cell division cycle at G2 phase.

Both sapacitabine and its major metabolite, CNDAC, have demonstrated potent anti-tumor activity in both blood and solid tumors in preclinical studies. In a liver metastatic mouse model, sapacitabine was shown to be superior to gemcitabine (Gemzar®; Lilly) or 5-FU, two widely used nucleoside analogs, in delaying the onset and growth of liver metastasis.

A number of clinical trials are evaluating sapacitabine in both solid and hematological tumors to establish a foundation for future Phase 2 studies and combination studies with other anti-cancer agents. Three Phase 1 studies have been completed, which evaluated safety and pharmacokinetics of a variety of dosing schedules in approximately 120 patients with solid tumors. Sapacitabine is currently being evaluated in Phase 2 trials in patients with advanced cutaneous T-cell lymphoma (CTCL), in elderly patients with acute myeloid leukemias (AML), and in therapy of NSCLC.

For more information about the CORT study in NSCLC, contact a CORT Research Coordinator at 972-566-5588 (Dallas), or 972-981-4012 (Plano).  Addtional information may be found at the CORT website: www.CORTPA.com.

CORT Study Tests Addition of Avastin (Bevacizumab) in Adjuvant Therapy for Non-Small Cell Lung Cancer

November 12, 2008

Post-operative chemotherapy for Stage IB-IIIA Non-Small Cell Lung Cancer (NSCLC) has become standard-of-care, improving survival modestly.  Commonly utilized chemotherapy regimens include cisplatin-vinorelbine (Navelbine), cisplatin-docetaxel (Taxotere), or cisplatin-gemcitabine (Gemzar).  Although carboplatin has also been commonly employed in treatment for lung cancer, meta-analysis comparing carboplatin and cisplatin has suggested a possible modest advantage to cisplatin therapy, so cisplatin is often the platinum analogue chosen in potentially curative (adjuvant therapy) patients.

Bevacizumab (Avastin) is a monoclonal antibody against vascular endothelial growth factor (VEGF).  The anti-VEGF action of bevacizumab leads to blockade in angiogenesis (new blood vessel formation).  Because VEGF acts to promote tumor growth by a number of mechanisms, bevacizumab probably has a number of other anti-tumor actions as well.  Bevacizumab has been studied in metastatic lung cancer in several trials, most notably, ECOG 4599.  That study showed a significant improvement in progression free survival (PFS) and response rate in first-line treatment of metastatic NSCLC.  Toxicities of bevacizumab have included bleeding, thrombosis, hypertension, proteinuria, delayed wound healing, infusion reactions, and rare bowel perforation or death.  Bevacizumab use in patients with metastatic NSCLC is modestly restricted, to avoid enrollment of patients with higher risk for serious bleeding, such as large, centrally-located tumors, and tumors of squamous histology.  Such a restriction is not necessary in the setting of resected disease.  

Bevacizumab is approved for use in metastatic lung, breast, and colorectal cancer.  Bevacizumab is not currently approved for use in adjvuant lung cancer treatment.  Therefore, because bevacizumab is not likely to be covered by insurers for adjuvant therapy, access to bevacizumab for adjuvant treatment is likely to be limited to patients who choose to participate in a clinical trial. 

The use of chemotherapy with or without bevacizumab for adjuvant therapy is being tested in the EGOG 1505 study.  Patients with good performance status, resected disease, no metastases, and adequate liver, lung, kidney, and marrow function are potentially eligible.   For more information about this study, visit the CORT website at www.CORTPA.com, or contact a Study Coordinator at 972-566-5588 (Dallas) or 972-981-4012 (Plano).

Advances in First-Line Treatment of Unresectable Non-Small Cell Lung Cancer: Pemetrexed Maintenance Therapy

November 3, 2008

Chemotherapy is the initial standard-of-care treatment for unresectable (stage IIIB/IV) non-small cell lung cancer (NSCLC).  Based upon historical information, the optimal duration of initial therapy with a platinum doublet (two-drug regimen) is 4-6 cycles.  The addition of bevacizumab (Avastin) to the carboplatin and paclitaxel first-line treatment regimen has improved progression free survival (PFS) from 4.5 (placebo) to 6.2 months (bevacizumab) (ECOG 4599, Sandler et al NEJM 355: 2542-2550, 2006).  Longer therapy initial therapy has, in some cases, improved progression free survival (PFS), without improvement in overall survival (OS).  That may be a result of the benefit of second-line treatment (at the time of progression), which may also extend overall survival (OS).  

The benefit of maintenance therapy, after initial treatment, was examined by a group of international investigators, reported by Dr. Ciuleanu (Romania) at the 2008 ASCO Annual Meeting  (J Clin Oncol 26: 2008 (May 20 suppl; abstr 8011)).  Patients received initial chemotherapy, and then the patients were randomly assigned to maintenance therapy with pemetrexed (Alimta) or placebo.  The study demonstrated a significant improvement in PFS for the patients who received maintenance pemetrexed therapy, with PFS of 4 months (versus 2 months for placebo).  In the subset analysis, patients with non-squamous cell histology benefited, while squamous cancers did not.  The observation that response to pemetrexed was superior in non-squamous histology lung cancer has been observed in two previous investigations.  This study also demonstrated a strong trend (nearing statistical significance) for improved overall survival (OS) in patients with non-squamous histology who received pemetrexed maintenance therapy.  The final results of OS in this study have not yet been reported.

The use of maintenance pemetrexed with bevacizumab was also reported at the ASCO 2008 Annual Meeting (J Clin Oncol 26: 2008 (May 20 suppl; abstr 8044)).  Dr. Patel reported the results of a study in which all patients received carboplatin and pemetrexed with bevacizumab as initial therapy x 6 cycles.  Patients without progression continued on pemetrexed and bevacizumab for maintenance therapy every 3 weeks.   This was a single arm study.  The PFS was 9.2 months, and the OS was 13.5 months.  Treatment with maintenance pemetrexed and bevacizumab was very well tolerated, and 60% of patients had >6 cycles, 18% had >18 cycles, and 14% had >24 cycles. 

The PFS of the study reported by Patel et al are favorable.  If one expects a PFS with a platinum doublet + bevacizumab of 6 months, and an additional 4 months of PFS with pemetrexed maintenance therapy, the the results of the Patel study are in line with those reporte by Ciuleanu et al.  The study of Patel did give bevacizumab until progression, as was done in the ECOG 4599 study. 

These studies mark continued progress in treatment of unresectable and metastatic NSCLC.  Integration of anti-angiogenic therapy (bevacizumab) and less toxic treatment with new agents like pemetrexed have incrementally extended PFS.  Overall survival may also be impacted. 

Additional improvements may come with the integration of other sorts of maintenance treatment, for example, anti-tumor vaccine therapy.  CORT is testing the anti-MUC-1 tumor vaccine, Stimuvax, as part of the START study, for patients who have completed initial chemotherapy and radiation therapy for unresectable Stage III NSCLC.  Information about that study is available in another post.  For further information about lung cancer therapy at CORT, including the START study, visit our webpage at www.cortpa.com, or contact a Research Coordinator at 972-566-5588. 

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.

Metastatic Lung Cancer Survival Improved by the Addition of Cetuximab to Chemotherapy: FLEX Study

June 6, 2008

The results of the FLEX study of cisplatin + vinorelbine (Navelbine) with or without cetuximab (Erbitux) therapy were presented at the ASCO 2008 Annual Meeting Plenary Session, in Chicago on 6/1/08.  The study was the first demonstration of an overall survival advantage of an anti-EGFR drug used in conjunction with first-line standard chemotherapy for advanced or metastatic (“wet” Stage III-B/IV) lung cancer.  The results of this 1,125 patient study are summarized in the table below.

The important aspects of this trial design were: 1) patients were EGFR positive by IHC (immunohistochemistry), 2) patients received up to 6 cycles of chemotherapy with or without Erbitux, and those who received Erbitux during chemotherapy continued on maintenance Erbitux after completion of chemotherapy, 3) patients were not excluded for squamous cell carcinoma, central tumors, or hemoptysis (factors that associated with an increased risk pulmonary hemorrhage or fatal hemoptysis), and 4) the trial was powered to assess overall survival, rather than the “softer” endpoint of progression free survival. 

The groups were well balanced for patient factors.  The only signficant additional toxicity associated with the addition of Erbitux were uncommon infusion reactions (4% versus <1% control), grade 3 rash (10% versus <1% control), and diarrhea (5% versus 2% control). 

Of interest, the Erbitux-containing treatment arm had improved overall survival, despite the fact that 27% of the control arm (versus 17% of the Erbitux arm) received post-progression EBFR inhibitor therapy, indicating that the up-front use of chemotherapy + Erbitux followed by maintenance Erbitux is likely a superior strategy in achieving longer survival for such patients when compared to chemotherapy followed by other standard therapy upon progression (including EGFR inhibitors) for progression. 

These results must be considered in light of other prevalent studies and practice patterns in management of NSCLC.  Other studies (AVAIL, ECOG 4599) have demonstrated modest improvements in survival when bevacizumab (Avastin) is added to standard chemotherapy.  The survival impact seen for Erbitux + chemotherapy in the FLEX study appears to be of comparable magnitude to that seen with Avastin + chemotherapy.  However, there are important toxicity differences between Avastin and Erbitux.  Avastin may increase the risk of bleeding and fatal hemoptysis, so patients with large central tumors, squamous cell lung cancer, and hemoptysis are not generally considered for treatment with Avastin.  Avastin is not given to patients with CNS metastases, because of the possible risk for CNS hemorrhage.  On the basis of these general preclusions, as many as 40-45% of metastatic lung cancer patients may not be eligible for Avastin.  Erbitux eligibility is broad, with EGFR immunostaining in 85% of the patients screened in the FLEX study.  Other serious risks of Avastin (thromboses, proteinuria, hypertension, would healing delay, and rare serious events such as bowel perforation or posterior leukoencephalopathy syndrome) are not seen with Erbitux. 

The FLEX study did not exclude patients for Erbitux therapy on the basis of ras mutations.  That is an important caveat to the FLEX findings.  Many investigations in lung and colorectal cancer have demonstrated that tumors with mutated ras oncoproteins are resistant to EGFR inhibiting drugs, including TKI inhibitors (erlotinib=Tarceva, gefiinib=Iressa) and EGFR antibody inhibitors (cetuximab=Erbitux, panitumumab=Vectibix).  Ras mutations are prevalent in NSCLC, in up to 40% of patients.  Therefore, the fraction of patients who are eligible for Erbitux therapy may be reduced, if ras assessment is including in pre-treatment screening to exclude patients who are unlikely to benefit from EGFR inhibitors.  It appears likely that regulatory or insurer guidelines will adopt a policy of ras assessment in the future, because of the significant costs of EGFR inhibitors. 

While IHC assessment of EGFR status was used in FLEX, there may be better methods for “enriching” a population of patients who benefit from EGFR inhibitors.  Response rates to single-agent EGFR inhibitors of EGFR IHC+ patients are 10-15%.  EGFR amplification by FISH is positive in about 40% of patients, and responses in these patients range up to 40-50%.  A much smaller group of patients (10-15%)  harbor activating mutations in EGFR (exon 19 and 20 predominantly), and response has been reported in 70-90%.   However, patients who are EGFR IHC+ without amplification and/or mutation might still benefit from therapy, so exclusion of these patients from treatment is not an accepted strategy at the present time.

CORT is testing EGFR inhibition with Erbitux in first- and second-line therapy trials.  For more information, call 972-566-5588 (Dallas), or 972-981-4012 (Plano), and ask to speak with a Research Coordinator.  Additional information is available at the CORT website, www.CORTPA.com.

 

Thoracic Surgeons at Medical City Dallas Hospital Begin Minimally-Invasive Cancer Surgery Program

September 22, 2007

The Thoracic Surgery Service at Medical City Dallas Hospital has begun a program of minimally-invasive cancer surgery to offer the latest technology to patients with lung and other thoracic malignancies.  Diagnostic and therapeutic procedures may be accomplished with less morbidity and shorter recuperative time, when these techniques are applied in appropriately selected patients.   For more information, contact Dr. Mitchell Magee at 972-566-4866.

Seliciclib (CYC-202) in Treatment of Refractory Non-Small Cell Lung Cancer

September 22, 2007

CYC-202 is a cyclin-dependent kinase (CDK) inhibitor. CDK proteins regulate the process of cell division, by controlling important “check points” in the mitotic cycle. CYC-202 is in testing at CORT in a Phase I study for patients with refractory lung cancer. The drug is given orally, twice daily for three days, repeated every two weeks. The risks of CYC-202 are nausea, vomiting, transient elevations in serum creatinine and liver function parameters and transient hypokalemia.

For more information on this study, visit www.CORTPA.com, or contact one of the CORT Research Coordinators at 972-566-5588. 

Lung Cancer Survival Improved by Cetuximab (Erbitux)

September 22, 2007

ImClone and Bristol Myers Squibb (BMS) released a press announcement on 9/12/07 that cetuximab (Erbitux), a monoclonal anti-epidermal growth factor receptor (EGFR) antibody, improved survival of advanced non-small cell lung cancer (NSCLC) patients when combined with standard chemotherapy when compared to standard chemotherapy alone. Data from the FLEX study have not been made public, but release is anticipated, based on the positive release of the announcement.Cetuximab is already an approved therapy in treatment of metastatic colon cancer and head & neck cancer.Cetuximab has been under study at CORT since 1999. It is well-tolerated, with rash and diarrhea as common side effects. Infusion reactions, and more rarely, drug-induced interstitial pneumonia may occur. Cetuximab is not yet approved in the treatment of NSCLC.Bevacizumab (Avastin), a monoclonal anti-vascular endothelial growth factor (VEFG) antibody, has also been shown to improve survival in advanced NSCLC, when combined with chemotherapy. Bevacizumab may cause increases in blood pressure, proteinuria, bleeding or thrombosis, slow wound healing, and uncommon infusion reactions. Rare cases of bowel perforation have occurred.

CORT is conducting a first-line trial of cetuximab and bevacizumab in NSCLC as part of a multicenter study. The study compares standard chemotherapy with carboplatin and paclitaxel to either cetuximab and bevacizumab alone, or the combination of both antibodies with carboplatin and paclitaxel.  For more information on this study, visit www.CORTPA.com, or speak with a Researh Coordinator at 972-566-5588.

Lung Cancer Vaccine Study: Stimuvax

August 4, 2007

CORT continues its investigation of a vaccine for prevention of recurrence of Stage III Non-Small Cell Lung Cancer )(NSCLC).  In collaboration with EMD Pharmaceuticals, CORT is conducting a study of Stimuvax, a vaccine for patients who have completed a standard program of chemotherapy and radiation therapy for treatment of unresectable Stage III NSCLC. 

Patients who qualify will randomly receive a placebo or active vaccine treatment for 8 weekly doses, followed by 4 additional doses every 6 weeks.  For information on this study, call 972-566-5588 and ask to speak with a Study Coordinator.  Additional information about CORT and the studies available may be found at www.CORTPA.com.

Patients who have unresectable Stage III NSCLC who complete a standard program of chemotherapy and radiation therapy continue to have a very high risk of recurrence.  The purpose of this study is to determine if the vaccination program can effectively reduce that risk.