Archive for June, 2008

Evolving Chemotherapy for Advanced and Metastatic Gastric Cancer

June 13, 2008

Gastric cancer is the fourth most common cancer worldwide, and the second leading cause of death worldwide.  The disease is often diagnosed at an advanced or metastatic stage, not curable by surgical means.  Therefore, palliative treatment to extend survival and to improve symptoms is important for patients.  Chemotherapy improves outcomes for advanced or metastatic gastric cancer patients, but standard cisplatin-5FU (flurouracil)-(CF) based regimens produce response in only 20-30% of patinets, and median overall survival (OS) remains poor at 7-8 months.   Median progression-free survival (PFS) for CF is 3-4 months. 

Recent studies have compared the addition of docetaxel (D) (Taxotere) to cisplatin-based regimens.  The final results of the TAX 325 Study comparing DCF to CF were reported in 2005 and published in 2007.  Response rate was 37% versus 25%, PFS was 5.6 months verus 3.7 months, and OS was 10.5 versus 9.6 months (all favoring DCF).  The 2-year survivals were 18 versus 9% (favoring DCF).  This was the highest reported 2-year OS in gastric cancer at the time.  Toxicities for both regimens were substantial, but manageable.  The problems of toxicity (febrile neutropenia, diarrhea, stomatitis, weight loss, nausea, vomiting) and poor QOL have made investigators and clinicians to question the risk/benefit ratio of  the regimen, at least in the schedule that was tested in TAX 325. 

The use of other regimens such as ECF (Epirubicin, Cisplatin, 5FU) has shown promise in advanced disease, but that regimen has potential cardiac risk, and reported OS is 8-9 months, not clearly advantageous when compared to CF. 

Therefore, recent efforts have focused on changes to schedule, infusion method, or the addition of new agents in an effort to reduce toxicity and to improve outcomes in gastric cancer.

At the ASCO Annual Meeting 2008, several abstracts were presented that employed such new schedules and/or agents in advanced or metastatic gastric cancer. 

2-day infusional 5FU, already commonly utilized in colon cancer therapy, is a less toxic method of 5FU delivery.  The abstract #4570 by Chiesa, et al. reported the outcome of DCF x 4 cycles every 2 weeks (with a modified dose and the 2-day infusion schedule of 5FU) followed by COFFI (oxaliplatin,irinotecan,5FU,Leucovorin, also with a 2-day infusional 5FU schedule) x 4 cycles every 2 weeks.  Treatment was every 2 weeks with peg-filgrastim support.  40 patients were enrolled.  28 were evaluable for response at the time of the report.  Dose reductions were required in 34% on DCF.  GI and hematologic toxicity were the main reasons.  After the DCF x 4, the overall response rate was 56% (2/28 CR + 16/28 PR).  21 patients proceeded to COFFI.  2 CRs after DCF maintained those durring COFFI.  Of the 16 PRs during DCF, 2 CRs were achieved, and 5 had further improvements in response).  2/7 patients with stable disease during DCF had PR with COFFI.  Two patients with liver metastases continue in CR at 33 and 16 months. The overall response rate to the entire program was 63%.  The 1 year survival was 31%.  The authors concluded that the program was feasible and highly effective.  

In abstract #4552, Enzinger et al. reported that bevacizumab (Avastin), cisplatin, docetaxel, and irinotecan in a three-week cycle produced a response rate of 63% in metastatic esophageal/gastric cancer.  UGT1A1 genotyping (*28 allele) predicted a high risk for occurrence of neutropenia and diarrhea from irinotecan in this regimen.

In abstract #4549, Han et al. reported the outcome of the the cetuximab (Erbitux) and FOLFOX6 regimen.  The response rate was 50%, with time-to-progression (TTP) 5.5 months, and OS 9.9 months.  The toxicity of this regimen appears to be more favorable than the other regimens noted above. 

These are good examples of the evolution of therapy options for gastric cancer.  Practicing physicians should not be limited in treatment choices for their gastric cancer patients because of rigid adherence to restricitve guidelines by payors or governmental agencies.  Such policies may function to limit cost of therapy (by restricting patients to CF or DCF approved therapy), with expected poor outcomes and higher than acceptable toxcities.  Newer treatments need to be promptly moved into clinical practice settintgs, potentially even when survival is not superior to existing standard therapy, if toxicity of the newer regimens are lower.  Such an approach will help better meet the goals of palliative therapy for patients. 

Abraxane (nab-paclitaxel) with or without Herceptin in First-Line Treatment of Metastatic Breast Cancer: ION 04-012 Study Results from the ASCO 2008 Annual Meeting

June 12, 2008

The International Oncology Network (ION) Study 04-012 results were presented in a poster presentation at the ASCO 2008 Annual Meeting.  This study was an open label Phase II study of Abraxane (nab-paclitaxel) therapy at 125 mg/M2 weekly for three out of four weeks, cycles every 4 weeks for first-line treatment of patients with metastatic breast cancer.  Patients with her-2 overexpressing or amplified disease also received Herceptin on a standard weekly schedule. 

This is a copy of the poster:

04-012-asco-poster-5-20-08

Abraxane is a protein-bound paclitaxel formulation, which can be given over shorter infusion duration than other taxanes, and it has a low rate of allergy or infusion reactions because it is cremaphor solvent-free.  Abraxane infusions do not require steroid premedication.   In previous studies of Abraxane in metastatic breast cancer, encouraging activity has been noted, even in pre-treated patient groups.  The response rate seen with Abraxane in other studies appears to be comparable or superior to responses seen with other taxane drugs. 

The ION Study enrolled 72 patients.  At the time of the analysis, 47 were evaluable for response.  There were 29 her-2 negative patients and 17 her-2 positive evaluable patients.  One patient had her-2 unknown status.  In the her-2 negative group, there were 9 partial responses (31%) and 18 (62%) patients with stable disease.  In the her-2 positive group, there were 2 complete responses (12%), 9 partial responses (53%), and 5 (29%) patients with stable disease.   Therefore, the overall response rate in her-2 positive patients was 65%.   Overall, for all patients, the response rate was 43%.  Median time to progression was 15.9 months, and median overall survival was 25 months.

Treatment was well tolerated and grade >=3 toxicities were mostly limited to neutropenia and/or fatigue.  Infections were uncommon. 

Dr. Barry Mirtsching of CORT was the Principle Investigator of this study.   Special thanks to Abraxis Oncology, the many ION investigator physicians, study coordinators, and participating patients who helped make this research study possible.  

ION is continuing to study Abraxane therapy in the setting of metastatic breast cancer.  Dr. Mirtsching at CORT is also the Principle Investigator for the study of Abraxane and Sorafenib (Nexavar) for first-line therapy of metastatic breast cancer.  Sorafenib is an oral drug with anti-angiogenic activity.  It is approved for the treatment of metastatic renal (kidney) cancer.  The combination of anti-angiogenic drugs and taxane therapy has shown promise in treatment of metastatic breast cancer.  Bevacizumab (Avastin), a monoclonal antibody with anti-VEGF (vascular endothelial growth factor) activity, and paclitaxel has been shown to improve progression-free survival when compared to paclitaxel alone.  Sorafenib would be a significant advance for breast cancer patients if it proves to be as active as Avastin, because it is oral and has a generally more favorable toxicity profile than Avastin.  Abraxane was chosen in this study for the clinical advantages noted previously.

For more information about the ION 06-025 Study of Abraxane and Sorafenib, please call 972-566-5588 (Dallas), or 972-981-4012 (Plano), or visit the www.CORTPA.com

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.

 

Melanoma Study at CORT: BMS-663513, agonist of CD137 Immune Stimulatory Molecule

June 6, 2008

CORT continues Dallas-Fort Worth leadership in clinical trials for patients with advanced and metastatic melanoma with its ongoing study BMS CA-185006 of the BMS-663513 drug, an agonist of the CD137 immune cell regulatory protein.  CD137 stimulates cell-mediated anti-melanoma tumor immunity.  Studies have demonstrated that stimulation of CD137 may enhance anti-tumor immune responses against melanoma.  BMS-663513 is a stimulator of CD137. 

Patients who have failed first-line therapy for advanced unresectable or metastatic melanoma are eligible, if they meet other criteria.  Patients who have not yet had first-line therapy for their disease are eligible for other melanoma studies at CORT.  For more information about this important study, call 972-566-5588 (Dallas) or 972-981-4012 (Plano), and ask to speak with a Research Coordinator.  Further information about CORT and CORT studies is available at www.CORTPA.com.

 

Bisphosphonate (Zoledronic Acid=Zometa) Improves Adjuvant Endocrine Therapy for Pre-menopausal Breast Cancer Patients; Ongoing CORT Study Assesses Bisphosphonates in Adjuvant Therapy in Broader Groups of Patients

June 6, 2008

Here is the ASCO (American Society of Clinical Oncology) News Post regard the Zoledronic Acid (Zometa) study presented at the ASCO 2008 Annual Meeting, demonstrating improved outcomes for pre-menopausal breast cancer patients receiving adjuvant endocrine therapy:

Zoledronic Acid Added to Endocrine Therapy Improves Outcome for Premenopausal Patients with Early Breast Cancer

 

Zoledronic acid has been found to increase disease-free survival by 36% and relapse-free survival by 35% for premenopausal patients who received adjuvant endocrine therapy for early breast cancer (Abstract LBA4). Michael Gnant, MD, of the Medical University of Vienna, Austria, presented the data on behalf of the Austrian Breast and Colorectal Cancer Study Group (ABCSG) during Sunday’s Plenary Session.

Adjuvant endocrine therapy with ovarian suppression is used as an effective alternative to standard cytotoxic chemotherapy for premenopausal patients with endocrine-responsive breast cancer. ABCSG-12 is the first study to compare endocrine suppression with goserelin plus tamoxifen to goserelin plus an aromatase inhibitor (anastrozole).

Adjuvant bisphosphonate therapy (zoledronic acid) was included in two of the four treatment arms both to mitigate the marked bone loss associated with complete ovarian suppression and to explore whether the antitumor effects demonstrated previously in preclinical and clinical settings might translate into a longer time to disease recurrence and improved survival.

The study was a randomized, open-label, phase III, modified 2×2, four-arm trial of oral tamoxifen and goserelin with or without zoledronic acid compared with oral anastrozole and goserelin with or without zoledronic acid for 3 years.

The primary endpoint of this trial was disease-free survival for the 903 patients who received anastrozole compared with the 900 patients who received tamoxifen. Secondary endpoints included overall survival and the effect of the treatments on local-regional relapse. The effect of treatment on bone metastasis-free survival was considered to be an exploratory endpoint.

At a median follow-up of 60 months, overall 5-year disease-free survival was 94% and overall survival was 98.2%. No difference in disease-free survival was detected among patients who received tamoxifen and those patients who received anastrozole. There was no advantage in relapse-free or overall survival rates for anastrozole over tamoxifen.

In the analysis of zoledronic acid, the bisphosphonate improved the primary endpoint of disease-free survival (hazard ratio [HR] = 0.643, p = 0.011). The incidences of contralateral breast cancer, distant metastases, and local-regional recurrence were all reduced by zoledronic acid (six vs. 10 cases, 29 vs. 41 cases, and 10 vs. 20 cases for the group treated with zoledronic acid compared with those patients who were not treated, respectively). Forest plots showed that the effect for all subgroups clustered around the main effect with no interaction. Treatment with zoledronic acid increased relapse-free survival (HR = 0.653, p = 0.014), with a trend toward improvement in overall survival (HR = 0.595, p = 0.101).

Zoledronic acid treatment was well tolerated. No renal toxicity or confirmed cases of osteonecrosis of the jaw occurred. Differences in side effects among the tamoxifen and anastrazole groups were seen. Arthralgia, bone pain, and fever were more frequent (all, p < 0.0001) in the anastrozole groups, especially for those patients who received zoledronic acid. The only serious adverse events that reached statistical significance included an increased incidence of uterine polyps (p < 0.0001) and thrombosis (p = 0.012) in the tamoxifen groups.

Dr. Gnant noted that differences in efficacy between tamoxifen and anastrozole may not have been detectable because of the effect of goserelin on suppression of ovarian function and that perhaps two large ongoing studies will provide better answers. The Suppression of Ovarian Function Trial (SOFT) has enrolled 3,000 patients, and the Tamoxifen and Exemestane Trial (TEXT) has enrolled 1,845.

With regard to zoledronic acid, Dr. Gnant said, “Zoledronic acid significantly improves clinical outcomes beyond those achieved with endocrine therapy alone.” The benefit was seen in and outside of bone (reduction in contralateral breast cancers, local-regional recurrence, and distant nonbone metastases) with acceptable toxicity. Dr. Gnant concluded that adjuvant therapy with zoledronic acid should be considered in order to improve the standard of care for premenopausal women, although the optimal dose, schedule, and treatment duration are yet to be addressed.

Discussant Martine J. Piccart-Gebhart, MD, PhD, of Jules Bordet Institute — Université Libre de Bruxelles, Belgium, referred to ABCSG-12 as elegant in design, but also noted some of its limitations: the study was not double-blind, the control arm (goserelin plus tamoxifen for 3 years) is not widely accepted, and there was no stratification for HER2. Another important observation was that the large confidence interval of the hazard ratio for disease-free survival comparing tamoxifen and anastrozole (HR = 1.096; 95% CI; 0.78, 1.53) suggests that this study was not adequately powered to detect a 20% difference between the two drugs. Dr. Piccart-Gebhart noted that the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial (Howell A, et al. Lancet. 2005;365[9453]:60-62) and the Breast International Group (BIG) 1-98 (Thurlimann BJ, et al. Abstract 511. Presented at: 2005 ASCO Annual Meeting) were powered to detect a 20% difference in disease-free survival between tamoxifen and an aromatase inhibitor. ATAC required 6,241 patients and 900 events, and BIG1-98 required 4,922 women and 770 events.

With regard to the zoledronic acid results, Dr. Piccart-Gebhart suggested that the data illustrate the 1889 “seed and soil” hypothesis of Paget (Paget S. Lancet. 1889;1:571-573), that is, zoledronic acid affects not only malignant cells (the “seed”), but also the tissues in which metastases grow (the “soil”). Dr. Piccart-Gebhart concluded that ABCSG-12 is not yet a practice-changing trial, but an important trial, “announcing a paradigm shift: targeting both seed and soil.”

END OF ASCO POST

The SWOG (Southwest Oncology Group) S0307 Study open at CORT continues enrollment.  This study evaluates the addition of one of three bisphosphonate drugs (Zoledronic Acid, Clodronate, or Ibandronate) in adjuvant therapy of breast cancer.  Patients with Stage I-III resected breast cancer are eligible.  They may have received chemotherapy and/or hormonal therapy.   ER+ and ER- patients are eligible.  The study enrolls pre- and post-menopausal patients. 

For more information about this study, call 972-566-5588 (Dallas) or 972-981-4012 (Plano), and ask to speak with a research coordinator.  More information about CORT and CORT studies is available at www.CORTPA.com.

Trial Assessing Femara (Letrazole) in Patients Intolerant to Arimidex (Anastrazole)

June 6, 2008

Femara (letrazole) is being assessed at CORT in a Novartis study for patients who have had intolerance to Arimidex (anastrazole) because of joint of muscle pain. Patients who have had NCI-CTC grade >=2 arthralgias or myalgias are eligible. After a 2-week period of discontinuation of Arimidex, patients will receive Femara, with continued standardized assessments of their joint and muscle symptoms. Femara will be provided by the study. The study will determine is patients are better able to tolerate Femara for their continued therapy.

For more information about this study, call 972-566-5588 (Dallas) or 972-981-4012 (Plano), and ask to speak to a Research Coordinator. More information about CORT and CORT studies is available at www.CORTPA.com.

Renal (Kidney) Cancer Trial at CORT: Immunotherapy and Sunitinib

June 6, 2008

CORT has opened the Phase II Argos Therapeutics trial of RNA-loaded autologous dendritic cell (DC)immunotherapy combined with standard sunitinib (Sutent) therapy for metastatic renal cell carcinoma (kidney cancer).  This study is open to newly diagnosed patients with Stage IV (metastatic) disease.  The trial employs Argos’ platform of enhanced DC technology to stimulate patient-specific immune response in a personalized DC preparation.  After consent and enrollment, the patient will undergo standard nephrectomy (removal of the cancerous kidney).  I a separate procedure, blood cells are collected by leukapheresis, a short procedure which removes circulating DC from the blood by the use of a machine.  Tissue from the tumor and the collected DC are processed by Argos to create DC that contain a DC product specific to the patient-specific tumor proteins.  After recovery from the surgery, the patient will receive standard sunitinib (Sutent) oral drug therapy and infusions of the personalized tumor DC product.  The outcomes of therapy (safety, responses, disease control, survival) will be followed.   Earlier phase studies have demonstrated safety of the Argos DC therapy. 

Unique advantages of a personalized, patient-specific immunotherapy include:

  • Dendritic cells transfected with RNA-encoding tumor antigens have been shown to stimulate potent immune cell responses equal or superior to other competing approaches
  • The immunotherapeutic is completely autologous (derived from the patient’s body), potentially offering maximum safety with minimal side effects
  • The immunotherapeutic targets the entire antigenic repertoire of the tumor including ‘private mutations’ unique to that patient
  • A single production run makes enough product to continuously treat the patient for several years
  • Production requires only a minute tumor specimen
  • Because it is important to be enrolled in the study prior to surgery, interested patients should seek referral at CORT for consultation PRIOR to surgery, so tumor tissue that is obtained at the time of surgery can be utilized in preparation of the individual DC product. 

    For more information about this study, contact one of our Research Coordinators at trials@cortpa.com or call 972-566-5588.   Information about CORT and this study is also available at www.CORTPA.com.