Immunotherapy and Sunitinib (Sutent) Investigation for Metastatic Renal Cell Carcinoma Opening at CORT

CORT has been chosen as an investigative site for a study of immunotherapy utilizing a primed autologous cellular vaccine in combination with standard sunitinib (Sutent) therapy for patients with metastatic renal cell carcinoma.  Patients who participate will have standard therapy with removal of the primary renal tumor, preparation of the cellular vaccine by harvest of peripheral blood cells by a simple procedure, and treatment with standard oral sunitinib therapy with delivery of the vaccine.  Patients will be followed for treatment response and long-term outcomes.

For more information about this study, visit the CORT website (www.CORTPA.com), or call and speak with a study coordinator at 972-566-5588.

Multiple Myeloma First-Line Treatment Study at CORT

Treatment options for multiple myeloma have significantly expanded over the past decade with the development of several new, effective combination drug therapy regimens.  These agents have been employed as stand-alone therapy for patients who are not candidates for high-dose melphalan and autologous bone marrow transplant (HD-BMT), as induction therapy (before HD-BMT), or for salvage treatment of patients who have failed HD-BMT.  Treatment response rates have approached or exceeded 90% in treatment-naive patients, and disease control and survival of patients receiving these therapies has significantly improved. 

Velcade (bortezomib) is a proteosome inhibitor with significant activity in myeloma therapy.  It has been FDA-approved for treatment of patients who have received at least one prior therapy, based on a large phase III study of Velcade with Dexamethasone.  In that study, patients received Velcade at 1.3 mg/m2 on day 1,4,8, and 11 every 21 days, with Dexamethasone 40 mg/d on days 1-4, 9-12 every 21 days.  After 8 three-week cycles, responding patients continued to receive Velcade weekly for 3 thiry-five day cycles.  The control group received high-dose Dexamethasone (HD-Dex) alone.   Cross-over was allowed in this study.  Velcade-Dexamethasone (VD) improved response compared to HD-Dex, 38% versus 18%.  Even with cross-over from HD-Dex to VD, the survival of patients who had initial VD versus HD-Dex was higher, with one-year survival of 80% versus 66%.  This was a 43% reduction in the risk of death at 1year. 

A subsequent study of VD versus HD-Dex (SUMMIT) confirmed these findings.

Velcade has been under extensive investigation as part of other drug therapy combinations for myeloma, both in the initial and salvage therapy treatment settings.  In the VISTA study presented at the American Society of Hematology meeting in 2007, the Velcade, Melphalan (oral), and prednisone (VMP) combination was compared to standard MP therapy for first-line treatment of myeloma.  MP therapy produced complete response (CR) in 4%, and partial response (PR) in 31%. The median duration of response (DOR) and of CR was 13 months each, the median time to progression (TTP) was 16.6 months, and the 2-year survival was 70%.  For VMP, the CR was 30%, PR 40%, median DOR 20 months, median duration of CR 24 months, median TTP 24 months, and 2-year survival 83%.  Treatment related death occurred in 1% of MP and 2% of VMP patients.  Most common toxicities included myelosuppression, fatigue, insomnia, infection, diarrhea, neuropathy, and nausea/vomiting, somewhat greater in the VMP treatment arm.

Thalidomide (Thalomid) is an oral drug with significant activity in myeloma.  The mechanism of action of Thalomid is not completely understood.  Thalomid and Dexamethasone may increase the risk of thrombosis in myeloma patients.  Anticoagulation strategies may reduce that risk.  Velcade, Thalomid, and Dexamethasone (VTD) has been compared to TD in a randomized study, the GIMEMA MMY-3006 Study reported at ASH in 2007.  The VTD regimen produced CR in 38% (versus 7% for TD) and PR in 63% (versus 25% for TD). 

Therefore, for newly diagnosed patients, the inclusion of first-line Velcade with either TD or MP appears to offer significant promise.  In the national US study UPFRONT, being conducted at CORT, first-line treatment with VD, VTD, or VMP are being randomly compared for efficacy and long-term outcomes.  For further information about this study, please visit the CORT website (www.CORTPA.com) or call to speak with a research coordinator at 972-566-5588.

Leukemia & Lymphoma Society “Ask the Doctor” Session 4/24/08

Dr. Barry Mirtsching will be the guest speaker for the LLS Dallas Chapter on Thursday, 4/24/08 at 7 PM.  The presentation title is “Ask the Doctor”.  Dr. Mirtsching will give a brief presentation on current therapy and investigational options for lymphomas and myeloma.  For more information or directions, please contact the Dallas Chapter of the Leukemia & Lymphoma Society:

8111 LBJ Freeway
Suite 425
Dallas, TX 75251
(972) 239-0959
(800) 800-6702 (Toll Free)

Predictive Markers for Breast Cancer Adjuvant Chemotherapy Benefit: Changing the Treatment Landscape?

The choice of adjuvant chemotherapy regimens for breast cancer patients has been primarily directed by the long-term results of clinical outcome (survival, freedom for relapse) that have been demonstrated in large, controlled clinical trials.   Such trials have most often been performed by NCI-sponsored national clinical oncology groups (”cooperative groups”), and they have involved hundreds or thousands of patients who have received an existing “standard-of-care” (SOC) therapy, or who have received an treatment under study for comparison to the SOC.  Patient eligibility for such studies was simply defined in most studies, incorporating factors such as TNM staging, estrogen receptor (ER) status, or menopausal status.  Results of such studies most often reported benefits for the treatment groups as a whole.  For example, the initial and follow-up reports of benefit for the addition of paclitaxel (Taxol) following AC (doxorubicin and cyclophosfamide) in the CALGB 9344 study demonstrated improved disease-free survival and overall survival. 

More recent updates of this study have retrospectively evaluated subgroups of patients according to ER and her-2 status to determine whether all patient groups appear to benefit from the addition of paclitaxel.  Not surprisingly, the study group published in the New England Journal of Medicine  (Volume 357:1496-1506, Oct 2007) an analysis demonstrating that ER positive and her-2 negative patients failed to benefit from the addition of paclitaxel.  Her-2 positive patients and ER negative, her-2 negative patients had substantial and significant benefit with the addition of paclitaxel.

Caution has been advised regarding changing the SOC for LN+ patients receiving adjuvant AC>Paclitaxel, based on the retrospective nature of the CALGB analysis, and conflicting information that exists in other studies such as NSABP B-28, MDAH FAC>paclitaxel versus FAC, and the BCIRG 001 Study.  The controversy has been discussed in this blog site previously.  However, the point to be considered is that as new molecular and genetic markers are defined, study of existing SOC treatments may determine that breast cancer patients do not benefit equally to these treatments.  Therefore, “cookie cutter” approach to selection of adjuvant therapy (without attention to individualized patient marker information) is not acceptable in designing new adjuvant studies.  However, it remains to be determined whether such marker-based selection of patients for specific therapy will result in improvements in overall clinical outcomes, when compared to more traditional selection of patients for specific therapy. 

The notion of individualized treatment selection, based on molecular or genetic profiles, is gaining ground as new information and testing capabilities evolve.  For instance, the TAILORx Study (offered at CORT) utilizes a predictive gene panel (OncoType Dx) to select patients at higher risk for recurrence.  Treatment selection is then determined based on the prediction of risk.  The ECOG 5103 Study (offered at CORT) uses the Oncotype DX score for ER+ patients who have tumors between 2-5 cm to determine eligibility for more aggressive therapy. 

Other markers are becoming available for helping in selecting patients at higher risk for treatment, or to assist physicians in selecting patients for specific therapies. The FDA approved the TOP2A FISH (fluorescent in situ hybridization) test (DAKO labs) on 15 January 2008. This test determines is the topoisomerase-2A gene is amplified or deleted in breast cancer tissue.  Tumors with these changes have a worsened prognosis, but are more likely to benefit from the addition of anthracycline-based therapy.  Recently, a meta-analysis of her-2 status as a predictor of anthracycline benefit (Journal of the National Cancer Institute, 2008; 100 (1): 14-20) showed that her-2 positive patients benefit from anthracycline versus non-anthracycline therapy, but her-2 negative patients do not.  This retrospective review must be interpreted with caution, because there may be subgroups of her-2 negative disease who may benefit from anthracyclines.  With the availability of the TOP2A test, one potential for testing involves her-2 negative patients, with selection of anthracycline treatment only in those where TOP2A is deleted or amplified, sparing other patients the risk of treatment.  

Microtubule-associated tau protein is under study as a predictor of benefit for taxane treatment.  Tumors with low tau expression have superior responses to taxane therapy (PNAS, 2005; 102 (23): 8315.).   Genetic profiles (delineating luminal, basal, her-2, or normal breast gene signatures) or immunohistochemical markers may identify classes of breast cancer with differences in prognosis and treatment response.  Specific gene mutations may also give rise to specific subtypes of breast cancer, with specific drug sensitivities (e.g., BRCA1 mutation tumors are more likely to be triple-negative, and lab studies show these tumors are more often sensitive to platinum drugs).  

In summary, the current adjuvant SOC treatments for breast cancer have been defined by large, randomized, well-controlled clinical studies, with established benefits when analyzed by the selection critieria that were utilized in the various studies.  However, in those older studies, selection methods have not integrated new molecular or genetic methods for defining patients at high risk for recurrence, or for defining tumor features that predict for benefit for specific drug therapy. These newly emerging test will require validation to determine their utility in practice, but clearly, the rapid integration of such testing is likely to drive an era of personalized medicine for breast cancer patients, with the potential rewards being better treatment outcomes with reduction in unnecessary treatment toxicities. 

For information on treatment studies at CORT, call 972-566-5588, or visit our website at:  www.CORTPA.com

Neoadjuvant Breast Cancer Chemotherapy Study Opening at CORT

A new drug combination and sequence for the pre-operative (neoadjuvant) treatment of localized breast cancer has begun at the Center for Oncology Research & Treatment (CORT) in Dallas, Texas.   Pre-operative chemotherapy for localized breast cancer is an established approach to therapy.  Reduction in tumor size may increase the proportion of breast cancer patients who are candidates for breast conservation surgery (lumpectomy).  Pre-operative therapy also may give important insight into what drug therapy benefits the patient individually, an observation that is not possible when chemotherapy is given after surgical excision of the breast cancer. 

An established sequence of pre-operative chemotherapy utilizes doxorubicin (Adriamycin, and anthracycline drug) and cyclophosphamide (Cytoxan) followed by paclitaxel (Taxol) therapy (AC>T>surgery).  Recently, improved response and survival in metastatic breast cancer has been demonstrated with the combination of gemcitabine (Gemzar) and paclitaxel (Taxol) (GT), when compared to paclitaxel therapy alone.  Based upon this promising finding, the integration of Gemzar into both adjuvant and neoadjuvant treatment studies has begun.  The NSABP (National Surgical Adjuvant Breast Project), an NCI-sponsored cooperative research group, has been testing the adjuvant post-operative treatment of AC>GT in comparison to standard AC>T.  In this study, drugs are given in a “dose dense” fashion, every 2 weeks. 

The International Oncology Network (ION) has initiated a study of pre-operative chemotherapy integrating gemcitabine and another new drug, Abraxane, into the treatment program.  Abraxane is paclitaxel packaged in microscopic albumin protein particles (nab-paclitaxel).  Studies of Abraxane in metastatic breast cancer have shown superior responses and disease control, compared to standard paclitaxel therapy.  In addition, because Abraxane is water soluble, it does not contain the solubility agent Cremaphor, which is responsible for most allergic reactions that are seen with standard paclitaxel.  Therefore, treatment with Abraxane is by short IV infusion (not requiring 3 hours, as with standard paclitaxel), and steroid premedication to prevent allergic reaction is not required.  Abraxane is more efficacious when administered as a weekly IV infusion.

The ION neoadjuvant study will treat localized breast cancer patients with weekly Abraxane x 8 weeks, along with gemcitabine (Gemzar) every 2 weeks x 4 cycles, followed by AC therapy every 2 weeks x 4 cycles (nab-PG>AC>surgery).  This study is unique in giving the non-anthracycline portion of therapy first.  This will allow the most direct observation of the benefit of the Abraxane-Gemzar combination in the treated patients.  All patients will have baseline clinical and radiographic assessments (breast MRI and sonography) of their tumors.  After completion of nab-PG and then AC, these assessments are repeated.  Assessment of the pathologic response to therapy will be made by examination of the surgical specimens obtained after after completion of all therapy.  A detailed analysis of clinical, molecular, and pathologic variables that influence response and outcomes will be assessed in the study.  Patients will be followed for long-term outcomes.

 For more information about this study, contact a Research Coordinator at 972-566-5588, or visit our website at www.CORTPA.com.   Dr. Barry Mirtsching or CORT is the author and National Principle Investigator for this study.

Satraplatin Fails to Improve Survival in Hormone Refractory Prostate Cancer

Satraplatin, a novel oral platinum compound under development, failed to improve overall survival in late-stage, pre-treated hormone refractory prostate cancer (HRPC).  Early evaluations of satraplatin in HRPC in the SPARC (Satraplatin and Prednisone Against Refractory Cancer) trial looked promising, but the final survival analysis did not show statistical improvement, and the Expanded Access Study Program has been closed to further accrual. 

The explanation of this finding is not yet known.  Investigators who had experience with Satraplatin were surprised, given the apparent activity that had been seen in some patients treated.   A careful analysis of the patients who responded may yield insight into what clinical or molecular/genetic determinants led to improvements in individual cases, which may lead to insights into how future trials with Satraplatin may be better designed to enrich the population of patients who are more likely to benefit from Satraplatin.

ASCENT-2 Novacea Study Halted

Novacea, Inc. (NASDAQ: NOVC) announced on 11/5/07 that the company has ended its Phase 3 ASCENT-2 clinical trial of Asentar(TM) (DN-101), the company’s lead investigational cancer therapy for the treatment of patients with androgen-independent prostate cancer, or AIPC, due to an imbalance of deaths between the two treatment arms, as observed by the Data Safety Monitoring Board (DSMB) for the clinical study.

The company and its partner, Schering-Plough, plan to fully analyze the clinical data to attempt to understand the cause of the higher death rate in the Asentar plus Taxotere(R) (docetaxel) treatment group. The study was comparing the benefits of weekly Asentar plus Taxotere to the current standard of care in the treatment of AIPC. To date, more than 900 of the planned total of 1,200 patients were enrolled in this study at multiple centers in various countries, including the United States, Canada, Germany, and Central Europe.
“The safety of the patients in our trials is our top concern. As such, Novacea and Schering-Plough have decided to end the ASCENT-2 trial, however, the product development alliance will continue,” said John P. Walker, chief executive officer of Novacea. “The findings in ASCENT-2 are extremely surprising and disappointing to us, given the promising clinical activity that we observed in our Phase 2 ASCENT trial. Importantly, preliminary analysis has not identified any unexpected safety findings with Asentar. Over the next few months, we plan to further analyze the data, and discuss the findings with ASCENT-2 principal investigators and with prostate cancer experts to attempt to determine the possible causes for this outcome. We have informed all relevant constituents, most importantly the clinical trial sites treating patients and the regulatory authorities, and have suspended enrollment in other ongoing or planned trials in other indications until we have had a chance to assess the data more completely,” said Mr. Walker.

Ixabepilone (Ixempra) Approved for Metastatic Breast Cancer

Ixabepilone (Ixempra) was approved on 10/16/07 for treatment of metastatic breast cancer.  The specific approval is: (1) Ixebepilone in combination with capecitabine (Xeloda) for treatment of metastatic or locally advanced breast cancer patients who have become resistant to anthracycline (such as Adriamycin) and taxane therapy (such as Taxotere or Taxol), or for patients who are resistant to taxane therapy, in whom further anthracycline therapy is contraindicated, and (2) Ixebepilone as monotherapy for treatment of metastatic or locally advanced breast cancer patients whose tumors are resistant to anthracyclines, taxanes, and capecitabine.

CORT was part of the multicenter study that established the efficacy of ixabepilone, and our physicians and nurses are experienced in management of this treatment.  CORT applauds the FDA decision to approve this drug, which should expand the treatment choices for these patients who have limited other treatment options.  For more information about treatment with ixabepilone, contact the CORT office at 972-566-5588 (Dallas), or at 972-981-4012 (Plano).  Information about CORT and the innovative treatments and studies offered can be found at our website: www.CORTPA.com.

Who Benefits from Taxanes: Controversy in Breast Cancer Management

The benefit of adjuvant paclitaxel (Taxol), in addition to anthracycline-based chemotherapy was evaluated in the CALGB 9344 study, which has previously been reported.  CALGB 9344 evaluated 4 cycles of escalating doses of doxorubicin (Adriamycin) combined with a fixed dose of cyclophosphamide (AC) with or without 4 cycles of sequential Taxol in 3170 women with node-positive primary breast cancer. After 52 months of follow-up, important changes were noted when compared with earlier interim analyses at 21 and 30 months follow-up.  Specifically, the addition of sequential paclitaxel to AC significantly improved the disease-free survival (P = .0324), but not overall survival (P = .0745). The disease-free survival rates for patients treated with sequential AC and Taxol versus those treated with AC alone at 48 months follow-up were 73% vs 70%, respectively. Overall survival rates for the 2 groups at 48 months were 84% vs 81%, respectively.

Molecular subtypes of breast cancer are now better defined.  Her-2 positive breast cancer (about 15% of all breast cancer) is an aggressive subtype, with growth driven by the over-expression of her-2 growth regulating receptors on the cancer cells.  Older studies, such as CALGB 9344 did not include the use of adjuvant anti-her-2 treatment, trastuzumab (Herceptin), in addition to chemotherapy, which is now the standard-of-care for her-2 positive disease.  It has been hypothesized that her-2 positive cancers benefit more from chemotherapy than other cancers, possibly because of increased levels of intracellular topoisomerase II (topo II), or because of a higher proliferation rate.  The question of whether her-2 positive breast cancer patients (when compared to her-2 negative patients) benefit to a greater degree by the addition of Taxol to AC was analyzed in a retrospective analysis of the CALGB 9344 study, which was published in the New England Journal of Medicine, October 11, 2007. 

In this analysis, Her-2 positivity was associated with a significant benefit from paclitaxel. The interaction between Her-2 positivity and the addition of Taxol to the treatment was associated with a hazard ratio for recurrence of 0.59 (P=0.01), a 41% reduction in risk. Patients with a Her-2-positive breast cancer benefited from paclitaxel, regardless of estrogen-receptor status.  Taxol did not benefit patients with HER2-negative, estrogen-receptor–positive cancers.   However, Her-2 negative, estrogen-receptor negative patients did have a significant reduction in the hazard ratio for recurrence (P=0.002), indicating that Taxol has benefit for some patients who are not Her-2 positive. 

Oncologists have been cautioned about premature interpretation and possible clinical practice changes until further study can confirm these results.  The CALGB analysis was retrospective, and the aggregate results of the study did show general benefit of Taxol adjuvant therapy for breast cancer patients.  Similar findings of benefit have been reported for adjuvant use of docetaxel (Taxotere) for adjuvant treatment of node-positive patients.  In addition, the use of taxol in the CALGB study (every 3 weeks) was not optimal, based on more recent studies that have demonstrated that Taxol is more effective when given on a more frequent schedule (weekly).  Therefore, the conclusion that adjuvant addition of weekly Taxol to AC might not be beneficial to estrogen-receptor positive patients requires confirmation.  Newer taxanes have been developed (for example, Abraxane, a nanoparticle of taxol in albumin protein), which may be more effective that Taxol.  A US Oncology study suggests that a more intensive taxane therapy and schedule may be a significant addition for her-2 negative and estrogen-receptor negative patients. Further study of taxanes in all molecularly-defined groups of patients is warranted, to determine what the degrees of benefits may be.  Finally, the substitution of taxane therapy for anthracycline-based treatment in the adjuvant setting appears to be a promising strategy in reducing possible cardiac toxicity of treatment. 

In summary, the CALGB study analysis is provacative, but not unexpected. Not all patients derive the same benefit from adjuvant treatments with different agents.  Taxane therapy should not be an immediate addition to every patient, but it should be considered based on a careful and individualized basis of each patient’s breast tumor characteristics, stage, and recurrence risk.  Additional study of taxane treatment in clinical trials, such as those offered at CORT, will be important in helping to improve treatment selection for patients.  In the meantime, it is premature to routinely deny patients with estrogen-receptor positive cancers the addition of a taxane in adjuvant therapy, without additional confirmatory study.

Screening for Colon Cancer: CT Colography (”Virtual Colonoscopy”) Compared to Traditional Colonoscopy

Software may  construct a three-dimensional CT scan image of the colon, which is termed CT colography, or “virtual” colonoscopy.  A report from the University of Wisconsin in the New England Journal of Medicine in October, 2007 compared virtual colonscopy (VC) to standard colonoscopy (SC) screening in approximately 6000 patients who were involved in parallel screening programs.  Prior studies of VC have shown that it can detect polyps of greater than or equal to 10 mm 90% of the time.  However, these prior reports have urged caution in the adoption of VC for screening.  The technique may miss smaller polyps, flat growths, or have diminished sensitivity for lesions in the right colon.  The preparation for VC is simpler and perhaps causes less distress.  However, at least 10% of VC studies were judged technically inadequate in prior studies, in some cases because of inadequate bowel cleansing.  The technique of VC is safe, and because it is non-invasive, the risk of bowel perforation is absent.  VC facilities are not widespread, software is potentially expensive, and radiologists are not all trained or experienced in VC interpretation.  When VC demonstrates a significant lesion requiring biopsy, then SC is required, which increases the cost (since both studies would be done) in such a patient.

The NEJM report demonstrated that the number of advanced neoplasms (polyps >=10 mm and/or cancers) found was the same for VC (3.2%) or SC (3.4%) screening, in a average risk population of patients.  The number of polypectomy procedures was significantly lower in the VC group (561) vs. the SC group (2434).  That finding is easily understood, since patients with 1-5 mm lesions found at VC were not further evaluated, and patients with 6-9 mm lesions found at VC were offered either observation or SC.  Only lesions >=10 mm at VC were referred for SC and biopsy.  Therefore, the referral rate for SC from the VC group was 7.9% (246/3120 patients).  7/3163 patients in the SC group experienced procedure-related bowel perforations. 

The potential drawback of VC noted by the authors is the possibility that failure to remove smaller lesions (<10 mm) might result in interval cancer development and progression, before the next planned VC follow-up.  The data does support that polyp size is a reasonable surrogate for histologically-advanced (pre-malignant or malignant) lesions, the ones that really should be removed.  In the study, lesions <10 mm were histologically advanced in only 20 polyps (15/6283 patients, prevalence 0.2%).  In the <=5 mm category of polyps (diminuative), only 4 polyps were histologically advanced. 

This study shows the promise of VC as a screening tool for average risk populations of patients.  The technique may help “filter” patients who require SC screening, which may improve resource-utilization and reduce costs.  The acceptance of VC be the general population might be superior as well.  The study supports that VC can be used by experienced centers to achieve screening outcomes that are equivalent to SC.  The risk of progression of small lesions that would be observed by serial VC (without biopsy) appears to be very small in this study.  Patients who may consider VC as an alternative to SC should do so with caution, investigating the experience of the center, and with attention to following a protocol for re-evaluations such as the one described in this study. 

Other methods of initial screening (to target patients who might require SC interventions) are under investigation, such as protein- or gene-based stool sample screening.   The use of these methods to identify patients who have cancer-related protein or gene products in the stool might serve as another non-invasive tool to identify patients who need SC.  However, these methods are not yet available or sufficiently validated.  Therefore, the prudent advice for patients is to continue with regular SC screening methods at intervals outlined in available accepted guidelines.