A PUBLICATION OF CAROLINAS HEALTHCARE SYSTEM UPDATES IN FOR CLINICIANS

JANUARY 2013

Updates from ASH 2012: Gene Encoding and Sequencing to Personalize Therapy

effector cells to the B cell-specific CD19 Dr. Ley summarized his own work antigen. CAR proteins expressed on T and that of others, including several cells were composed of an antibody that presentations at the meeting, using could bind to a specific target (here the whole genome sequencing to study CD19 antigen found on B cell leukemias) clonal evolution in large numbers of fused to a transmembrane domain patients with AML. By sequencing followed by one or more cytoplasmic several hundred primary tumor and Edward Copelan, MD (right) signaling domains to generate relapse genomes, Ley and colleagues Chair of the Department of Hematologic Oncology proliferative and antitumor activity. A T have provided an unprecedented view and Blood Disorders cell engineered with this design could of the development and evolution of specifically recognize a leukemia cell, AML. A series of non-transforming Belinda Avalos, MD (left) kill it, disengage and kill another—then mutations appear to accumulate with Vice Chair of the Department of Hematologic age in pre-leukemic stem cells. A Oncology and Blood Disorders divide and make more engineered T cells so that one cell could kill more dominant mutation cluster consisting Two important themes of the 2012 than 1,000 leukemia cells following of genes recurrently mutated in AML ASH meeting emerged from special injection, meriting it the moniker “serial leads to leukemic transformation by a lectures given by Carl June, MD, from killer.” In addition to achieving sustained founding clone. Extensive mutational the University of Pennsylvania and complete remissions in four of nine analysis can be used to discriminate recipient of the Ernest Beutler Award, evaluable patients with refractory CLL, intermediate risk AML patients into and Tim Ley, MD, from Washington complete remission was also obtained clinically relevant groups with distinct University and E. Donnall Thomas in a child with ALL who experienced life- prognoses and to delineate patients Award recipient. Dr. June presented threatening cytokine storm associated who would and would not benefit striking results using tumor-specific with tumor lysis that was successfully from intensified and/ cellular immunotherapy in two lymphoid treated with TNF and IL-6 antagonists. or transplantation. Relapse of AML malignancies, CLL and ALL. June and Along with accrual of larger numbers of results either from a founding clone colleagues introduced genes encoding patients with B-Cell malignancies, new which gains mutations that confer a artificial receptors called chimeric protocols are currently being developed survival advantage or from a subclone antigen receptors (CARs) into patients’ to extend the groundbreaking work of of the founding clone, detectable at autologous T cells in vitro in order to cancer-specific T cells to pancreatic, diagnosis, which survives initial therapy, redirect the specificity of these immune prostate and breast cancer. gains new mutations and expands at

CONTINUED ON PAGE 6

Stay Connected for Clinical Updates and Download The Cancer Letter, featuring Levine Cancer Institute: New Treatment Options Development of www.carolinashealthcare.org/updates-in-cancer Message from for Lung Cancer Highlights from Targeted Translational the President Patients with EGFR SABC 2012 Chemotherapy in Science Mutations Message from the President of Levine Cancer Institute

of Texas MD Anderson Comprehensive Cancer Center, Edward S. Kim, MD, will serve as chair of the Department of Solid Tumor Oncology. Edward A. Copelan, MD, FACP, from Cleveland Clinic’s Taussig Cancer Institute will serve as chair of the Department of Derek Raghavan, MD, PhD, President Hematologic Oncology and Blood Disorders. We have recruited more Carolinas HealthCare System’s than 50 faculty from the Carolinas and Levine Cancer Institute Research and Levine Cancer Institute is built on the across the USA. Administrative Headquarters. concept of cancer care without walls, Updates in Cancer for Clinicians will spanning throughout the system’s inform you on exiting news from Levine network of affiliated hospitals and Cancer Institute. providers in the Carolinas. The Institute is working to define the future of cancer We welcome your feedback at care – where innovations in research, [email protected] clinical trials, patient support and and look forward to bringing you more treatment are brought closer to home news in the future! for patients. We continue to build an elite cancer program, with the recruitment of A view of the infusion floor at internationally renowned experts to lead Levine Cancer Institute. the clinical teams. From the University

Translational Science Pharmacogenic Approaches to Personalize Cancer Therapy

A key event in the development of inhibiting its activity, the therapeutic AML is the disruption of the myeloid efficacy of ATRA could be potentiated. differentiation program and aberrant Specifically, the combination of ATRA self-renewal of leukemic stem cell. and topoisomerase II inhibitors, such as Differentiation therapy with the retinoic ICRF-193 or dexrazoxane (a clinically acid analog, all-trans retinoic acid active topoisomerase II inhibitor), (ATRA) has been successful in treating led to enhanced differentiation and Ram Ganapathi, PhD (left) acute promyelocytic leukemia, a preferential activation of the cell death Chair of Cancer Pharmacology cytogenetically distinct subtype of AML pathway, as compared to differentiation characterized by the PML-RARα gene coupled growth arrest induced by Marukh Ganapathi, PhD (right) translocation. However, ATRA has ATRA alone. Based on this preclinical Senior Scientist shown little promise in differentiation finding, we were able to formulate a therapy of other subtypes of AML. To clinical hypothesis that the combination Complexities in the genetic landscape develop strategies that would improve of ATRA with the clinically relevant of tumors significantly impact the differentiation therapy for other forms topoisomerase II catalytic inhibitor, design of optimal strategies for effective of AML, including relapsed/refractory dexrazoxane, leads to improved treatment of cancer. The goal of Cancer disease, we studied the role of a key response in AML patients. We are Pharmacology/Translational Research nuclear enzyme, topoisomerase II, in now poised to test this hypothesis in at Levine Cancer Institute is to support ATRA-induced differentiation of AML and develop novel paradigms for cancer cells. Using different AML cell lines and care. As such, our ongoing translational AML blast cells from relapsed/refractory CONTINUED ON PAGE 7 research has focused on the areas of patients, we were able to demonstrate acute myeloid leukemia (AML), renal cell that by targeting topoisomerase II, carcinoma and ovarian cancer. either by deleting the enzyme or

2 I UPDATES IN CANCER FOR CLINICIANS A PUBLICATION OF CAROLINAS HEALTHCARE SYSTEM

Novel Treatments for Lung Cancer Patients With EGFR Mutations

of 13.6 versus 6.9 months (HR, 0.47; molecular profiling is necessary in order p<0.0001). (2) Additionally, objective to provide the best available therapy. response rate, disease control, cancer- This requires sufficient tissue sampling related symptoms and quality of life for precise pathologic diagnosis. While were also improved with afatinib. The patients with unknown driver mutations most frequent adverse events were are still treated with chemotherapy, diarrhea and rash, although no patients those with EGFR mutations or ALK Edward S. Kim, MD (left) discontinued afatinib for rash. LUX- rearrangements have expanding options Chair of the Department of Solid Tumor Lung 3 is the first randomized study to for targeted personalized treatment. Oncology and Investigational Therapeutics demonstrate benefit of an oral targeted REFERENCES therapy versus chemotherapy in a 1. http://seer.cancer.gov/statfacts/html/lungb.html Kathryn Mileham, MD (right) molecularly selected population. Based 2. Yang JC, Schuler MH, Yamamoto N, et al. LUX-Lung 3: Medical Oncology on these results, afatinib is currently A randomized, open-label, phase III study of afatinib versus and as first-line treatment for patients with available through an open label advanced adenocarcinoma of the lung harboring EGFR-activating Lung cancer remains the leading expanded access program at a starting mutations. J Clin Oncol 2012;30(suppl): LBA7500. cause of cancer-related deaths in the dose of 40 mg/daily. United States, (1) and non-small cell While management of lung cancer lung cancer (NSCLC) accounts for more is in rapid evolution the standard of than 85 percent of the cases. With most “chemotherapy for all” no longer exists. patients presenting with advanced National guidelines concur that disease, there is an urgency to maximize treatment efficacy while minimizing drug toxicity. Through a deeper EXTRACELLULAR understanding of the biology driving DOMAIN NSCLC, novel treatment paradigms EGFR HER2 HER2 are based on disease biomarkers with EGFR HER2 EGFR A HER2 corresponding . This HER4 HER3 has been best achieved with advanced EGFR

HER2 treatment options for the two-thirds HER3

HER4 of adenocarcinoma patients in whom EGFR driver mutations are identified. Somatic mutations in the tyrosine B kinase domain of the epidermal growth factor receptor (EGFR) are found in 15-

20 percent of lung adenocarcinomas. KINASE INTRACELLULAR TYROSINE Afatinib is an oral small-molecule DOMAIN EGFR-tyrosine kinase inhibitor that binds irreversibly to EGFR and NU HER2. Recent compelling data from CLE US the LUX-Lung 3 trial have been reported. In this randomized phase III PROLIFERATION study, patients with EGFR-mutated, PROGRESSION DIFFERENTIATION advanced lung adenocarcinomas were treated frontline with afatinib versus pemetrexed-cisplatin. The A: The epidermal growth factor family of B: Afatnib is an oral, small-molecule, EGFR- extracellular protein ligands includes cell surface tyrosine kinase inhibitor that irreversibly binds to study enrolled 345 patients and met receptors EGFR (ErB-1), HER2 (ErB-2), HER3 (ErB- the ErbB family homo- and heterodimers inhibiting 3), and HER4 (ErB-4). When EGFR is dimerized, signal transduction. its primary endpoint demonstrating intrinisic intracellular tyrosine kinase activity significantly prolonged progression is stimulated by autophosphorylation causing downstream activation and signaling leading to DNA free survival (PFS) in patients treated synthesis and cell proliferation. with afatinib (11.1 vs 6.9 months; HR, Mutations in EGFR are clustered near the tyrosine 0.58; p=0.0004). In preplanned analysis, kinase domain possibly providing stabilization and additive gain. Therapeutic approaches targeting those patients with common mutations EGFR tyrosin kinase halt this signaling cascade. (Del19 or L858R) had a median PFS

www.carolinashealthcare.org/updates-in-cancer I 3 Levine Cancer Institute: Built on the Strength of a Network

At Levine Cancer Institute we’ve developed a sophisticated The Institute’s research and administrative headquarters academic and clinical cancer institute without walls, located in Charlotte, NC, opened in October 2012. While the spanning Carolinas HealthCare System (CHS) and providing Institute functions as a series of integrated cancer programs state-of-the-art treatment and research programs are closer distributing high-quality cancer care system-wide, this to where our patients live. building serves as its center for communication, research and administration. It houses the technology infrastructure to seamlessly connect physicians and care teams and share best practices and programs. The building features nine cancer clinics, infusion therapy, palliative care, as well as cutting-edge teleconferencing technology that allows physicians to collaborate long-distance, further breaking down geographic barriers and improving care across CHS. With six floors and more than 171,000 square feet of space, the building includes an extensive clinical trials operation with a special Phase I therapeutic unit designed to evaluate new treatment options, and multidisciplinary clinics to treat complex and rare . “The opening of the building is symbolic of the entire Levine Cancer Institute network being fully functioning, for the advancement of patient care across the Carolinas,” said Dr. Derek Raghavan. “The new resources and technology this space affords will enable us to be better connected to our partner institutions across the Carolinas to share knowledge, standard protocols and research, while offering patients in Charlotte a state-of-the-art CHANGING THE COURSE OF CANCER CARE place to receive their cancer care.”

Integration of Roper St. Francis Cancer Care Into Our Network

provided by Roper St. Francis Cancer is a national model that shows how we Care physicians, who help more than are investing in our community and the 1,700 newly diagnosed cancer patients lives of patients by removing barriers each year. Top tumor sites include that separate them from access to breast, prostate, lung and colorectal breakthrough research and treatments.” cancers. Roper St. Francis Cancer “ The providers and patients of Roper Care is the market leader by volume for St. Francis Healthcare are excited Steve Akman, MD, breast, prostate and colorectal cancers*. about our partnership with Levine Medical Director, Roper St. Francis Cancer Care The relationship between Levine Cancer Institute,” said Steven Akman Cancer Institute, Roper St. Francis MD, Medical Director of Roper St. In 2012, Carolinas HealthCare System’s Cancer Care and other member Francis Cancer Care. “This partnership Levine Cancer Institute announced institutions brings increased access facilitates rapid access to advanced its charter member institutions, to cancer specialists, research and cancer therapies and technologies in our including Roper St. Francis Cancer innovative programs and services to Charleston community that heretofore Care, as part of the system’s new patients closer to where they live. had only been available to institutions cancer care network. “We take cancer care very seriously. of the size and scale of Levine Cancer Roper St. Francis Cancer Center Through our elite network of affiliated Institute.” was established in 2010 through a hospitals and physicians across partnership between Roper St. Francis *Based upon 2010 data provided by the Commission on Cancer the Carolinas, we are able to bring of the American College of Surgeons Healthcare and Charleston Hematology patients the best cancer care in a Oncology Associates. The 76,000 more convenient way,” said Derek square-foot outpatient cancer center Raghavan, MD, PhD, and President of is home base for many of the services the Institute. “Levine Cancer Institute

4 I UPDATES IN CANCER FOR CLINICIANS A PUBLICATION OF CAROLINAS HEALTHCARE SYSTEM

Highlights from SABC 2012

percent for controls (absolute risk compared to 62 percent of the black reduction 3.7 percent). Breast cancer women (p<0.001). Further analysis mortality during these same years noted differences between 7 and 15 was 12.2 percent versus 15 percent, percent for every year from 2002 to for an absolute mortality reduction of 2007. With adjusted analysis, black 2.8 percent. The greatest additional women were 33 percent less likely benefit was seen in the second decade to undergo SLNB than white women Wendy Brick, MD (left) after diagnosis, as there was almost (relative risk=0.74, 95 percent CI 0.67- Medical Oncology no difference in death and recurrence 0.81, p<0.001). between the two groups during the five Black women in the U.S. have a 41 Richard White, MD, FACS (right) years of extra tamoxifen. The difference percent higher breast cancer death Surgical Oncology came in later years, consistent with rate than white women despite a lower the understanding that tamoxifen incidence. 45 percent of black women has an effect that lasts long after are diagnosed with regional or distant women stop taking it. Breast cancer disease versus 35 percent of white mortality during the second decade women [MMWR 2012]. Van Ravesteyn after diagnosis was decreased almost [2011] proposed a model suggesting 30 percent in women who continued that differences in screening use tamoxifen for 10 years. explained 8 percent and differences in These results are relevant for any adjuvant therapy explained 19 percent woman currently taking tamoxifen and of these disparities. Methods to address Steven Limentani, MD (left) may be even more so for premenopausal disparities are being tested throughout Medical Oncology women, who have little risk of tamoxifen the U.S. and are critical to changing the causing uterine cancer or venous course of cancer care. MD, FAC Teresa Flippo-Morton, (right) thrombotic events. Women and their REFERENCE: Surgical Oncology doctors should consider this evidence Black DM, San Antonio abstract 2012 when deciding how long to continue Axillary Node Dissection May The ATLAS Trial: tamoxifen or any other endocrine therapy. Not Be Needed For Everyone Treatment Implications Evaluation of the long-term side ACOSOG Z-1071 studied the use of While current treatment guidelines effects of longer term tamoxifen sentinel node biopsy in a group of women recommend that women with estrogen will require lengthier follow up and with breast cancer who had previously receptor positive breast cancer receive meta-analysis of all relevant trials for been considered contraindicated for anti-estrogen therapy for five years, final assessment. this procedure; biopsy-proven node the recently published results of the REFERENCE: positive women. This multicenter trial Adjuvant Tamoxifen: Longer Against The Lancet, 2012 DOI: 10.1016/S0140-6736(12)61963-1 enrolled 756 women with node positive Shorter (ATLAS) results suggest that 10 breast cancer. years of adjuvant treatment should be Racial and Staging Disparities All patients received neoadjuvant considered for some women. Racial disparities in the care of chemotherapy prior to surgery. All The international trial recruited women with breast cancer have women had re-evaluation of the axilla patients from 1996-2005 and enrolled become the norm rather than the with ultrasound and then surgery patients were randomized to stop exception (MMWR 2012, Lund 2008, with a sentinel lymph node procedure tamoxifen at five years (control) van Ravesteyn 2011). Investigators (encouraging both blue dye and or continue for a total of 10 years. from MD Anderson Cancer Center radionucleotide for mapping), followed Allocation to continue tamoxifen for used SEER Medicare data to assess by complete axillary node dissection. 10 years versus stopping at five years the utilization of the relatively new reduced breast cancer recurrence (617 technology of axillary sentinel lymph CONTINUED ON PAGE 6 recurrences in 3,428 women allocated node biopsy (SLNB) in the staging of to continue versus 711 in 3,418 controls women with breast cancer. The use of p=0.002) and breast cancer mortality SLNB was compared in white women (311 deaths with recurrence in women versus the use in black women. allocated to continue versus 397 in 5.7 percent of 31,274 women controls p=0.01). Risk of recurrence retrieved from the database were black during years 5-14 was 21.4 percent while 89 percent were white. 74 percent for continuing tamoxifen versus 25.1 of the white women underwent SLNB,

www.carolinashealthcare.org/updates-in-cancer I 5 Highlights from SABC 2012

CONTINUED FROM PAGE 5 treated in the neoadjuvant setting TDM-1, and revealed eight of nine (88 percent) Results demonstrated that 40 percent Pertuzumab in Breast Cancer treated with the doublet and three of of patients with positive sentinel lymph Patients five (60 percent) treated with the triplet node prechemotherapy had a complete T-DM1 is a drug in which Trastuzumab regimen achieved a pathologic complete pathologic response in the axilla. The has been covalently linked to a novel response in the breast and lymph nodes. false negative rate of the procedure was chemotherapeutic emtansine, also More data will be available once all 12.6 percent, though the SLN procedure known as DM1. Pertuzumab, in contrast, patients have undergone the surgical was able to correctly identify nodal interferes with her2- her3 dimerization, portion of their treatment. Although the status in 91 percent of patients. Further a novel action different from the numbers are small, the rate of pathologic evaluation of the data is needed before mechanism action of Trastuzumab. complete response is encouraging. Data this can routinely change practice, but it This phase I dose escalation study will be utilized as the basis for a phase III does give hope that a subset of women was performed beginning with stage IV randomized trial that will compare these with node positive disease in the axilla disease patients, but also those with combinations to the current standard may, in the future, be able to omit an stage II and stage III breast cancer treated of care for women with breast cancer automatic axillary node dissection. in the neoadjuvant setting followed by an treated in the neoadjuvant setting. expansion cohort. Sites for this study REFERENCE: REFERENCE: Martin Miguel; “Interim Results From a Phase 1b/2a Study 1. Boughey Judy C, Suman Vera J, Mittendorf Elizabeth A, et. al; included Levine Cancer Institute, Baylor of Trastuzumab Emtansine and Docetaxel, With and Without “The role of sentinel lymph node surgery in patients presenting Pertuzumab, in Patients With HER2-Positive Locally Advanced with node positive breast cancer (T0-T4, N1-2) who receive College of Medicine and multiple sites in or Metastatic Breast Cancer”, presented at San Antonio Breast neoadjuvant chemotherapy results from the ACOSOG Z1071 Cancer Symposium, Dec. 5, 2012, San Antonio, Texas. trial”, Abstract presented at: 35th San Antonio Breast Cancer Europe. Symposium: abstract S2-1. Presented Dec 5, 2012, San Antonio, Genetically engineered adoptive cell therapy Texas. The study demonstrated that doublet 2. Johnson K, “ In Node-Positive Breast Cancer, Sentinel Biopsy via CAR-expressing T-cells Could Avert ALND”, Medscape, Dec 6, 2012. and triplet combinations were well tolerated. Early analysis of patients

Updates from ASH 2012: Gene Encoding and Sequencing to Personalize Therapy

CONTINUED FROM FRONT PAGE Malignant Malignant B-Cell relapse. A comparison of relapse versus but offers clinicians B-Cellbetter tools for risk primary tumor mutations demonstrated assessment and selection of existing CD19 increased numbers of transversions at initial therapy and CD19 new weapons, relapse, likely resulting from cytotoxic including “serial killer” cells, for the chemotherapy. melee.

In addition, Francesco Lo-Coco, MD, REFERENCES: from the University of Rome Tor Vergata, 1. Lo-Coco Francesco, et. all; 54th American Society of Hematology Annual Meeting, Atlanta, GA, 2012 Abstract 6. Chimeric 2. Adamia Sophia, et. all; 54th American Society of Hematology Antigen presented interesting results from a Annual Meeting, Atlanta, GA, 2012 Abstract 652. Receptor 3. Fisher A, Daniel C, et. all; 54th American Society of Hematology phase III, randomized, prospective trial Annual Meeting, Atlanta, GA, 2012 Abstract 706. (CAR) from the Italian GIMEMA group and 4. Porter David L, et. all; 54th American Society of Hematology Annual Meeting, Atlanta, GA, 2012 Abstract 717. German SAL and AMLSG groups at the 5. Kalos Michael, et. all; 54th American Society of Hematology Annual Meeting, Atlanta, GA, 2012 Abstract 756. Plenary Session. Data demonstrated 6. Ley Timothy J; 54th American Society of Hematology Annual Meeting, Atlanta, GA, 2012, E. Donnal Thomas Lecture: The AML a two-year, non-inferior EFS in adult Genome. 7. Blazar BR, June CH; 54th American Society of Hematology patients with newly diagnosed non- Annual Meeting, Atlanta, GA, 2012, Ernest Beutler Lecture: T-Cell CAR-Expressing Infusions: A New Tool for Transfusion Medicine That Has Come of T-Cell high-risk APL (WBC ≤10x109/L) treated Age. with a chemotherapy-free regimen of

ATRA and compared to CD19

standard ATRA + . Single chain of linked variable heavy Together, these presentations + light regions of anti-CD19 mAb demonstrate that the leukemic genome Transmembrane domain in an individual patient is a “moving Co-stimulatory domain target”, whose cure requires eradication Signaling domain Figure 1: Genetically Engineered Adoptive of the founding clone and its subclones, Cell Therapy Via Car-Expressing T-Cells. TCR-derived CD3ζ chain

6 I UPDATES IN CANCER FOR CLINICIANS A PUBLICATION OF CAROLINAS HEALTHCARE SYSTEM

Translational Science Pharmacogenic Approaches to Personalize Cancer Therapy

CONTINUED FROM PAGE 5 preclinical mouse models that mimic suggest that specific single nucleotide Using high throughput sequencing relapsed/refractory AML. This study will polymorphisms (SNPs) in the VEGF strategies, we sought to identify genes serve as a platform in the development gene and the combination of VEGF that are deregulated in ovarian cancer of a clinical protocol for treating AML. and VEGF-receptor may be useful as and contribute to failure of adjuvant In the past few years, treatment of markers to define treatment associated treatment or disease recurrence renal cell cancer has included the toxicity and overall survival, respectively. following an initial complete response. discovery and approval of drugs that Ovarian cancer is a major cause Our preliminary studies have identified target angiogenesis related pathways. of mortality among gynecologic a subset of genes that can distinguish However, the rapid entry of these malignancies in the United States and tumors that respond well to therapy drugs in clinical practice has not Western Europe. The standard of care and those that potentially lead to kept pace with our understanding for patients with advanced disease early relapse or recurrence. Following of treatment associated toxicity and includes surgical cytoreduction of validation of these genes in a larger mechanisms governing response to tumor burden followed by adjuvant patient cohort, we plan to carry out optimize therapy. We have embarked chemotherapy with a platinum-based prospective clinical trials using the gene on a pharmacogenomic approach of regimen that in most cases includes a signature to predict treatment failure or screening for DNA polymorphisms in . Although response rate with recurrent disease. Results from these gene(s) associated with angiogenesis this approach is high (>70 percent), studies could allow us to offer alternate related pathways that can be exploited resistance to primary therapy and therapeutic strategies to patients with to maximize efficacy and reduce toxicity subsequent recurrence (relapse) is resistant or recurrent disease. of targeted therapy for kidney cancer. substantial. A further complication REFERENCE: Studies analyzing polymorphisms in is the limited success of second line Genome Med. 2011 Dec 30;3(12):79; Cancer 118: 1946-1954, vascular endothelial growth factor therapy in patients failing primary 2012. (VEGF) and VEGF-receptor (VEGFR) therapy or those with recurrent disease.

Figure 1: Preclinical Studies in AML Evaluating Response of Patient Blast Cells to the Combination of ATRA and ICRF-193.

Figure 2: Association of VEGF and VEGFR2 SNPs with Toxicity (P = .01) and Overall Survival (P = .03) in Renal Cell Carcinoma Patients Treated with Sunitinib.

www.carolinashealthcare.org/updates-in-cancer I 7 Targeted Receptor Therapy for Ovarian Cancer The PRECEDENT Study

targeted cancer therapy.[6] Further, FR had the best clinical response [8] and expression appears to be a negative this hypothesis was supported by results prognostic factor in ovarian cancer from the PRECEDENT trial. In this group, patients and may allow targeting of the hazard ratio for disease progression cells that are resistance to conventional was 0.381 (p=0.013) resulting in a median chemotherapy.[4, 5] PFS increase from 1.5 to 5.5 months. The therapeutic agent vintafolide This is the first randomized trial to show is a folate-chemotherapy conjugate a significant benefit to combination Wendel Naumann, MD, FACOG, FACS, (left) designed to deliver desacetylvinblastine chemotherapy in platinum resistant Gynecologic Oncologist monohydrazide (DAVLBH) directly to ovarian cancer.[7] FR-expressing cells while minimizing Based on the success of the James Symanowski, PhD (right) exposure of vintafolide to non- randomized phase II trial, the PROCEED Biostatistician FR-expressing cells.[6] Normally, trial has been launched as an international DAVLBH is so toxic that it cannot be phase III approval trial for vintafolide Epithelial ovarian cancer is the second used systemically. However, it can in women with FR-positive ovarian most common gynecologic malignancy be conjugated with folate in such a cancer by etrafolatide scan. The trial in the United States.[1] The combination way that the drug is only active when will be conducted in approximately 600 of aggressive surgery, platinum- taken up into the cell and the linkage participants, with a primary objective to based chemotherapy, intraperitoneal is broken by the lower intracellular compare PFS between the study arms in chemotherapy and the development pH. Toxicity from this agent is minimal FR-positive participants. of new drugs has resulted in a median due to nonspecific hepatic breakdown survival of approximately five years in REFERENCE: resulting in constipation. 1. Siegel R., D. Naishadham and A. Jemal, Cancer statistics, 2012. women with advanced ovarian cancer. We conducted the first randomized, CA: a cancer journal for clinicians, 2012.62(1): p. 10-29. [2] When patients become resistant to 2. Armstrong D.K., et al., Intraperitoneal cisplatin and in open label, international phase II ovarian cancer. The New England Journal of Medicine, 2006.354(1): platinum, response rates are less than p. 34-43. clinical trial with this compound in the 3. Naumann R.W. and R.L. Coleman, Management strategies for 20 percent and overall survival (OS) is recurrent platinum-resistant ovarian cancer. Drugs, 2011.71(11): p. PRECEDENT trial comparing vintafolide 1397-412. less than one year [3]. The development 4. Low P.S. and A.C. Antony, Folate receptor-targeted drugs for in combination with pegylated liposomal cancer and inflammatory diseases. Advanced drug delivery reviews, of new drugs is needed, but until 2004.56(8): p. 1055-8. (PLD) versus PLD alone, in 5. Kalli K.R., et al., Folate receptor alpha as a tumor target in recently, no clinical trial has generated epithelial ovarian cancer. Gynecologic oncology, 2008.108(3): p. women with platinum-resistant recurrent 619-26. any advantage over single agent therapy. 6. Reddy J.A., et al., Preclinical evaluation of EC145, a folate-vinca ovarian cancer.[7] The primary objective alkaloid conjugate. Cancer research, 2007.67(9): p. 4434-42. Folate is a vitamin required for DNA 7. Naumann R.W., et al., PRECEDENT: A randomized phase II trial was to compare the PFS population comparing EC145 and pegylated liposomal doxorubicin (PLD) in replication and cell division. Folate of patients with measurable disease, combination, versus PLD alone, in subjects with platinum-resistant receptor (FR) is strongly expressed ovarian cancer. J Clin Oncol, 2011.15_suppl(29): p. 5045. and results were statistically significant 8. Symanowski J., et al., Use of 99m-Tc-EC20 (a folate-targeted in many cancers, including over 80 imaging agent) to predict response to therapy with EC145 (HR=0.626; p=0.031). Previous studies (folate-targeted therapy) in advance ovarian cancer. J Clin Oncol, percent of epithelial ovarian cancers 2010.28(15_suppl): p. 5034. suggested patients in whom all lesions but not in normal tissues, making FR expressed the folate receptor by scan an excellent molecular candidate for

Stay Connected for Clinical Updates and Download The Cancer Letter, featuring Levine Cancer Institute: www.carolinashealthcare.org/updates-in-cancer