Northfelt, Donald W.

e13052 Background: The combination of GEM and CDDP has shown activity in a variety of cancers, including biliary tract/gallbladder. Preclinical testing shows a potential benefit to the addition of EV. Methods: Using a standard 3+3 design, the MTDs of GEM + EV (Cohort I) and GEM + CDDP + EV (Cohort II) were determined as shown in the table. The MTD was defined as the dose level below the lowest dose that induces a DLT in at least one-third of pts. At the MTD of Cohort II, 10 patients were enrolled with biliary tract/gallbladder cancer (Cohort III). A weekly CBC was obtained. Assessments occurred every 3 weeks and imaging for response at every other cycle. Results: In Cohort I (N=12), no DLT occurred at dose level 0, and in dose level 1, grade 3 thrombocytopenia was found in 2 of 6 pts. The MTD for Cohort I was determined to be dose level 0. Responses were seen in 3 pts: 2 CRs (primary peritoneal, pancreatic) and 1 PR (breast). In Cohort II (N=15) DLTs at dose level 0 were neutropenia and thrombocytopenia in 2 of 3 pts and at dose level -1, thrombocytopenia in 2 of 6 pts. At dose level -2, 1 of 6 pts experienced a DLT (grade 3 thrombocytopenia), establishing this dose level as the MTD. Responses were seen in 2 pts, both PRs (ampullary, pheochromocytoma). All 10 pts have been enrolled in Cohort III with 2 DLTs (neutropenia and thrombocytopenia). Stable disease seen in 5 of 7 evaluable pts. Conclusions: Gem + EV was well tolerated at dose level 0, though dose escalation was limited by thrombocytopenia. GEM + CDDP + EV had DLTs of neutropenia and thrombocytopenia leading to the MTD of dose level of -2. Cohort III is fully accrued and the 2 DLTs are hematologic. [Table: see text]

6527 Background: Biomarker information can risk stratify patients based on potential for benefits/toxicity from therapy. Ideally, a biomarker will identify those who benefit with limited toxicity. However, the impact of biomarkers is unclear when indicting individuals with greatest benefit are also at increased risk for toxicity. Methods: We surveyed participants at 18 month follow-up in the Decision-Making/Quality of Life (DM-QOL) component of ECOG5103, a RCT where patients were randomized to receive adjuvant chemotherapy for breast cancer with either placebo or bevacizumab (in 2 schedules). We asked patients for the preferred treatment in two hypothetical scenarios: 1) preference for chemo A or chemo A + B without biomarker information; 2) preference for chemo A or chemo A+B when participants tested positive for a “B-receptor” which increased both the benefit and toxicity of chemo A+B. McNemar’s test was used to examine changes in preferences. Results: 439 patients completed both scenarios on 18-month survey. The Table shows the treatment preferences in each scenario. The positive biomarker information in scenario 2 led 60/439 (14%) participants to switch their preference. The main reason for treatment preference in scenario 2 was greater benefits of chemo A+B (64%), the lower risks with chemo A (20%) and positive biomarker (10%). Among participants who changed preference, those randomized to receive bevacizumab were more likely to switch to chemo A in scenario 2. Conclusions: Information about a positive biomarker, indicating increased benefit and increased risk from additional chemo, did not significantly change participants’ preferred treatment. All participants were involved in a large placebo controlled double blind trial and the majority (70%) preferred the most aggressive course of treatment in both scenarios. Whether patients not enrolled in the trial would be more sensitive to the increased risk information is unclear. [Table: see text]

522 Background: In the adjuvant setting, patients with HER2 breast cancer treated with trastuzumab and chemotherapy have superior survival compared to patients treated with chemotherapy alone. We previously showed that trastuzumab and chemotherapy induces HER2-specific antibodies which correlate with response to therapy in patients with HER2+ metastatic breast cancer. It remained unclear from those studies, however, whether the HER2-specific immunity played a role and if antibody immunity was associated with improved disease free survival in the adjuvant setting. In the present study, we addressed these questions by analyzing sera samples from a subset of patients enrolled in the NCCTG adjuvant trial, N9831, which includes an arm (Arm A) in which trastuzumab was not used. Arms B and C received trastuzumab sequentially or concurrently to chemotherapy, respectively. Methods: Pre-and post-treatment initiation sera were obtained from 50 women enrolled in N9831 (22 Arm A; 14 Arm B, and 14 Arm C). Lambda IgG antibodies (to avoid detection of trastuzumab) to HER2 were measured and presented as an index (>0.2 was considered a positive response). Results: Prior to therapy, across all three arms, N9831 patients had similar mean HER2 IgG levels (0.19 units in Arm A, 0.14 in Arm B, and 0.23 in Arm C, P=0.85). Following treatment, the mean levels of antibodies increased in Arm B to 0.35 units and in Arm C to 0.56 units and were higher (p<0.001) than in Arm A where levels did not increase. The proportion of patients who demonstrated antibody immunity increased by 9% in Arm A, 50% in Arm B and 28% in Arm C (P=0.026). Although the event rate was low in this cohort, Cox modeling suggested that larger increases in antibodies were associated with improved disease free survival (HR=0.23; p=0.04). Conclusions: These results show that the increased antibody immunity observed in adjuvant patients treated with combination trastuzumab and chemotherapy is clinically significant and results from the inclusion of trastuzumab. The findings may have important implications for improving treatment outcomes in patients treated with trastuzumab.

521 Background: The addition of trastuzumab to chemotherapy improves responses to therapy and extends survival among patients with metastatic HER2 breast cancer. Several mechanisms have been proposed for the activity of this combination therapy. Trastuzumab, specifically, is thought to activate NK cells and blunt HER2 signaling. Prior work from us has shown that combination trastuzumab and chemotherapy induces HER2-specific antibodies which correlate with response to therapy. Despite that, it remains unclear whether the immunity that was induced was due to complexing of non-tumor derived HER2 or antigen derived from the tumor site. In the present work, we addressed this question by assessing if combination therapy induced epitope spreading to tumor antigens other than HER2. Methods: Pre-and post-treatment sera were obtained from 56 women enrolled in 2 NCCTG clinical trials, N0337 and 98-32-52. IgG antibodies to HER2 intracellular domain (HER2), p53, IGFBP2, CEA and tetanus toxoid (TT) were examined using ELISAs. Sera from an age-matched group (N=56) of controls and 12 patients treated in the adjuvant setting were also examined. Results: Prior to therapy, metastatic patients had higher IgG levels (≥ 2-fold) to p53 and HER2 but not CEA, IGFBP2 and TT, relative to the controls. Similarly, adjuvant patients had elevated IgGs to multiple tumor antigens prior to therapy, relative to controls. Following therapy, levels of IgG to IGFBP2, HER2, and p53 increased in 81% of metastatic patients, with mean increases of 3.2 (±0.6 sem), 6.2 (±2.7) and 2.7 (±0.7) fold, respectively (p<0.05). Levels of antibodies to TT and CEA were not elevated by treatment. In contrast, IgGs were not increased in adjuvant patients; consistent with the idea that immunity depends on the presence of threshold levels of antigens. Conclusions: These results show that combination treatment induces adaptive immunity to antigens released by tumor and that metastatic patients remain capable of responding immunologically to their cancer. Thus, in metastatic breast cancer patients, combination trastuzumab and chemotherapy may behave as a vaccine.

7073 Background: In preclinical studies, combinations of bortezomib and RT result in synergistic tumor killing (Cancer Chemother Pharmacol. 2007;59:207-15). Our group reported the results from the phase I portion of this study previously (J Clin Oncol. 200;28 (suppl; abstr 7085)). Based on these data, we undertook a phase II study of bortezomib in combination with paclitaxel/CBCDA and RT. Methods: Based on results from our previously reported phase I trial, systemic therapy included bortezomib (1.2 mg/m² IV days 1,4,8,11), paclitaxel (175 mg/m² IV day 2), and carboplatin (CBCDA; AUC=6 day 2) given every 3 weeks for 2 cycles. Thoracic radiotherapy (RT) included 60Gy/30 daily fractions starting day 1. The primary endpoint was the 12-month survival rate. If 41 or more of these 60 patients (68%) were alive at least 12 months after study entry, the trial would be deemed as positive and further study would be warranted. Results: 27 pts were enrolled to the phase II portion: M/F=17/10; stage IIIA/IIIB=13/14; ECOG PS 0/1=9/18; and median age: 58 (range 43-79). 18 pts (67%) completed therapy per protocol. At a planned interim analysis, 23 of 26 evaluable patients (88.5%, 95% CI: 70-98%) survived for at least 6 months, which exceeded the boundary of 21 or more needed to continue to full accrual. This trial could have continued per protocol, but was closed early due to slow accrual. With a median follow-up of 15.0 months in the 17 patients still alive, the 12-month survival rate was 71% (95% CI: 49 – 85). The median OS was 19 months (95% CI: 11 – no upper). Grade 3 or higher adverse events (regardless of attribution) were reported in 22 (82%) patients. Grade 4/5 adverse events were reported in 15 (56%) patients. There was one grade 5 event (pneumonitis). The most common (5 or more patients) grade 3/4 adverse events were fatigue (22%), leukopenia (63%), neutropenia (67%), and thrombocytopenia (44%). Conclusions: The addition of bortezomib resulted in high levels of severe hematologic toxicity, but also demonstrated evidence of activity with a 12-month survival rate of 71% and a median OS of 19 months. Further testing of this regimen in a larger study appears warranted.

3060 Background: EP-100 is a synthetic 28 amino acid LHRH peptide conjugated to an 18 aa cytolytic peptide. Selective targeting in LHRH-R expressing cells occurs via direct binding to the extracellular membrane receptor followed by disruption of the membrane by the cytolytic peptide portion. A first in human, phase I study was performed. Methods: Eligible pts had adequate organ function and LHRH-R tumor expression, as determined by IHC. EP-100 was given IV (30-60 min) weekly x 3 for cohorts 1- 6 (n=20 at 0.6 - 5.2 mg/m2) and then twice weekly x 3 for cohorts 7- 11 (n=18 at 7.8 - 40 mg/m2) with a week break. The pharmacokinetic profile of EP-100 and antibody production against EP-100 was determined by a validated HPLC/MS and ELISA respectively. Potential activity of EP-100 on the pituitary gonadotropes was determined by plasma LH and FSH. Results: We screened 97 pts, archival tumor tissue obtained from 81 pts; 53 (65%) were positive for LHRH-R, of which 37 were enrolled (female 76%) and treated. The LHRH-R expression rate in breast was 81% (N=21) and in ovarian cancer 56% (n=18). Most pts had breast (n= 16, 42%) ovary (n=7,18%), colon (n=4, 11%) or uterine (n=3, 8%) cancer. Pts were treated in a 3 + 3 standard dose escalation scheme. Doses were escalated 100% in the absence of a grade 2 drug related toxicity. MTD was not reached at the highest dose level of 40 mg/m2. Only one DLT occurred, a grade 2 increase in ALT/AST. The only other drug-related toxicity was a self limited infusion-related skin reaction (grade 1-2) in 10 pts. EP-100 was rapidly cleared from circulation, mean half life ranged from 7.1 ± 3.8 min to 15.9 ± 3.6 min. Best response was stable disease for >12 weeks in 5 pts. In 3 pts rapid, sustained decreases in LH/FSH levels were noted. Antibody production against EP-100 was absent in all pts. Conclusions: The study has completed accrual, the phase II dose is 30-40 mg/m2 twice a week x 3 weeks.EP-100is safe, well tolerated and not antigenic/immunogenic. Preclinical studies indicated synergy with paclitaxel and doxorubicin. A phase II study of EP-100 plus paclitaxel in ovarian cancer is planned.

6087 Background: In the last two decades, success in breast cancer screening and treatment has resulted in evolution of a growing patient population with unique medical needs. The American Cancer Society currently estimates a 98% relative five-year survival rate for patients with localized breast cancer, 88% for all stages combined. Caring for survivors represents both opportunity and challenge for the medical community. The integrated team approach in a multidisciplinary breast center is the ideal model to incorporate PAs in providing comprehensive long-term surveillance and support in this setting. Methods: The core mission of a PA-managed survivorship practice is outlined as follows: Maximize health and quality of life in breast cancer survivors, recognizing physical, psychological and spiritual factors; Provide early detection of disease recurrence and/or new breast cancer occurrence in women with a breast cancer history; Aggressively manage and overcome problems resulting from breast cancer treatment; Aid women in understanding and overcoming risks, including genetic risks, for developing breast cancer. Evidenced-based algorithms defining standards of care create the foundation for clinical decision making and establish precedent for continuity of care. The scope of care is enhanced by opportunities to incorporate research and genetic counseling. Results: Of 205 patients seen between 9/1 and 12/31/2005, 48% were younger than 70, 55% were Stage I, 82% were less than 5 years post-treatment, 63% were on hormone therapy. Conclusions: With continued trends in breast cancer survival, specialized long-term surveillance and support is essential to providing quality, comprehensive care that addresses the unique medical needs of these patients. A PA-managed breast cancer survivorship practice within a multidisciplinary breast clinic not only provides forum for such endeavors, but also fosters opportunity for life-long partnership focusing on quality of life, health and well-being. [Table: see text] No significant financial relationships to disclose.

16018 Background: Second opinions (SO) are common in medical practice. Aside from case series, little evidence exists to demonstrate a clinical benefit associated with SO. Lack of relevant data limits knowledge of numbers of patients, diseases, and motivations of SO seekers. Within the field of medical hematology/oncology (H/O), no specific demographic data are available to characterize patients seeking SO in the United States. Methods: To typify such patients at Mayo Clinic in Arizona (MCA), we recorded demographic and disease-related information for patients seeking these evaluations over a six month period from 1/1 through 6/30/05. Results: A total of 683 patients contacted MCA for medical H/O SO over the 6 month study period. A complete set of demographic and disease-related information was obtained from 655 patients; the remainder were excluded from the data set. Demographically, the majority of patients were female (53%), married (66%), and lived nearby (i.e., from Arizona-58%, or bordering state-22%). Average age was 62.3 years. Among oncologic diagnoses, the majority of patients (60% of 374 reported oncologic diagnoses) stated a diagnosis of breast, lung, colorectal, pancreatic or prostate cancer. Approximately 1/3 of patients had metastatic disease at the time they sought evaluation at MCA. There were 278 patients seeking evaluation for hematologic abnormalities, with the majority (160 patients, 58%) seeking evaluation for non-malignant conditions. Of those with malignancies, lymphoma (including Hodgkin and non-Hodgkin) was the most common (45%), followed by multiple myeloma (21%) and chronic lymphocytic leukemia (15%). Conclusions: This study provides insight into demographics and disease processes of patients seeking medical H/O SO at a tertiary care center in the United States. Although no definite conclusions can be drawn about motivations for seeking H/O SO, future research should examine patient motivation to better understand factors leading to this behavior. Given a lack of evidence for clinical benefit associated with SO seeking, and its potential costliness, better knowledge of demographic and motivational factors may allow for a more constructive approach to be taken toward the needs of SO seekers. No significant financial relationships to disclose.

577 Background: BAY 43–9006 targets the ras/raf signaling pathway and inhibits VEGFR-2, VEGFR-3 and or PDGFR-β growth factors. A study was conducted to assess anti-tumor activity and the toxicity profile in patients (pts) with metastatic breast cancer (MBC). Methods: A two-stage phase II study was conducted with pts with MBC who had measurable disease and were candidates for 1 st or 2 nd line chemotherapy and had previously received an anthracycline and/or a taxane in the neoadjuvant, adjuvant, or metastatic setting. Pts started with a dose of 400 mg twice daily on days 1–28 of each 4 week cycle. Based on interval adverse events (AEs), a dose reduction was considered as 400 mg given one time daily. Primary endpoint was tumor response defined as a complete or partial response (PR) according to RESIST. The study required 40 pts, but was to be terminated if 0 or 1 responses occurred among 1 st 20 eligible pts. Results: 23 pts enrolled with a median age of 54 (range 37–70) but 3 were declared ineligible. All 23 pts were included in all analyses except efficacy analysis as stated per protocol. Fifteen (65%) had visceral metastasis; 22 (96%) had prior anthracycline treatment (tx); 16 (70%) had prior taxane tx.; 10 (44%) had received prior chemotherapy for metastatic disease and 14 (61%) had a prior relapse free interval of 12 months (mos) or more. Pts received tx for a median of 2 cycles (range 1–8) with a median follow-up of 7.2 mos. Dose reductions were due to dermatitis/skin rash (3), hand/foot skin reaction (2), hypertension (1) and cramping hands/feet (1). No grade 4 AEs occurred and grade 3 AEs included acne (2), hand/foot skin reaction (1), neutropenia (1), cough (1), wound infection (1), and prolonged PTT (1). Among the 20 pts eligible for efficacy analysis one pt (5%; 95% CI 0.5–20.5%) achieved a PR with duration of 3.6 mos and one pt achieved stable disease for at least 6 mos. The 6-month overall survival rate was 81% and the progression-free survival rates were 53% at 2 mos, 24% at 4 mos and 6% at 6 mos. Median time to progression was 2 mos. Based on the lack of sufficient response, we did not proceed with the 2nd stage of this study. Conclusion: Treatment with oral BAY 43–9006, while well tolerated, does not have sufficient activity to warrant further testing as a single agent in this disease setting. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech

3585 Background: CX-3543 inhibits over-expressed ribosomal RNA synthesis in cancer cells by disrupting an essential protein-rDNA quadruplex complex, thereby inducing selective apoptosis. A phase I clinical trial for CX-3543 was undertaken to determine the dose limiting toxicities (DLTs), maximum tolerated dose (MTD), and pharmacokinetics (PK) of this agent. Methods: Eligible patients with advanced solid tumors received CX-3543 in successive dose cohorts at: 10, 20, 40, 80, 160, 240, 360 and 480 mg/m2. Drug is administered by daily intravenous infusion on the first five consecutive days of a three week cycle, and the infusion duration has varied from one hour to six hours. Response by RECIST is determined after every 2 cycles. Results: Thirty-three patients (M/F:19/14; median age 69, range 44–83) with advanced solid tumors were treated with intravenous CX-3543. No drug related serious adverse events (SAEs) were encountered. DLTs of infusion-related cough and headache were identified at 480 mg/m2 (The MTD was 360 mg/m2). These adverse events were fully and rapidly reversible upon slowing or interrupting the infusion. Other drug-related adverse events were of mild to moderate intensity. Four patients had stable disease for longer than 4 months and one patient, with stable disease for over one year, currently continues on study. CX-3543 demonstrated an increasing plasma terminal half life at the higher dose levels due to a ‘reservoir‘ effect from CX-3543 reversibly binding to blood cells. Conclusions: CX-3543 administered as a 6 hour infusion for five consecutive days of a three week cycle is well tolerated and has stabilized disease in a number of patients enrolled in this phase I study. This trial is now in an expanded enrollment phase at 360 mg/m2 and pharmacodynamic measures, specifically FDG-PET scans and circulating tumor cells, have been included to detect biological activity at this dose level. No significant financial relationships to disclose.