Citations

Abstract Background: I-SPY 2 is a multicenter, phase 2 trial using response-adaptive randomization within biomarker subtypes to evaluate novel agents when added to standard neoadjuvant therapy for women with high-risk stage II/III breast cancer - investigational agent(I) +paclitaxel(T) qwk, doxorubicin & cyclophosphamide(AC) q2-3 wk x 4 vs. T/AC (control arm). The primary endpoint is pathologic complete response (pCR) at surgery. The goal is to identify/graduate regimens that have ≥85% Bayesian predictive probability of success (statistical significance) in a 300-patient phase 3 neoadjuvant trial defined by hormone-receptor (HR) & HER2 status & MammaPrint (MP). Regimens may also leave the trial for futility (< 10% probability of success) or following accrual of maximum sample size (10%< probability of success <85%). We report the results for experimental arm Ganitumab, a type I insulin-like growth factor receptor (IGF1R) inhibitor. IGF1R inhibitors are known to induce insulin resistance and all patients assigned to Ganitumab received metformin. Methods: Women with tumors ≥2.5cm were eligible for screening. MP low/HR+ and HER2+ tumors were ineligible for randomization. Hemoglobin A1C≥ 8.0% were ineligible. MRI scans (baseline, 3 cycles after start of therapy, at completion of weekly T and prior to surgery) were used in a longitudinal statistical model to improve the efficiency of adaptive randomization. Ganitumab was given at 12mg/kg q2 weeks and metformin at 850mg PO BID, while receiving ganitumab. Analysis was intention to treat with patients who switched to non-protocol therapy counted as non-pCRs. Ganitumab/metformin was open only to HER2- patients, and eligible for graduation in 3 of 10 pre-defined signatures: HER2-, HR+HER2- and HR-HER2-. Results: Ganitumab/metformin did not meet the criteria for graduation in the 3 signatures tested. When the maximum sample size was reached, accrual to this arm stopped. Ganitumab/metformin was assigned to 106 patients; there were 128 controls. We report probabilities of superiority for Ganitumab/metformin over control and Bayesian predictive probabilities of success in a neoadjuvant phase 3 trial equally randomized between Ganitumab/metformin and control, for each of the 3 biomarker signatures, using the final pathological response data from all patients. Safety data will be presented. SignatureEstimated pCR Rate (95% probability interval)Probability Ganitumab/ Metformin Is Superior to ControlPredictive Probability of Success in Phase 3 Ganitumab/ Metformin N = 106Control N = 128 All HER2-22% (13%-31%)16% (10%-23%)89%33%HR+/HER2-14% (4%-24%)12% (4%-19%)66%21%HR-/HER2-32% (17%-46%)21% (11%-32%)91%51% Conclusion: The I-SPY 2 adaptive randomization study estimates the probability that investigational regimens will be successful in a phase 3 neoadjuvant trial. The value of I-SPY 2 is to give insight about the performance of an investigational agent's likelihood of achieving pCR. For Ganitumab/metformin, no subtype came close to the efficacy threshold of 85% likelihood of success in phase 3, and this regimen does not appear to impact upfront reduction of tumor burden. Our data do not support its continued development for the neoadjuvant treatment of breast cancer. Citation Format: Yee D, Paoloni M, van't Veer L, Sanil A, Yau C, Forero A, Chien AJ, Wallace AM, Moulder S, Albain KS, Kaplan HG, Elias AD, Haley BB, Boughey JC, Kemmer KA, Korde LA, Isaacs C, Minton S, Nanda R, DeMichele A, Lang JE, Buxton MB, Hylton NM, Symmans WF, Lyandres J, Hogarth M, Perlmutter J, Esserman LJ, Berry DA. The evaluation of ganitumab/metformin plus standard neoadjuvant therapy in high-risk breast cancer: Results from the I-SPY 2 trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-11-04.

Abstract Background:Pathologic complete response(pCR) after neoadjuvant therapy is an established prognostic biomarker for high-risk breast cancer(BC). Improving pCR rates may identify new therapies that improve survival. I-SPY 2 uses response-adaptive randomization within biomarker subtypes to evaluate novel agents when added to standard neoadjuvant therapy for women with high-risk stage II/III breast cancer; the goal is to identify regimens that have ≥85% Bayesian predictive probability of success (statistical significance) in a 300-patient phase 3 neoadjuvant trial defined by hormone-receptor (HR), HER2 status and MammaPrint (MP). We report the results for Ganetespib, a selective inhibitor of Hsp90 that induces the degradation/deactivation of key drivers of tumor initiation, progression, angiogenesis, and metastasis.Ganetespib + taxanes previously have resulted in a superior therapeutic response compared to monotherapy in multiple solid tumor models including BC. Methods:Women with tumors ≥2.5cm were eligible for screening and participation. MP low/HR+ tumors were ineligible for randomization. QTcF >470msec and HbA1C >8.0% were ineligible. MRI scans (baseline, +3 cycles, following weekly paclitaxel, T, and pre-surgery) were used in a longitudinal statistical model to improve the efficiency of adaptive randomization. Ganetespib was given with weekly T at 150 mg/m2 IV weekly (3 weeks on, 1 off). Patients were premedicated (dexamethasone 10mg and diphenhydramine HCl 25-50 mg, or therapeutic equivalents). Analysis was intention to treat with patients who switched to non-protocol therapy counted as non-pCRs. The Ganetespib regimen was open only to HER2- patients, and eligible for graduation in 3 of 10 pre-defined signatures: HER2-, HR+/HER2- and HR-/HER2-. Results:Ganetespib did not meet the criteria for graduation in the 3 signatures tested. When the maximum sample size was reached, accrual stopped. Ganetespib was assigned to 93 patients; there were 140 controls. We report probabilities of superiority for Ganetespib over control and Bayesian predictive probabilities of success in a neoadjuvant phase 3 trial equally randomized between Ganetespib and control, for the 3 biomarker signatures, using the final pCR data from all patients. Safety data will be presented. SignatureEstimated pCR Rate (95% probability interval)Probability Ganetespib Is Superior to ControlPredictive Probability of Ganetespib Success in a Phase 3 Trial Ganetespib N = 93Control N = 140 All HER2-26% (16%-37%)18% (8%-28%)91%47%HR+/HER2-15% (4%-27%)14% (4%-24%)60%19%HR-/HER2-38% (23%-53%)22% (9%-35%)96%72% Conclusion:The I-SPY 2 adaptive randomization model efficiently evaluates investigational agents in the setting of neoadjuvant BC. The value of I-SPY 2 is that it provides insight as to the regimen's likelihood of success in a phase 3 neoadjuvant study. Although no signature reached the efficacy threshold of 85% likelihood of success in phase 3, we observed the most impact in HR-/HER2- patients, with a 16% improvement in pCR rate. While our data do not support the continued development of Ganetespib alone for neoadjuvant BC, combinations with Ganetespib, which could potentiate its effect, may be worth pursuing in I-SPY 2 or similar trials. Citation Format: Forero A, Yee D, Buxton MB, Symmans WF, Chien AJ, Boughey JC, Elias AD, DeMichele A, Moulder S, Minton S, Kaplan HG, Albain KS, Wallace AM, Haley BB, Isaacs C, Korde LA, Nanda R, Lang JE, Kemmer KA, Hylton NM, Paoloni M, van't Veer L, Lyandres J, Perlmutter J, Hogarth M, Yau C, Sanil A, Berry DA, Esserman LJ. Efficacy of Hsp90 inhibitor ganetespib plus standard neoadjuvant therapy in high-risk breast cancer: Results from the I-SPY 2 trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-11-02.

The purpose of this study was to introduce a planning strategy for dynamic conformal arc therapy (DCAT), named negative margin technique (NMT), and evaluate its dosimetric gain in lung stereotactic body radiation therapy (SBRT). In DCAT, the field aperture is continuously conformed to the planning target volume (PTV) with an aperture margin (AM) to compensate for the penumbra effect with gantry rotation. It is a common belief the AM should be positive (or at least ‘zero'). However, the radial penumbra width becomes significantly wider because of continuously overlapped beams in arc delivery. Therefore, we hypothesize if the ‘negative margin’ is applied in the radial direction, it would improve the PTV dose conformation while reducing normal tissue dose. For verification, trial plans were made using the NMT and compared with ‘zero margin (ZM)’ plans for five lung SBRT cases representing different situations depending on the location of the PTV and organs at risk. All plans met 95% PTV coverage with the prescription dose and spared the spinal cord below the tolerance. Two conventional conformation indices (the ratio of prescription isodose volume to the PTV (CI100) and the ratio of 50% prescription isodose volume to the PTV (CI50)) and a modified conformation index were investigated. The maximum dose at 2 cm from the PTV and the percent of lung volume receiving 20 Gy were also evaluated. Another planning simulation was performed with a total of ten randomly selected lung SBRT cases to mimic actual practice. In this simulation, optimization with ZM was first performed and further optimization using the NMT was processed for cases that could not meet a goal of with the ZM optimization. In all cases, both the and values were significantly reduced (overall, and for and , respectively). The modified conformation index values also showed similar improvement (overall, increase). Reduction of was also observed in all cases . values decreased in all cases but one (, excluding the increased case). In the random group simulation, it was possible to achieve the goal with just one NMT trial for five out of six cases that did not meet the goal in the ZM optimization. Interestingly, however, one case needed as many as six iterations to get the goal. The NMT turned out to be an effective planning strategy that could bring significant improvement of dose conformation. The NMT can be easily implemented in most clinics with no prerequisite.PACS number: 87.55.D‐

498 Background: Surgery for RCC patients with IVC thrombus above the hepatic veins is complex and associated with an increased risk of perioperative morbidity and mortality. However, minimal data exist that describe contemporary perioperative outcomes at major referral centers or the prognostic factors associated with adverse surgical outcomes. The objective of this study is to determine the preoperative predictors of major complications and 90 day mortality after surgery in RCC patients with IVC thrombus above the hepatic veins. Methods: Records were reviewed of all RCC patients with IVC tumor thrombus above hepatic veins who had surgery from 1/2000 to 12/2012 at Mayo Clinic, MD Anderson, UT Southwestern and the University of Wisconsin. Major complications were recorded were defined as 3A or greater according to the Clavien- Dindo system within 90 days of surgery. Univariate and multivariate (MV) analyses were used to evaluate associations of preoperative clinical, pathological or laboratory variables with risk of major complications or 90-day mortality. Results: A total of 162 patients were identified for study (thrombus level 3,4 in 69 and 93 patients, respectively, according to Neves classification). Cardiopulmonary bypass was used in 60/162 (37.5%), while 40 (24.7%) patients underwent pre-operative angioembolization. Major complications were reported in 55 (34.0%) patients, with the most common being respiratory (12.4%), hematologic (9.2%) and cardiac (8.6%). On MV analysis, preoperative systemic symptoms and level 4 thrombus were independently associated with an increased risk of major complications. Mortality was reported in 17 (10.5%) patients within 90 days after surgery. On MV analysis, ECOG performance status and low serum albumin were independently associated with increased risk of 90 day mortality. Conclusions: Contemporary perioperative mortality and major complication rates for RCC patients with upper level thrombus are 10 and 34%, respectively. ECOG PS >1 and low serum albumin are associated with an increased risk of perioperative mortality, and should be considered when selecting patients for neoadjuvant systemic therapy trials.

91 Background: Formal mechanisms to share data on quality remain immature in specialty palliative care. As the field grows, infrastructure that promotes collaboration among academic and community-based practice will be required to foster comparisons and benchmarking of data to inform areas for quality improvement. Further, such relationships will create a palliative care “quality improvement laboratory”, where proposed guidelines and best practices can be developed, implemented, and tested. Methods: We set out to bring together specialty palliative care practices with a shared vision for collaborative quality improvement. We modeled our approach after the Institute for Healthcare Improvement Breakthrough Series alongside our Rapid Learning Quality Improvement paradigm. We use a set of common data collection procedures, across an electronic point-of-care platform called Quality Data Collection Tool (QDACT), alongside a centralized data registry. Further, we meet and discuss challenges and issues, compare best practices, and brainstorm new projects through biweekly conference calls. Results: We have created a multi-institutional collaboration for quality assessment and improvement in specialty palliative care. Termed the Global Palliative Care Quality Alliance, we have brought together 11 academic and community organizations, both general and oncology-specific, across six states to study various areas of quality practice. Short-term, we will conduct rapid-cycling quality improvement projects addressing National Quality Forum domains for quality palliative care, including documentation of spiritual assessment and timely advance care planning. Long-term, we aim to study the link between quality measure adherence and outcomes and further align our initiatives with those of other large consortia, like the Palliative Care Research Cooperative and Palliative Care Quality Network. Conclusions: Collaborative quality improvement is needed in specialty palliative care across a national platform. Developing the infrastructure to perform standardized quality improvement is achievable across multiple palliative care settings.

211 Background: The current standard of care for locally advanced esophageal cancer includes chemoradiotherapy with or without surgery. Radiation is usually delivered via a 3D technique. IMRT has been utilized in the treatment of multiple tumors and demonstrated similar efficacy while offering the possibility of decreased toxicity. Methods: Thirty-six patients were treated with IMRT and chemotherapy. Twenty-one patients underwent surgical resection. Eleven underwent open surgery and the remainder underwent minimally invasive surgery. Chemotherapy consisted primarily of 5-FU with oxaliplatin or cisplatin. All but two patients received 50.4 Gy; one patient received 41.4 Gy without surgery and one patient discontinued treatment after 25.2 Gy. Eleven patients required a treatment break during radiotherapy. The median age was 69 (range 46-87). Approximately two-thirds of tumors were adenocarcinomas located in the lower thorax. Two thirds of patients were staged as T3 and had positive lymph nodes. The median tumor size was 5 cm (range 2-13). Results: With a median follow-up of 21.3 months (range 2.4-44.8) and 33.9 months for survivors (range 3.7-44.8), overall survival at 24 months was 55%. The 24 month overall survival was 75% vs 24% for surgical and non-surgical patients, respectively. Seven patients had a complete pathologic response. Twenty-four patients experienced grade 3 or higher acute toxicity and there was one grade 5 toxicity. Acute toxicity was similar between surgery and non-surgery patients. Fourteen patients experienced grade 3 or higher late toxicity; 9 surgery and 5 non-surgery patients. The most frequent late toxicity was grade 3 stricture (21%). On multivariate analysis, advanced age (RR [10 year increase] 2.01, p=0.032) and heart maximum dose >55 Gy (RR 3.73, p=0.011) were associated with decreased survival. Conclusions: Patients who undergo surgery after chemoradiotherapy demonstrate improved survival; however, this may be related to underlying comorbidities that preclude surgery. IMRT appears to be a reasonable treatment option that may reduce complications from radiotherapy. Careful attention should be given to heart dose during treatment planning.

88 Background: There is not yet a consensus on the efficacy and safety of IMRT for the treatment of patients with esophageal carcinomas. We report on our experience with outcomes and toxicity with IMRT for these patients. Methods: Fifty-five patients with esophageal carcinoma were treated with IMRT at our institution from 12/2008 and 12/2014. Medical records were retrospectively reviewed. All patients received concurrent chemotherapy (majority 5-FU with oxaliplatin). Thirty-one (56%) patients underwent surgery. Fifty (91%) received 50.4 Gy in 28 fractions. Seventy-three percent of cases were adenocarcinoma. Regions include mid-thoracic (15%), lower thoracic (64%), and GE junction (22%). Clinical uT-stages were as follows: T1 (2%), T2 (20%), T3 (69%), and T4a (5%). Clinical N-stages were as follows: N0 (33%), N1 (53%), N2 (13%), and N3 (2%). Results: Median follow-up for all patients was 15 months (1.5 - 64.5) and 25.5 months (1.5 - 64.5) for patients who were alive at follow-up (n = 31). Fifty-one (93%) patients completed RT. Of the 31 patients who underwent surgery, 9 (29%) were found to have a complete pathologic response. Site of first recurrence was local (n = 2, 4%), regional (n = 3, 6%), and distant (n = 14, 26%). At 12 and 24 months, overall survival was 72% and 58%, freedom from recurrence was 78% and 65%, and freedom from distant recurrence was 78% and 68%. On univariate analysis, improved OS was noted with patients who underwent surgery (RR 0.29) or were cN0 (RR 0.27). Twenty eight patients (51%) experienced > / = CTCAE v.4grade 3 acute toxicity; notable were hematologic (n = 14, 25%), esophagitis (n = 6, 11%), acute coronary event (n = 1, 2%), and post-chemoRT pneumonia (n = 1, 2%). Fifteen patients (31%) experienced > grade 3 late toxicity; notable were esophageal stricture (n = 7, 14%), post-op pneumonia (n = 3, 6%), post-CRT pneumonia (n = 2, 4%), and COPD exacerbation (n = 1, 2%). Conclusions: Patient receiving IMRT with concurrent chemotherapy for esophageal carcinomas have good LC rates, with or without surgery. Majority of patients are able to finish treatment with acceptable rates of late toxicity. Patient who underwent surgery or were cN0 had better OS.