Citations

569 Background: BBI-608 is an oral first-in-class cancer stemness inhibitor that blocks STAT3-mediated transcription of cancer stemness genes. Potent anti-CSC activity was observed in vitro and in vivo,in mono and combination therapy. In phase I studies, BBI-608 was generally well tolerated with encouraging signs of anti-tumor activity. Methods: A phase Ib open label, multi-center study in pts with advanced CRC was undertaken to confirm the RP2D of BBI-608 in combination with FOLFIRI with or without BEV. BBI-608 was administered at 240 mg BID in combination with FOLFIRI (5-FU 400 mg/m2 bolus with 2400 mg/m2, irinotecan 180 mg/m2, and leucovorin 400 mg/m2infusion) with or without BEV 5 mg/kg, administered bi-weekly until progression of disease, unacceptable toxicity, or other discontinuation criterion was met. Results: 18 heavily pretreated pts with an average of > 3 prior lines of therapy of which 10 pts (56%) previously progressed on FOLFIRI were enrolled. Of the 17 pts evaluable for response, 8 pts received FOLFIRI and 9 pts received FOLFIRI with BEV in combination with BBI-608. Most common adverse events included grade 1 and 2 diarrhea, abdominal pain, nausea, vomiting and anorexia. No dose limiting toxicity or new adverse events were seen, and the safety profile was similar to that of each regimen as monotherapy. Grade 3 events related to protocol therapy included diarrhea occurring in 3 pts, fatigue in 2 pts and dehydration in 1 pt. All events resolved after dose reduction and/or start of anti-diarrheal medications. No significant pharmacokinetic interactions were observed. Disease control (PR+SD) was observed in 16 of 17 evaluable pts (94%) with 2 PR (per RECIST 1.1 criteria: 44% and 33% regression) and 14 SD (of which 13 (93%) had tumor regression < 25%). In the evaluable pts, median progression free survival was 5.54 months. Of 17 pts, 7 (41%) had prolonged SD of > 6 months. Conclusions: This phase Ib study confirmed that BBI-608 at 240 mg bid can be safely combined with FOLFIRI with and without BEV, and shows encouraging anti-tumor activity in heavily pretreated CRC pts, even in pts with prior progression on FOLFIRI-based therapy. Clinical trial information: NCT02024607.

75 Background: The focus of palliative radiotherapy (RT) is on improving quality of life (QOL) for patients with serious illnesses by eliminating or decreasing physical symptoms. The importance of assessing distress levels in palliative care patients is recognized due to the relevance of QOL, as treatment is given to provide symptom-relief rather than curative results. We sought to identify the most common causes of patient reported distress during palliative RT. Methods: Retrospective review was performed for patients who received palliative RT from 11/1/2012 to 6/4/2015 for various types of metastatic cancer at our institution. All patients completed a Patient Reported Distress (PRD) questionnaire with 30 specific questions and an overall distress thermometer prior to beginning treatment. The PRD survey quantified 30 areas of current concern ranging in patient-reported values from 1 to 5 in addition to a linear analog measure from 0 to 10 of overall reported distress in the last month. Results: Completed PRD surveys were available for a total of 297 patients, 149 (50.2%) female and 148 (49.8%) male. All patients were undergoing external beam radiation therapy for treatment of metastatic disease. 49 (16%) received chemotherapy and 46 (9%) underwent surgery. Overall distress ranged from 0 to 10, with a median of 5.0. The mean distress scores for the top five concerns ranged from 1.4 to 2.7. Top distresses were “Fatigue” (2.7), “Pain that affects daily functioning” (2.6), “How will I feel during treatment” (2.5), “Sleep difficulties” (2.4), and “Out of pocket medical costs” (2.3). Least troubling symptoms were “Transportation” (1.4), “A loved one relying on me for their physical care” (1.5), “My job” (1.5), “Housing during treatment” (1.5), “Spirituality” (1.5), and “Anger” (1.5). Conclusions: Patients demonstrated concern for distress related to interruption of activities of normal life, such as tiredness and insomnia, pain, and overall burdens from treatment. Medical costs were also a major concern. Importantly, housing and transportation were not issues in the current study but could be of concern in other regions. Providers should be aware that patients’ primary concerns may not be directly related to the symptom being palliated.

211 Background: Distress is known to be elevated in patients receiving cancer therapy, such as palliative radiotherapy (PRT). Many patients will experience distress during treatment and it is not always addressed in part due to a lack of guidance regarding the significance of distress. Methods: All RT patients in our clinic are asked to complete a patient reported distress (PRD) survey during treatment course. PRD forms consist of 30 categorical questions that assess distress subscales. Patients have the option to rate each question from 1 (low distress) to 5 (high distress). The survey also includes the National Comprehensive Cancer Network distress thermometer, which allows patients to rate overall distress level from 0 (no distress) to 10 (extreme distress). Patients’ records were retrospectively reviewed to abstract the needed information to assess survivorship. Results: 270 patients were included from 01/18/2012-08/07/2015. Overall PRD was analyzed as a continuous and a categorical variable (low: 0-3, moderate: 4-6, high: 7-10). Continuous and categorical variable PRD did not show a correlation of distress to survival (P = 0.26) and (P = 0.10) respectively. A correlation was noted in moderate distress category (RR: 1.51, P = 0.034), however, this was not noted in high distress category (RR: 1.25, P = 0.33). There was no statistical significant correlation with the adjusted variables. Patients with primary site of gastrointestinal cancer had worst prognosis (RR: 1.34, P: 0.14), while hematological origin had best prognosis (RR: 0.35, P: 0.038).Age had the strongest correlation with survival, as older patients receiving RT had poorer survival (RR: 1.13, P: 0.079). Conclusions: This study suggests that PRD is not predictive of survival in PRT. The primary goal of PRT is to improve quality of life (QoL) by assessing, anticipating and alleviating suffering; not necessarily improve survival. It also demonstrated that the most common stressors were related to reversible short-term side effects of RT such as fatigue and pain rather than long-term stressors related to daily activities and social measures which might affect QoL. It is imperative to explore assessment tools to mitigate suffering and improve strategies to enhance QoL in all medical disciplines.

79 Background: A significant percentage of cancer patients experience psychosocial distress with the highest prevalence observed in breast cancer patients. The importance of psychosocial distress screening and assessment in women with breast cancer has clearly been established. Patients in our clinic are screened for distress. The results were reviewed in an attempt to better understand the psychosocial distress of breast cancer patients undergoing radiotherapy. Methods: Patients treated curatively for breast cancer prospectively completed the 30 question patient reported distress (PRD) survey that also included a linear analog measure of overall distress. The recorded clinical results of the PRD survey were retrospectively assessed in patients receiving breast radiotherapy from June 1, 2013 to February 2, 2015. Results: Completed PRD questionnaires were available on 179 female patients. 21 (12%) were treated for ductal carcinoma in situ and 91 (51%), 35 (20%), and 32 (18%) were treated for invasive carcinoma Stages I, II, and III. 85 (47%) received chemotherapy. Overall distress ranged from 0 to 10, with a median value of 5. Mean distress scores per category ranged from a low of 1.25 to a high of 2.52. Top concerns in descending order of importance were: “How will I feel during treatment” (2.52), “Fatigue” (2.46), “Sleep difficulties” (2.32), “How will I feel about appearance related to treatment” (2.23), & “Pain that affects daily functioning” (2.19). Least distressing symptoms “Spirituality” (1.25), “Housing during treatment” (1.26), “Control of anger” (1.28), “End of life concerns” (1.32), & “Transportation” (1.34). Conclusions: Distress over tumor related issues ranked low among women’s concerns in comparison to distress related to the side effects of therapy concerning treatment related discomfort, fatigue, and changes in appearance, and anxiety. Pain was a significant concern, although in this group of patients receiving definitive, adjuvant or neoadjuvant therapy, this was likely related to treatment associated discomfort rather than from disease progression. These findings highlight the importance of careful patient education and communication of the expected symptoms and effects of therapy.

LBA500 Background: The primary endpoint of NSABP B-35, a phase III trial comparing 1 mg/day anastrozole to 20 mg/day tamoxifen, each given for 5 years, was breast cancer-free interval (BCFI), defined as the time from randomization to any breast cancer (BC) event including local, regional, or distant recurrence or contralateral disease, invasive or DCIS. Methods: Postmenopausal women with ER-receptor or PgR-receptor positive (by IHC analysis) DCIS and no invasive BC who had undergone a lumpectomy with clear resection margins were randomly assigned to receive either 20 mg/day tam or 1 mg/day A (blinded) for 5 years. Stratification was by age (<60 v ≥60). Results: From 1/6/2003 to 6/15/2006, 3,104 pts were entered and randomized (1552 in groups tam and A each). As of 2/28/15, follow-up information was available on 3,083 pts for OS and on 3,077 pts for all other disease-free endpoints, with mean time of follow-up of 8.6 years. There were 198 BCFI events, 114 in the tam group and 84 in the A group (HR, 0.73; p=0.03). 10-year point estimates for BCFI were 89.2% for tam and 93.5% for A. A significant time-by-treatment interaction (p=0.02) indicated that the effect was not evident until later in the study. There was a significant interaction between treatment and age group (p=0.04); benefit of A is only in women <60 years old. As to secondary endpoints, there were 495 DFS events, 260 in the tam group and 235 in the A group (HR, 0.89; p=0.21). 10-year point estimates for DFS were 77.9% for tam and 82.7% for A. There were 186 deaths, 88 in the tam group and 98 in the A group (HR, 1.11; p=0.48). 10-year point estimates for OS were 92.1% for tam, 92.5% for A. There were 8 deaths due to breast cancer in the tam group and 5 in the A group. There were 63 cases of invasive breast cancer in the tam group and 39 in the A group (HR, 0.61; p=0.02). There was a non-significant trend for a reduction in breast second primary cancers with A (HR, 0.68; p=0.07). Conclusions: Anastrozole provided a significant improvement compared to tamoxifen for BCFI, which was seen later in the study, primarily in women <60 years. Support: CA12027, 37377, 69651, 69974; 180868, 180822, 189867 196067, 114732; AstraZeneca Pharmaceuticals LP. Clinical trial information: NCT00053898.

261 Background: Mapatumumab is a fully human agonist monoclonal antibody to the tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1). Sorafenib targets Mcl-1, a key TRAIL resistance protein, and accordingly could enhance mapatumumab's pro-apoptotic activity. Based on this and on preclinical data on mapatumumab in HCC cell lines, the current dose-escalation study is evaluating mapatumumab in combination with sorafenib in patients with advanced HCC. Methods: Eligible patients had advanced HCC, Child-Pugh A or Model for End-Stage Liver Disease score < 15, and were positive for hepatitis B surface antigen or hepatitis C antibody. Intravenous mapatumumab was administered at 3, 10 or 30 mg/kg every 21 days with sorafenib (400 mg twice daily) until disease progression or unacceptable toxicity. Dose-limiting toxicities (DLTs) included events considered at least possibly related to mapatumumab and/or its interaction with sorafenib. Tumor measurements were performed every 2 cycles. Dose escalation required at least 3 patients in a cohort to receive >= 50% of full-dose sorafenib in the first 2 cycles. Results: To date, 19 patients have been enrolled in the 3 mg/kg (n=6), 10 mg/kg (n=9) and 30 mg/kg (n=4) cohorts and have received a median of 4 cycles (range 1 to 24 cycles); 4 patients have received >= 11 cycles. The maximum tolerated dose has not been reached. DLTs that prompted expansion of the 3 mg/kg and 10 mg/kg cohorts were elevations of amylase and/or lipase (1 at 3 mg/kg, 1 at 10 mg/kg). Other Grade 3-4 events considered at least possibly related to mapatumumab and/or its interaction with sorafenib included hepatic pain (1/17), thrombocytopenia (1/17), increased aspartate aminotransferase (1/17), increased lipase (1/17), and increased gamma-glutamyltransferase (1/17). Two patients have had a partial response and 4 patients have had stable disease lasting > 12 weeks, based on investigator assessment. Conclusions: Mapatumumab was well-tolerated at doses up to 30 mg/kg in combination with sorafenib in patients with HCC and viral hepatitis. A randomized phase II study of this combination in patients with advanced HCC is planned. [Table: see text]

Purpose To determine the pathologic complete response (pCR) rate in estrogen receptor (ER) –positive primary breast cancer triaged to chemotherapy when the protein encoded by the MKI67 gene (Ki67) level was > 10% after 2 to 4 weeks of neoadjuvant aromatase inhibitor (AI) therapy. A second objective was to examine risk of relapse using the Ki67-based Preoperative Endocrine Prognostic Index (PEPI). Methods The American College of Surgeons Oncology Group (ACOSOG) Z1031A trial enrolled postmenopausal women with stage II or III ER-positive (Allred score, 6 to 8) breast cancer whose treatment was randomly assigned to neoadjuvant AI therapy with anastrozole, exemestane, or letrozole. For the trial ACOSOG Z1031B, the protocol was amended to include a tumor Ki67 determination after 2 to 4 weeks of AI. If the Ki67 was > 10%, patients were switched to neoadjuvant chemotherapy. A pCR rate of > 20% was the predefined efficacy threshold. In patients who completed neoadjuvant AI, stratified Cox modeling was used to assess whether time to recurrence differed by PEPI = 0 score (T1 or T2, N0, Ki67 < 2.7%, ER Allred > 2) versus PEPI > 0 disease. Results Only two of the 35 patients in ACOSOG Z1031B who were switched to neoadjuvant chemotherapy experienced a pCR (5.7%; 95% CI, 0.7% to 19.1%). After 5.5 years of median follow-up, four (3.7%) of the 109 patients with a PEPI = 0 score relapsed versus 49 (14.4%) of 341 of patients with PEPI > 0 (recurrence hazard ratio [PEPI = 0 v PEPI > 0], 0.27; P = .014; 95% CI, 0.092 to 0.764). Conclusion Chemotherapy efficacy was lower than expected in ER-positive tumors exhibiting AI-resistant proliferation. The optimal therapy for these patients should be further investigated. For patients with PEPI = 0 disease, the relapse risk over 5 years was only 3.6% without chemotherapy, supporting the study of adjuvant endocrine monotherapy in this group. These Ki67 and PEPI triage approaches are being definitively studied in the ALTERNATE trial (Alternate Approaches for Clinical Stage II or III Estrogen Receptor Positive Breast Cancer Neoadjuvant Treatment in Postmenopausal Women: A Phase III Study; clinical trial information: NCT01953588).