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Background: CFI-400945 is a selective oral inhibitor of Polo-like Kinase 4 (PLK4), a controller of centriole duplication and mitotic progression identified by functional screening of genomically unstable breast cancer (BC). IND.237 (NCT01954316) is an open label, multicentre, phase 2 study in HER2 negative metastatic breast cancer (MBC) with 3 cohorts, 1 enriched for PTEN loss of function. Enrollment started in 2018 at 64mg based on a previously established recommended phase 2 dose (RP2D). The initial patients had higher than expected grade 3/4 neutropenia which led to a voluntary hold and dose de-escalation; the new RP2D was declared at 32mg as previously reported Here we report the results of the phase 2 study of CFI-400945 in advanced BC patients. Materials and Methods: 49 patients were enrolled across 3 cohorts: 1: triple negative; 2: ER+/HER2- PTEN low (by IHC); 3: ER+/HER2-, PTEN intact. The primary outcome is objective response rate (ORR); secondary outcomes included disease control rate (DCR) >16w, and safety. A Simon 2-stage design was used (9 – 25 pts planned for each cohort). CFI-400945 would be considered active if ≥3 responses were observed in any given cohort. Eligibility included ECOG 0-1, adequate organ function and receipt of at ≥1 prior line of cytotoxic chemotherapy in any setting including anthracycline taxane (unless contraindicated). Treatment was 32mg 7d on 7d off in cycle 1 (cycle length=28d), then continuously starting cycle 2. Safety assessments were performed each cycle and response (RECIST 1.1) every 2 cycles. Results: 60 patients have been screened, 49 enrolled: 10 were in initial dose ranging and were excluded from phase 2 response assessment. 10 patients were enrolled in cohort 1, 4 in cohort 2, and 25 in cohort 3. Table 1 presents patient characteristics and response results. 1 patient in cohort 3 has not had disease re-assessed at time of abstract submission. The most common adverse events have been cytopenias, nausea, fatigue, headache, constipation and vomiting. Less than 5% of patients experienced a non-hematologic AE > grade 3; 33% experienced ≥ grade 3 neutropenia. Conclusions: CFI-400945 32mg is well tolerated in this MBC population with moderate incidence of uncomplicated neutropenia. The TNBC cohort so this arm has been closed to further accrual for lack of responses. The PTEN loss group has been slow to accrue and remains open. Responses in the ER+/HER2- arm are encouraging – results from patients remaining on study are awaited and correlative studies to identify features associated with responses are underway. Acknowledgements: Sponsored by the Canadian Cancer Trials Group. Supported by Stand Up To Cancer Canada (scientific partner AACR) Canadian Cancer Society (CCS) Breast Cancer Dream Team Research Funding, Ontario Institute for Cancer Research (funding provided by the Government of Ontario) and grants from CCS to CCTG. Table 1. Table 1. Patient characteristics and response rates in each cohort treated with CFI-400945. Citation Format: David W. Cescon, John Hilton, Philippe Bedard, Phillip Blanchette, Rossanna C. Pezo, Ayesha Bashir, Vikaash Kumar, Terry L. Ng, Arif Awan, Anthony Lott, Jacques Antoun Raphael, Linda Hagerman, Mark Bray, Lindsay Muyot, Jesus Fuentes Antras, Lesley Seymour, Dongsheng Tu, Pierre-Olivier Gaudreau, Moira Rushton. A phase II study of CFI-400945 in patients with advanced/metastatic cancer: Canadian Cancer Trials Group (CCTG) IND.237 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-14.

Background: For patients with ABC being treated with CDK4/6is palliative (RT may still be necessary to metastatic sites that are symptomatic or at risk for complications. Although preclinical data suggests synergy between CDK4/6is and RT, clinical data regarding the safety of this combination are conflicting, with some reports of increased toxicity in the radiation field. Our aim was to review the practice regarding holding CDK4/6is during RT and subsequent clinical outcomes at the cancer centre with the largest volume of ABC patients in Canada. Methods: Chart review was completed for 313 ER positive and Her2 ABC pts treated with CDK4/6is at the Sunnybrook Health Sciences Centre from 2016 to 2020. All patients who received RT during the course of treatment with CDK4/6is were included in this analysis. Greater than expected toxicity events were defined as higher than grade 1 non-hematological toxicity as per Common Terminology Criteria for Adverse Events during RT or in the 30 days post RT. Descriptive statistics were used for demographics and treatment outcomes. Results: Fifty patients received RT to 74 different sites during treatment with CDK4/6is (46 palbociclib and 4 ribociclib). Median age was 56 (41-88) years. Most frequent RT sites were: bone (n=51), brain (n=7), lung (n=4), breast (n=4) and liver (n=3). CDK4/6is were held during RT of 55 sites (37 patients), starting a median of 7 (0-43) days prior to first fraction of RT and restarted a median of 7 (0-71) days after completing the RT. A CDK4/6i was administered concomitantly with RT to 19 sites (15 patients). No greater than expected toxicity was observed in patients for whom the CDK4/6i was held during RT. Among patients who received concomitant treatment, we observed 4 non-hematological adverse events (21%) in organs included in the field of radiation. In combination with palbociclib we observed grade 3 colitis after 30 Gy to hip/pelvis bones, grade 2 esophagitis after 30 Gy to C1-C4 vertebrae and grade 2 enteritis after 30 Gy to the upper femur. In combination with ribociclib one patient developed grade 3 hepatitis after 20Gy to T10-L2 vertebrae. Conclusions: This retrospective observational study of 50 patients with advanced ER positive Her2 negative BC treated with CDK4/6is who received palliative RT demonstrated a high rate of radiation toxicity (21%) in those patients for whom the CDK4/6i was given concurrently. Quality improvement work in this area, including practice guidelines, is warranted. Citation Format: Neda Stjepanovic, Alia Thawer, Dilshad Nathoo, Danilo Giffoni, Maria Romero, Anthony Lott, Andrea Eisen, Rossanna Pezo, Katarzyna Jerzak, Maureen Trudeau, Sonal Gandhi, Ellen Warner. Radiation therapy (RT) induced toxicity in advanced breast cancer (ABC) patients treated with CDK4/6 inhibitors (CDK4/6is) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-20.

Background: For Hormonal Receptor positive/HER2 negative (HR+/HER2-) metastatic Breast Cancer (mBC) the optimal treatment post-progression on a CDK4/6 inhibitor is still not defined. We aim to identify real-world patterns of systemic treatment choice following palbociclib use at a large tertiary cancer centre and to determine the outcomes for this patient population. Methods: We identified HR+/HER2- mBC patients treated with palbociclib between January 2016 and June 2020 using the institutional computerized prescriber order entry (CPOE) system. Patients with a 2nd primary other than breast, male, or with HER 2 overexpression were excluded. Electronic medical records were retrospectively reviewed to determine clinical, pathological characteristics, and treatment patterns. Our primary outcome was Time to Treatment Failure (TTF) for the subsequent treatment, using the Kaplan Meier survival method. Results: A total of 136 patients were included. At first diagnosis the median age was 52 years; 52% were premenopausal, the most prevalent primary tumor features were ductal histology (79%), and lymph node positive disease (54%). Regarding initial treatment 77% underwent surgery, 52% had adjuvant radiation therapy, 61% had chemotherapy (CT) and 67% had endocrine therapy (ET). The most frequent metastatic sites were bone 70%, liver 36%, and lung 33%. 63 tumors were rebiopsied, in 21 (33.3%) biomarkers had changed. Palbociclib was indicated as 1 Line in 45% of patients, 2 Line 26%, and ≥ 3 Line 27%. The most tolerated dose was 75 mg (44% v 33% tolerating 125 mg). The most prescribed endocrine backbones were AI (66%) and fulvestrant (30%). mTTF was 29.9 mo. (95%CI 12.68-47.11) for 1L, 33.2 mo. (95%CI 22.45-44.08) for 2L, 7.03 mo. (95%CI 2.29-11.76) for ≥ 3L. After a median follow-up of 18.7 mo, 74 patients (54%) had discontinued palbociclib due to progression (46%), toxicity (5%), or death (4%). Sites of progression were liver 37%, bone 29%, pleura 11%, lung 10% and peritoneum 6.5%. 63 patients had subsequent systemic therapy, with mTTF of 5.6 mo. 46 patients (34%) received chemotherapy, 29 patients had capecitabine, mTTF was 4.8 mo. 13 patients (9%) received endocrine therapy, 9 patients had fulvestrant +/- others, mTTF was 8.9 mo. For 5 patients (4%) the subsequent treatment was CDKi-based, 4 patients continued with palbociclib plus another endocrine backbone, mTTF was 16.5 mo. Only 1 patient (.7%) received everolimus-based subsequent treatment, with a TTF 5.6 mo. Conclusion: In this real-world analysis, we found that palbociclib was most tolerated at 75 mg and most prescribed with an AI. After progression on CDKi, the tendency was to prescribe a chemotherapy-based subsequent line, mainly capecitabine. Citation Format: Maria Luisa Romero Lagunes, Faisal Sickandar, Alia Thawer, Neda Stjepanovic, Katarzyna Jerzak, Maureen Trudeau, Andrea Eisen, Sonal Gandhi, Ellen Warner, Danilo Giffoni M. M. Mata, Abdullah MA Al-Humiqani, Anthony Lott, Rossanna C Pezo. Single-centre retrospective study of treatment choices and outcomes of metastatic breast cancer post-progression on the CDK4/6 inhibitor palbobiclib [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-54.

Background: Pathologic complete response (pCR) following neoadjuvant chemotherapy (NAC) is associated with improved survival outcomes among women with HER2 positive (HER2+) breast cancer. We aimed to analyze the clinical, pathological and molecular factors associated with pCR in our series of HER2+ breast cancer patients. Methods: Between 2009 and 2019, breast cancer patients receiving NAC at our centre were enrolled in a prospective database. For this study we selected women with HER2+ unilateral breast cancer stages II or III who received anthracycline-taxane NAC regimens (with trastuzumab given concurrently with the taxane) and subsequently underwent breast and axillary surgery with curative intent. Medical charts of these 161 women were retrospectively reviewed to determine what clinical, pathological and molecular characteristics were associated with pCR using bivariate and multivariate analysis. Results: Of the 161 HER2+ women median age at diagnosis was 49 years (range 25-78) with 90 (56%) women under age 50. Total of 104 (65%) tumors were stage II, 108 (67%) expressed estrogen and/or progesterone receptors, 139 (86%) had HER2 3+ expression by immunohistochemistry (IHC) and 22 (14%) had HER2 IHC 2+ expression with amplified HER2 on fluorescence in situ hybridization (FISH) test. The NAC regimens were: Doxorubicin-Cyclophosphamide-Paclitaxel for 83 (52%) and Fluorouracil-Epirubicin-Cyclophosphamide-Docetaxel for 78 (48%) women. A total of 73 patients [45%; 44/108 HR+ (41%) and 29/53 HR- (55%)] achieved pCR (p=0.94). pCR rate among HER2 IHC 3+ tumors was 69/139 (50%), while for HER2 IHC 2+ tumors was 4/22 (18%). On bivariate analysis HER2 IHC 3+, absence of estrogen receptors and absence of progesterone receptors were predictive of pCR, while age, menopausal status, histologic subtype, tumor grade and NAC regimen were not. In the multivariate model only HER2 IHC 3+ expression remained a significant predictor of pCR (OR =4.443, 95% CI 1.376 - 14.344). Conclusion: Our analysis suggests that for HER2+ breast cancers treated with NAC with anthracycline-taxane and trastuzumab, HER2 IHC 3+ expression is associated with a higher rate of pCR compared to HER2 IHC 2+ expression with FISH amplification. Further analysis in a larger cohort is warranted. Citation Format: Neda Stjepanovic, Katarzyna Jerzak, Maureen Trudeau, Andrea Eisen, Sonal Gandhi, Ellen Warner, Danilo Giffoni MM Mata, Anthony Lott, Maria Romero, Sharon Lemon-Wong, Althea VanMassop, Xingshan Cao, William Tran, Rossanna Pezo. Analysis of factors associated with pathological complete response (pCR) in patients with HER2+ breast cancer receiving neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-33.

BACKGROUND: People with cancer are at risk for initial, late, and long-term effects of cancer and its treatments. Cancer rehabilitation (CR) focuses on prevention/treatment of these sequelae and optimization of physical, social, and vocational functioning. Our center has a multidisciplinary impairment-driven outpatient CR program, but referrals of patients with GI cancer were low. AIMS: We aimed (for 2019, relative to 2018) (1) to increase CR referrals of patients with GI cancer by 50% and (2) to increase the proportion of referrals coming from oncologists. Balancing measures included inappropriate referrals and cancellations. METHODS: A rapid cycle improvement approach was used to optimize GI referrals to the CR program. Barriers to CR referral were identified through a literature review and informal interviews of GI clinicians. Barriers included (a) knowledge of CR program existence, (b) awareness of the referral process, (c) time, and (d) lack of CR program exposure. The team used Plan-Do-Study-Act (PDSA) cycles every 2 months from January to December 2019 to address barriers. A p-chart was used to analyze the results. RESULTS: PDSA cycles included CR program advertisement, a presentation to GI staff, nurse-led patient identification, patient-facing posters, and clinician thank-you emails. The p-chart showed a 100% relative increase in referral numbers and an improvement in the percentage of patients referred by oncologists from 51% to 75%. There was no significant change in inappropriate referrals or cancellations. CONCLUSION: Through PDSA cycles, we improved the total number of patients with GI cancer and percentage referred by an oncologist to a CR program. Future work will assess sustainability.

Background Text messaging is increasingly replacing paging as a tool to reach physicians on medical wards. However, this phenomenon has resulted in high volumes of nonurgent messages that can disrupt the learning climate. Objective Our objective was to reduce nonurgent educational interruptions to residents on general internal medicine. Design, setting, patients This was a quality improvement project conducted at an academic hospital network. Measurements and interventions took place on 8 general internal medicine inpatient teaching teams. Intervention Interventions included (1) refining the clinical communication process in collaboration with nursing leadership; (2) disseminating guidelines with posters at nursing stations; (3) introducing a noninterrupting option for message senders; (4) audit and feedback of messages; (5) adding an alert for message senders advising if a message would interrupt educational sessions; and (6) training and support to nurses and residents. Measurements Interruptions (text messages, phone calls, emails) received by institution-supplied team smartphones were tracked during educational hours using statistical process control charts. A 1-month record of text message content was analyzed for urgency at baseline and following the interventions. Results The interruption frequency decreased from a mean of 0.92 (95% CI, 0.88 to 0.97) to 0.59 (95% CI, 0.51 to0.67) messages per team per educational hour from January 2014 to December 2016. The proportion of nonurgent educational interruptions decreased from 223/273 (82%) messages over one month to 123/182 (68%; P Conclusions Creation of communication guidelines and modification of text message interface with feedback from end-users were associated with a reduction in nonurgent educational interruptions. Continuous audit and feedback may be necessary to minimize nonurgent messages that disrupt educational sessions.

Explanations of state behavior in international relations theory and international law are frequently divided between norms and self-interest. In most discussions, these two competing explanations are portrayed as mutually exclusive. By examining one recent example of US international legal behavior-the International Criminal Court-we argue that these parallel arguments about state actions may actually converge. That is, both lines of argument may, in many instances, be complementary, and it may be hard to find sharp differences in the logic of arguments from self-interest and of arguments from norms.

Introduction Pembrolizumab is a humanized monoclonal antibody that disrupts programmed cell death 1 (PD-1) receptor signaling and unmasks native cytotoxic T-cell activity against tumor cells. Early clinical trials show that pembrolizumab induces a prolonged and sometimes dramatic antitumor response in advanced melanoma, renal cell carcinoma, and non-small cell lung cancer (NSCLC) (Topalian et al., 2012; NEJM: 366;26). Consequences of immunomodulation include immunopathologies of skin, endocrine, and/or gastrointestinal organs (Patnaik et al., 2015; Clin Cancer Res: 21;15). Herein we describe the first reported case of Evan's syndrome following the use of pembrolizumab. Case A 67-year old man with 70-pack year smoking history presented to hospital with right-sided weakness and gait ataxia. Radiologic studies of head, thorax, abdomen, and limbs revealed left-sided frontal lobe mass, pulmonary lesions, multiple liver metastases, and left lower extremity venous thrombosis. The patient underwent cranial metastasectomy, which confirmed NSCLC primary neoplasm, followed by cranial irradiation, dexamethasone treatment, and indefinite enoxaparin. First and second-line chemotherapy with gemcitabine-carboplatin and pemetrexed failed to control his disease; he was therefore enrolled in the MK 3475-001 clinical trial and received investigational pembrolizumab (10mg/kg every 2 weeks). Following 4 cycles of pembrolizumab therapy, repeat CT scans showed a marked reduction in cerebral, liver, and lung tumor burden. Treatment continued with transient interruption of therapy at cycle 8 due to delayed side effects of cranial radiation. An additional 10 cycles (18 cycles total) of therapy were delivered, after which the patient was admitted to hospital for new-onset fatigue, exertional dyspnea, and jaundice. Laboratory evaluation showed a hemoglobin of 6.2 g/dL, reticulocyte count 239 ×103/µL, and platelet count 113 × 103/µL, with elevated total bilirubin of 1 mg/dL, LDH 398 U/L, haptoglobin level less than 20 mg/dL, and normal creatinine and liver enzymes. Peripheral blood film revealed microspherocytes and thrombocytopenia, indirect and direct testing revealed a pan-reactive IgG autoantibody, while serologic testing was negative for infectious and rheumatologic diseases. Diagnosis of warm-autoimmune hemolytic anemia was made and the patient was initiated on prednisone, azathioprine, cyclophosphamide, and IVIG therapy in conjunction with erythropoietin injections and transfusion support. Hemoglobin reached a nadir of 3.2 g/dL before recovering to 11.6 g/dL at 2 weeks into admission, followed by discharge on daily oral prednisone at 105 mg and cyclophosphamide 100 mg. Sustained hematologic stability permitted gradual prednisone taper to a dose of 20 mg. Fourteen weeks post-admission, the patient returned to hospital with severe bruising and epistaxis. Laboratory evaluation showed hemoglobin of 11.6 g/dL and platelet count of 6 × 109/L, concerning for ITP and fulfilling criteria for Evan's syndrome. Salvage therapy commenced with weekly rituximab and re-initiation of high-dose prednisone, until platelets recovered to 146 × 109/L following the fourth/final dose of rituximab. Prednisone taper was re-trialed with complete discontinuation of steroids after 24 weeks. Despite a persistently positive Coombs test, the patient maintained normal hemoglobin and platelet counts 40 weeks after rituximab therapy. Opportunistic Aspergillus fumigatus pulmonary infection followed salvage therapy, but was successfully treated with voriconazole over 12 weeks. CT staging scans at 48 weeks post-discontinuation of pembrolizumab demonstrated stable metastatic disease. Conclusion Reversal of cancer-induced immune suppression through PD-1 inhibition has the potential to provoke immunodysregulation against multiple hematologic lineages. Though autoimmune hyperactivation persists for months after pembrolizumab cessation, immune-related hemolysis and thrombocytopenia remain amenable to treatment with corticosteroids and rituximab. Despite immune downregulation with corticosteroids and rituximab, pembrolizumab appears to exhibit sustained immune control over advanced malignancy in this case. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Off Label Use: Rituximab to treat refractory ITP. Butler:Merck: Consultancy.