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Highlights • Acute patient-reported outcomes were compared with investigator-reported outcomes. • We identified low agreement between IR-CTCAE and PRO-CTCAE for prostate cancer. • Physicians underestimated the frequency and severity of GU symptoms and diarrhea. • The end of treatment was a key timepoint showing high levels of discordance., Purpose We report acute patient-reported outcomes using CTCAE (PRO-CTCAE) of proton beam radiotherapy for high-risk or unfavorable intermediate-risk prostate cancer in a prospective clinical trial. PRO-CTCAE were correlated with investigator reported-CTCAE (IR-CTCAE) to assess the degree of concordance. Methods and materials 11 PRO-CTCAE questions assessed gastrointestinal (GI), genitourinary (GU), or erectile function side effects. The correlation scheme between PRO-CTCAE and IR-CTCAE was independently developed by two physicians. Analyses of PRO-CTCAE and IR-CTCAE were conducted using both descriptive terms and the converted grade scores. The Kappa statistic described the degree of concordance. Results 55 patients were included. IR-CTCAE underestimated diarrhea compared to PRO-CTCAE at the end of treatment (EOT), with a 28% rate of underestimation (11% by ≥ 2 toxicity grades). Similarly, urinary tract pain was underestimated in 45% of cases (17% by ≥ 2 grades) at EOT. Differences were less pronounced at baseline or 3 months after radiotherapy. The incidence of urinary urgency and frequency tended to be overestimated prior to treatment (36% and 24%, respectively) but underestimated at EOT (35% and 31%, respectively). The degree of interference with daily activities was consistently overestimated by investigators (45%-85%). Finally, erectile dysfunction showed a 36–56% rate of discordance by ≥ 2 toxicity grades. Conclusions Our study shows a low agreement between IR-CTCAE and PRO-CTCAE in the setting of proton therapy for prostate cancer. Compared to patient-reported outcomes, physicians underestimated the frequency and severity of urinary symptoms and diarrhea at the end of treatment. Continued use of PROs should be strongly encouraged.

Background: Patients with myeloproliferative neoplasms (MPNs) suffer from chronic and progressive symptom burden. MPN trials capturing patient-reported symptoms routinely administer the MPN Symptom Assessment Form (SAF). The MPN-10 assesses 10 of the most clinically relevant symptoms, including fatigue and generates a Total Symptom Score (TSS). The original MPN-10 included a fatigue item from the Brief Fatigue Inventory (BFI). The myelofibrosis-specific symptom assessment tool called the MFSAF v4 utilizes a fatigue item developed to be consistent with other items within the SAF. This study sought to validate a modified version of the MPN-10 TSS using the SAF fatigue item for harmonization with MFSAF v4. Methods: Survey data from two cohorts of patients with essential thrombocythemia, polycythemia vera, or myelofibrosis assessing MPN characteristics and symptom burden were used. Results and conclusion: BFI and SAF fatigue items were highly correlated in raw score (Pearson r = 0.88), comparable in their severity categorizations (89% agreement for severe versus non-severe) and respective contributions to the TSS (both Cronbach’s alpha = 0.89). Reliability of SAF fatigue was acceptable and independently associated with known disease-related characteristics (splenomegaly, low quality-of-life, and distress). Fatigue in patients with MPNs is measured with high similarity using the SAF fatigue item within the MPN-10 in harmonization with the MFSAF v4. J Hematol. 2021;10(5):207-211 doi: https://doi.org/10.14740/jh914

Summary Background Palbociclib added to endocrine therapy improves progression-free survival in hormone-receptor-positive, HER2-negative, metastatic breast cancer. The PALLAS trial aimed to investigate whether the addition of 2 years of palbociclib to adjuvant endocrine therapy improves invasive disease-free survival over endocrine therapy alone in patients with hormone-receptor-positive, HER2-negative, early-stage breast cancer. Methods PALLAS is an ongoing multicentre, open-label, randomised, phase 3 study that enrolled patients at 406 cancer centres in 21 countries worldwide with stage II–III histologically confirmed hormone-receptor-positive, HER2-negative breast cancer, within 12 months of initial diagnosis. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance score of 0 or 1. Patients were randomly assigned (1:1) in permuted blocks of random size (4 or 6), stratified by anatomic stage, previous chemotherapy, age, and geographical region, by use of central telephone-based and web-based interactive response technology, to receive either 2 years of palbociclib (125 mg orally once daily on days 1–21 of a 28-day cycle) with ongoing standard provider or patient-choice adjuvant endocrine therapy (tamoxifen or aromatase inhibitor, with or without concurrent luteinising hormone-releasing hormone agonist), or endocrine therapy alone, without masking. The primary endpoint of the study was invasive disease-free survival in the intention-to-treat population. Safety was assessed in all randomly assigned patients who started palbociclib or endocrine therapy. This report presents results from the second pre-planned interim analysis triggered on Jan 9, 2020, when 67% of the total number of expected invasive disease-free survival events had been observed. The trial is registered with ClinicalTrials.gov (NCT02513394) and EudraCT (2014-005181-30). Findings Between Sept 1, 2015, and Nov 30, 2018, 5760 patients were randomly assigned to receive palbociclib plus endocrine therapy (n=2883) or endocrine therapy alone (n=2877). At the time of the planned second interim analysis, at a median follow-up of 23·7 months (IQR 16·9–29·2), 170 of 2883 patients assigned to palbociclib plus endocrine therapy and 181 of 2877 assigned to endocrine therapy alone had invasive disease-free survival events. 3-year invasive disease-free survival was 88·2% (95% CI 85·2–90·6) for palbociclib plus endocrine therapy and 88·5% (85·8–90·7) for endocrine therapy alone (hazard ratio 0·93 [95% CI 0·76–1·15]; log-rank p=0·51). As the test statistic comparing invasive disease-free survival between groups crossed the prespecified futility boundary, the independent data monitoring committee recommended discontinuation of palbociclib in patients still receiving palbociclib and endocrine therapy. The most common grade 3–4 adverse events were neutropenia (1742 [61·3%] of 2840 patients on palbociclib and endocrine therapy vs 11 [0·3%] of 2903 on endocrine therapy alone), leucopenia (857 [30·2%] vs three [0·1%]), and fatigue (60 [2·1%] vs ten [0·3%]). Serious adverse events occurred in 351 (12·4%) of 2840 patients on palbociclib plus endocrine therapy versus 220 (7·6%) of 2903 patients on endocrine therapy alone. There were no treatment-related deaths. Interpretation At the planned second interim analysis, addition of 2 years of adjuvant palbociclib to adjuvant endocrine therapy did not improve invasive disease-free survival compared with adjuvant endocrine therapy alone. On the basis of these findings, this regimen cannot be recommended in the adjuvant setting. Long-term follow-up of the PALLAS population and correlative studies are ongoing. Funding Pfizer.

Background: The association between obesity and prognosis in HER2-positive early breast cancer remains unclear, with limited data available. This study aimed to determine the impact of body mass index (BMI) at baseline and weight change after 2 years on outcomes of patients with HER2-positive early breast cancer. Methods: ALTTO was a randomized phase III trial in patients with HER2-positive early breast cancer. BMI was collected at randomization and 2 years after. WHO BMI categories were used: underweight, 2; normal weight, 18.5 to 2; overweight, ≥25 to 2; and obese ≥30 kg/m2. A weight change from baseline of ≥5.0% and ≤5.0% was categorized as weight gain and weight loss. The impact of BMI at randomization and of weight change on disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) were investigated with multivariate analyses, adjusting for baseline patients and tumor characteristics. Results: A total of 8,381 patients were included: 187 (2.2%), 3,797 (45.3%), 2,690 (32.1%), and 1,707 (20.4%) were underweight, normal weight, overweight, and obese at baseline, respectively. Compared with normal weight, being obese at randomization was associated with a significantly worse DDFS (adjusted hazard ratio [aHR], 1.25; 95% CI, 1.04–1.50) and OS (aHR, 1.27; 95% CI, 1.01–1.60), but no significant difference in DFS (aHR, 1.14; 95% CI, 0.97–1.32). Weight loss ≥5.0% at 2 years after randomization was associated with significantly poorer DFS (aHR, 1.34; 95% CI, 1.05–1.71), DDFS (aHR, 1.46; 95% CI, 1.07–1.98), and OS (aHR, 1.83; 95% CI, 1.18–2.84). Hormone receptor and menopausal status but not anti-HER2 treatment type influenced outcomes. Toxicities were more frequent in obese patients. Conclusions: In patients with HER2-positive early breast cancer, obesity at baseline is a poor prognostic factor. Weight loss during treatment and follow-up negatively impacts clinical outcomes. Dietary counseling should be part of survivorship care programs.

Myeloproliferative neoplasms (MPNs) are characterized by significant symptom burden. Integrative medicine (IM) offers unique symptom management strategies. This study describes IM interventions utilized by MPN patients and the association with symptom burden, quality of life, depression, and fatigue adjusted for lifestyle confounders. MPN patients were surveyed online for IM utilization, MPN symptom burden (MPN‐Symptom Assessment Form Total Symptom Score), depression (Patient Health Questionnaire), fatigue (Brief Fatigue Inventory), and a single question on overall quality of life. Measures were compared by IM participation and adjusted for alcohol and tobacco use, BMI, diet, and MPN type using multiple linear and logistic regression. A total of 858 participants were included in the analysis. Aerobic activity (p =, This study describes integrative medicine interventions utilized by myeloproliferative neoplasms (MPN) patients and the association with symptom burden, quality of life, depression, and fatigue adjusted for lifestyle confounders. Which, in an internationally diverse MPN patient population and adjusting for healthy lifestyle practices, an overall pattern of lower symptom burden, fatigue, depression, and higher quality of life were revealed with integrative medicine utilization.

Background Philadelphia chromosome negative myeloproliferative neoplasms (MPNs), including essential thrombocythemia, polycythemia vera, and myelofibrosis, have severe function‐limiting symptom burden that is experienced by the majority of patients. Previous studies have suggested that depression may be present in over a quarter of MPN patients, but to date no studies have evaluated the relationship between depression and other variables such as symptoms. Methods A 70‐item internet based survey regarding fatigue and mood symptoms was developed by a multidisciplinary team of MPN investigators, patients and patient advocates including Patient Health Questionnaire and the Myeloproliferative Neoplasm Symptom Assessment Form was completed by over 1300 patients with MPN diagnosis. Results There were 309 respondents (23%) with PHQ‐2 scores ≥ 3. In this analysis, we found worse systemic symptom burden in individuals reporting depressive symptoms. Conclusion This analysis suggests the importance of depression in contributing to as well as confounding symptomatology in MPN patients, and suggests that this critical variable should also be addressed by clinicians and researchers alike when comprehensively assessing symptom burden etiologies., A survey of over 1300 patients with myeloproliferative neoplasms revealed 23% reported depressive symptoms and these symptoms were associated worse systemic symptom burden.

BACKGROUND: The goal of this study was to assess the impact of trastuzumab on locoregional failure. METHODS: The analysis included 2763 patients with HER2-positive (HER2+) breast cancer who were randomly assigned to adjuvant doxorubicin (A), cyclophosphamide (C), paclitaxel (T) and trastuzumab (H) (arm A, AC→T [n = 922]; arm B, AC→T→H [n = 988]; arm C, AC→T+H→H [n = 853]). Radiotherapy was given after AC→T concurrently with H. Radiotherapy was given after lumpectomy (L) or after mastectomy (M) with ≥4 positive lymph nodes but was optional for 1 to 3 positive lymph nodes. Locoregional failures at 10 years (LFR10) as first events were compared using competing risk analysis. RESULTS: The median follow-up was 13.0 years. The first site of failure was local-only in 96 cases, locoregional in 16 cases, regional in 32 cases, and not specified in 2 cases; LFR10 was 4.8% (95% CI 4.1%–5.7%). LFR10 was 5.5% (95% CI 4.3%–7.2%), 4.9% (95% CI 3.7%–6.4%), and 2.8% (95% CI 1.9%–4.1%) in arms A, B, and C (B vs A: hazard ratio [HR] 0.91, P = .62; C vs A: HR 0.72, P = .12). For estrogen receptor–positive patients, LFR10 was 3.7% (95% CI 2.8%–4.8%) and for estrogen receptor–negative patients, it was 6.1% (95% CI 5.0%–7.4%; HR 0.61, P = .004). Local treatment included L+RT (n = 1044 [38%]), M+RT (n = 1025 [37%]), and M (n = 694 [25%]). LFR10 was 6.% (95% CI 5.0%–7.8%), 3.0% (95% CI 2.1%–4.3%), and 5.5% (95% CI 4.0%–7.4%) for L+RT, M+RT, and M, respectively (M+RT vs L+RT: HR 0.43, P < .001; M vs L+RT: HR 0.88, P = .57). For 1 to 3 positive lymph nodes, LFR10 was 6.5% (95% CI 4.8%–8.9%), 4.1% (95% CI 2.4%–7.0%), and 4.3% (95% CI 2.9%–6.5%) in L+RT, M+RT, and M, respectively (M vs L+RT: HR 0.68, P = .14; M vs M+RT: HR 1.2, P = .6). CONCLUSION: Low 10-year LFRs were seen regardless of trastuzumab use. Differences in local therapy in patients with 1 to 3 positive lymph nodes did not appear to improve local control. Local therapy studies for HER2+ and other tumor characteristics are important as the role of local therapies continues to evolve.

Background: Side effects of and adherence to aromatase inhibitors in women with ductal carcinoma in situ are not well described. Methods: Postmenopausal women in a prospective phase II study of neoadjuvant letrozole for estrogen receptor positive DCIS completed questionnaires on side effects [Menopause Specific Quality of Life Questionnaire (MENQOL), Brief Pain Inventory-short form (BPI-SF), Arthritis Impact Measurement Scales (AIMS2)], well-being (FACT-G), and adherence [Medication-Taking questionnaire] at baseline, 1, 3 and 6 months (mo), and study completion. We used descriptive statistics and paired t-tests to compare 1, 3 and 6 mo results to baseline. Hierarchical linear mixed modeling, controlling for baseline symptom or well-being level, was used to examine effect of symptoms and well-being on intentional and nonintentional nonadherence, based on the Medication-Taking Questionnaire. Results: Included were 84 women, mean age 63 (39-83) years. In univariate analyses, compared to baseline, menopausal symptoms increased [physical (p=0.001 at 3, p0.05). Lower emotional (p=0.049) and functional (p=0.002) well-being by FACT-G and higher joint pain (p=0.03) by AIMS2 were associated with higher nonintentional nonadherence; higher physical side effects of menopause (p=0.001) by MENQOL were associated with lower intentional nonadherence. Conclusions: Among women taking letrozole for DCIS, menopausal symptoms and joint pain/stiffness increased over time with most differences noted at 3 and 6 mo. Lower well-being and higher symptom levels were associated with higher nonintentional nonadherence. NCT01439711.U10CA180821, U10CA180882, UG1CA189823, Breast Cancer Research Foundation, https://acknowledgments.alliancefound.org. Citation Format: Gretchen Kimmick, Amylou C Dueck, Rebecca Shelby, Michelle Naughton, Abigail Caudle, Briant Fruth, E. Shelley Hwang. Musculoskeletal side effects over time and association with adherence in women taking neoadjuvant letrozole for estrogen receptor positive DCIS: CALGB 40903 (Alliance) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-14-17.

Context Summarizing longitudinal symptomatic adverse events during clinical trials is necessary for understanding treatment tolerability. The Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) provides insight for capturing treatment tolerability within trials. Tolerability summary measures, such as the maximum score, are often used to communicate the potential negative symptoms both in the medical literature and directly to patients. Commonly, the proportions of present and severe symptomatic adverse events are used and reported between treatment arms among adverse event types. The toxicity index is also a summary measure previously applied to clinician-reported CTCAE data. Objectives Apply the toxicity index to PRO-CTCAE data from the COMET-2 trial alongside the maximum score, then present and discuss considerations for using the toxicity index as a summary measure for communicating tolerability to patients and clinicians. Methods Proportions of maximum PRO-CTCAE severity levels and median toxicity index were computed by arm using all trial data and adjusting for baseline symptoms. Results Group-wise statistical differences were similar whether using severity level proportions or the toxicity index. The impact of adjusting for baseline symptoms was equivalently seen when comparing arms using severity rates or the toxicity index. Conclusion The toxicity index is a useful method when ranking patients from those with the least to most symptomatic adverse event burden. This study showed the toxicity index can be applied to PRO-CTCAE data. Though as a tolerability summary measure, further study is needed to provide a clear clinical or patient-facing interpretation of the toxicity index.

Introduction Essential thrombocythemia (ET) and polycythemia vera (PV) patients suffer from various symptoms that worsen quality of life (QOL), yet serial data on symptom changes resulting from therapy are sparse in the literature. Patient questionnaires from 2 large multicenter trials (MPN-RC 111, 112) were used to assess change in symptom burden and QOL over 12 months and impact of baseline symptom burden on subsequent change in ET / PV patients on hydroxyurea (HU) or pegylated interferon alfa-2a (PEG). Methods Trials MPN-RC 111 was a single-arm, open-label, phase II trial evaluating response to PEG in high-risk ET / PV patients with HU resistance/intolerance or splanchnic vein thrombosis (SVT; NCT01259817). MPN-RC 112 was a randomized, open-label, phase III trial comparing response to PEG versus HU in cytoreductive therapy naïve high-risk ET / PV patients diagnosed < 5 years ago (NCT01258856). Measures Patients reported disease-related symptoms via the validated Myeloproliferative Neoplasms Symptom Assessment Form (MPN-SAF), QOL via the European Organisation for the Research and Treatment of Cancer Core QOL Questionnaire (EORTC QLQ-C30), and (if applicable) PEG-related symptoms (flu-like symptoms, injection site irritation, blurry vision, vision change, flushing) at baseline, 3, 6, 9, and 12 months. Analysis Mixed models assessed mean changes from baseline in the MPN-SAF Total Symptom Score (TSS), MPN-SAF items, QOL, and PEG-related symptoms in MPN-RC 111, 112 PEG, and 112 HU patients. Mixed models also assessed the impact of baseline symptom burden (high [TSS ≥ 20] versus low) on subsequent change in PEG (MPN-RC 111 and 112) and HU patients. Results Patients Of the 135 enrolled MPN-RC 111 patients, 20 with SVT and 1 with no questionnaires were excluded. Of the remaining 114, 64 (56%) / 50 (44%) had ET / PV. Patients were 51% / 48% female. Median age was 65 / 64 years, and median time since diagnosis was 38 / 55 months. 31% / 22% had prior thrombosis, and 19% / 56% had splenomegaly. Of the 168 enrolled MPN-RC 112 patients (82 PEG, 86 HU), 2 with no questionnaires were excluded. Of the remaining 166, 79 (48%) / 87 (52%) had ET / PV. Patients were 50% / 33% female. Median age was 60 / 62 years, and median time since diagnosis was 3 / 3 months. 25% / 29% had prior thrombosis, and 11% / 37% had splenomegaly. Symptoms Questionnaire completion rates ranged from 90 - 99%, 87 - 100%, and 75 - 96% for on-treatment MPN-RC 111, 112 PEG, and 112 HU patients. At baseline, TSS (0 [absent] - 100 [worst imaginable]) and QOL (0 [very poor] - 100 [excellent]) means (SDs) were 19.5 (18.4) and 71.6 (20.1) for MPN-RC 111, 17.0 (13.6) and 67.9 (24.3) for MPN-RC 112 PEG, and 14.6 (11.4) and 73.8 (18.8) for MPN-RC 112 HU patients. On average, MPN-RC 111 patients had significant improvement of TSS, fatigue, abdominal pain, abdominal discomfort, dizziness, numbness, night sweats, and fever; MPN-RC 112 PEG patients had significant worsening of fever; and MPN-RC 112 HU patients had significant worsening of inactivity (no mean changes indicating improvement were observed). PEG patients had significant worsening of PEG-related symptoms. The greatest improvements occurred in the 46 (40%), 27 (33%), and 23 (28%) MPN-RC 111, 112 PEG, and 112 HU patients with high baseline symptom burden. On average, PEG patients with high baseline symptom burden had significant improvement of TSS, fatigue, early satiety, abdominal pain, abdominal discomfort, inactivity, headache, concentration, dizziness, numbness, insomnia, cough, night sweats, itching, bone pain, fever, weight loss, and QOL, while those with low baseline symptom burden had significant worsening of TSS, early satiety, headache, itching, and bone pain. On average, HU patients with high baseline symptom burden had significant improvement of TSS, early satiety, abdominal discomfort, headache, dizziness, numbness, insomnia, itching, and weight loss, while those with low baseline symptom burden had significant worsening of TSS, early satiety, abdominal discomfort, inactivity, concentration, and sexual desire/function (Figures 1 and 2). Conclusions Although no statistical comparisons were made across trials, overall improvements were seen in MPN-RC 111 but not 112. Patients with high baseline symptom burden experienced the greatest improvements in symptom burden and QOL during treatment with PEG or HU, which may explain the improvements seen in the more advanced patients in MPN-RC 111 compared to 112. Disclosures Mascarenhas: Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy; Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution). Yacoub:Dynavax: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Cara Therapeutics: Current equity holder in publicly-traded company; Hylapharm: Current equity holder in private company; Incyte: Speakers Bureau; Agios: Honoraria, Speakers Bureau; Novartis: Speakers Bureau; Roche: Other: Support of parent study and funding of editorial support. Hoffman:Protagonist: Consultancy; Forbius: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Dompe: Research Funding. Silver:PharmaEssentia: Speakers Bureau. Mesa:Bristol Myers Squibb: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; Samus Therapeutics: Research Funding; Genentech: Research Funding; CTI BioPharma: Research Funding; Promedior: Research Funding; Sierra Oncology: Consultancy; LaJolla Pharmaceutical Company: Consultancy; Novartis: Consultancy.

Preclinical Rationale: Myelofibrosis (MF) is a chronic myeloproliferative neoplasm for which there are limited therapies. TGFβ plays a pivotal role in the pathobiology of MF by not only promoting bone marrow fibrosis (BMF) and collagen deposition, but also by enhancing the dormancy of normal but not MF hematopoietic stem cells (HSCs). TGFβ has also previously been reported to inhibit normal megakaryocyte (MK) production (Bruno et al Blood 1998). TGFβ1 promotes the synthesis of collagen by normal human mesenchymal stromal cells (MSCs) and activates the TGFβ receptor I/SMAD pathway as well as non-canonical TGFβ pathways. We generated MKs from MF subject mononuclear cells (MNCs) and showed that they elaborated significantly greater levels of TGFβ1 than TGFβ2/3 TGFβ1 treatment reduced the numbers of hematopoietic colonies generated by normal but not MF MNCs. Treatment of MSCs with AVID200, a potent TGFβ1/3 protein trap, significantly decreased MSC proliferation, phosphorylation of SMAD2, and collagen expression. Robust expression of pSMAD2 was observed in the absence of exogenous TGFβ in normal donor or MF-MKs, Addition of AVID200 to -MKs decreased pSMAD2 without affecting total SMAD2/3, indicating that AVID200 blocks the effects of autocrine TGFβ produced by MKs and led to increased numbers of MKs. Moreover, treatment of primary MF MNCs with AVID200 led to increased numbers of progenitor cells with wild type JAK2 and a reduction of mutated colonies. AVID200 blocked TGFβ1-induced p57Kip2 expression and SMAD2 activation by MF MNCs allowing the normal progenitor cells to preferentially cycle, proliferate, and form hematopoietic colonies. Clinical Trial Design: Based on these findings, a phase 1 trial of AVID200 is ongoing in INT-2/high risk MF subjects resistant or intolerant to ruxolitinib; baseline platelet count of ≥ 25 x 109/L, and grade 2/3 BMF. Subjects received intravenous AVID200 (Lots A and B) in dose cohorts of 180 mg/m2 (A), 550 mg/m2 (A), 180 mg/m2 (B) on Day 1 of a 21 day cycle. Cohorts of 3 subjects with a target toxicity rate of 30% were enrolled to estimate the maximum tolerated dose (MTD). A modified toxicity probability interval design was used. Response was assessed by IWG/ELN criteria after 6 cycles of AVID200. Subjects attaining at least a CI or SD with a decrease in BMF by ≥1 grade, continued AVID200. Clinical Trial Results: 10 subjects were enrolled (1 withdrew before receiving treatment) and 9 were treated with AVID200 and were evaluable for DLT assessment [Table1]. Median time after ruxolitinib discontinuation was 3.5 months (0.5-12.2). No DLTs were observed. Grade 3/4 AEs (regardless of attribution) were observed in 6 (66.7%) subjects. Grade 3/4 non-hematologic AEs observed were epistaxis (1, 11.1%), extraocular muscle paresis (1, 11.1%), fatigue (1, 11.1%) and rash (1, 11.1%). Grade 3/4 hematologic AEs were anemia (3, 33.3%) and thrombocytopenia (2, 22.2%) [Table 2]. The median number of cycles received was 5.7 (range 0 - 12). 5 subjects received 6+ cycles and were evaluable. CI occurred in 2 subjects [anemia, spleen and TSS (n=1); TSS (n=1)] 1 of which is still being treated, 2 subjects had SD, 1 subject with 21% blasts prior to study treatment had progressive MPN-BP. 4 subjects failed to reach response evaluation after 6 cycles, 2 had PD due to increasing splenomegaly, 1 subject received an allogeneic transplant and 1 is still being treated [Cycle 2]. The median platelet count at baseline was 114 (range: 42-290) and 159 after cycle 6 [Figure 1]. Maximum changes in platelets from baseline was +64% [range -73%, 169%] in all subjects. 7 subjects had an increase in platelets from baseline during treatment. 2 subjects normalized their platelet count from thrombocytopenic levels. The effect of AVID200 on BMF is currently being examined. 2 subjects remain on treatment. Conclusions: AVID200 a TGFβ1/3 protein trap is well tolerated in advanced MF subjects. Clinical responses were observed at the 550 mg dose and the expansion efficacy cohorts at doses 2 and 3 are enrolling 12 additional subjects. Furthermore, AVID200 therapy improved thrombocytopenia in MF subjects which may be due to AVID200 inhibiting the effects of TGFβ1 on normal MKpoiesis. Updated subject safety and efficacy data along with correlative data will be presented. Disclosures Mascarenhas: Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy; Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution). Kuykendall:Blueprint Medicines: Research Funding; BMS: Research Funding; Incyte: Research Funding; Novartis: Research Funding. Komrokji:Jazz: Honoraria, Speakers Bureau; Abbvie: Honoraria; Agios: Speakers Bureau; BMS: Honoraria, Speakers Bureau; Geron: Honoraria; Incyte: Honoraria; Acceleron: Honoraria; Novartis: Honoraria. Gerds:Gilead Sciences: Research Funding; Imago Biosciences: Research Funding; Sierra Oncology: Research Funding; Celgene: Consultancy, Research Funding; Roche/Genentech: Research Funding; CTI Biopharma: Consultancy, Research Funding; Apexx Oncology: Consultancy; AstraZeneca/MedImmune: Consultancy; Pfizer: Research Funding; Incyte Corporation: Consultancy, Research Funding. Migliaccio:Novartis: Research Funding. O'Connor-McCourt:Forbius: Current Employment. Tremblay:Forius: Current Employment. Nadler:Forbius: Consultancy; Nadler Pharma Associates: Current Employment; Symphogen: Consultancy; Iksuda Therapeutics: Consultancy; Tessa Therapeutics: Consultancy. Mesa:Celgene: Research Funding; Genetech: Research Funding; Samus: Research Funding; Promedior: Research Funding; CTI: Research Funding; LaJolla Pharma: Consultancy; Incyte: Research Funding; Sierra Onc: Consultancy; Abbvie: Research Funding; Novartis: Consultancy. Hoffman:Forbius: Consultancy; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Dompe: Research Funding; Protagonist: Consultancy.

Background: Myelofibrosis (MF) is a bone marrow disorder characterized by anemia, splenomegaly and constitutional symptoms. There has been substantial work documenting quality of life (QoL) in patients with MF, however, very little data about patients following allogeneic stem cell transplant (alloSCT) for MF. Many patients decline alloSCT due to concerns secondary to QoL. Methods: Medical facts and patient reported outcomes (PRO) measures were collected within a month prior to transplant, at day 30, 100 and 1 year post alloSCT. PRO measures include Brief Fatigue Inventory, Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT), global assessment of change and the Myeloproliferative Neoplasms Symptom Assessment Form (MPN-SAF). The group was measured as a whole, and the patients in the upper quartile of MPN-TSS (the aggregate score of the 10 core items of the MPN-SAF) were also considered. Results: Fifty patients were enrolled on this study, 47 who proceeded with transplant. The median age of the patients was 63, ranging from 35-74. The majority of the patients were male (29, 66%), and Caucasian (43 (96%)). Most patients had primary MF (26, 59%), 9 patients had post-PV MF, and 9 patients had post-ET MF. Twenty patients had DIPSS Intermediate 2 risk disease, and 16 had DIPSS high risk disease. Twenty-six (51%) had a matched unrelated donor, 12 (30%) had a matched related donor and 5 (12%) had a mismatched unrelated donor. The majority of the patients had RIC regimens (35, 88%). At baseline the mean MPN-TSS was 27.7 (out of possible 100), and at day 30, day 100 and 1 year it was 24.6, 32.0, and 25.0, which reflected no significant change between the time points. Interestingly, all the MPN specific symptoms (including fevers, night sweats, pruritis, abdominal pain) had a significant improvement at least one time point following alloSCT. Patients in the highest quartile based on baseline TSS score (12 patients with scores at baseline greater than or equal to 37), had significant improvement in TSS score at day 100, headache at day 30, insomnia at day 100, night sweats at day 100, itching at day 100 and overall QOL at day 100. With regards to the FACT BMT, as would be expected, there was a significant decline in the FACT BMT total score, as well as trial outcome index (TOI) at day 30, but a return to close to baseline by one year. In the global assessment of change, on day 30, 11 (27.5%) of patients reported feeling a little/moderately/very much better overall quality of life since their transplant and 27 (67.5%) felt a little/moderately/very much worse quality of life. At day 100, 11 (31.4%) reported better quality of life and 20 (57%) reported worsening since transplant. By one year, 17 (60.7%) reported feeling better and 7 (25%) reported worsening. These findings did not appear to have a correlation with presence or absence of graft versus host disease. We were unable to assess the impact of conditioning as the majority of the patients had RIC conditioning. Discussion/ Conclusions: Our study evaluated the quality of life in patients with myelofibrosis who have undergone bone marrow transplantation. We have shown that there is very little change in symptom burden over the first year following transplant in general; however, significant improvement was observed in MF specific symptoms, and in patients who had a high symptom burden at baseline. By one year 61% felt that their QoL was better than it was prior to transplant. Our findings suggest that many of the patients do not experience a significant decline in QoL at 1 year after alloSCT, and actually report that their QoL improves. Further investigation is required to validate these findings. Figure. Figure. Disclosures Palmer: Novartis: Research Funding. Dueck:Phytogine: Employment; Pfizer: Honoraria; Bayer: Employment. Mesa:Novartis: Consultancy; NS Pharma: Research Funding; Incyte Corporation: Research Funding; UT Health San Antonio - Mays Cancer Center: Employment; Pfizer: Research Funding; CTI Biopharma: Research Funding; Celgene: Research Funding; Promedior: Research Funding; Gilead: Research Funding; Genentech: Research Funding.

A limited number of drugs are available to treat patients with polycythemia vera (PV) and essential thrombocythemia (ET). We attempted to identify alternative agents that may target abnormalities within malignant hematopoietic stem (HSCs) and progenitor cells (HPCs). Previously, MDM2 protein levels were shown to be upregulated in PV/ET CD34+ cells, and exposure to a nutlin, an MDM2 antagonist, induced activation of the TP53 pathway and selective depletion of PV HPCs/HSCs. This anticlonal activity was mediated by upregulation of p53 and potentiated by the addition of interferon-α2a (IFN-α2a). Therefore, we performed an investigator-initiated phase 1 trial of the oral MDM2 antagonist idasanutlin (RG7388; Roche) in patients with high-risk PV/ET for whom at least 1 prior therapy had failed. Patients not attaining at least a partial response by European LeukemiaNet criteria after 6 cycles were then allowed to receive combination therapy with low-dose pegylated IFN-α2a. Thirteen patients with JAK2 V617F+ PV/ET were enrolled, and 12 (PV, n = 11; ET, n = 1) were treated with idasanutlin at 100 and 150 mg daily, respectively, for 5 consecutive days of a 28-day cycle. Idasanutlin was well tolerated; no dose-limiting toxicity was observed, but low-grade gastrointestinal toxicity was common. Overall response rate after 6 cycles was 58% (7 of 12) with idasanutlin monotherapy and 50% (2 of 4) with combination therapy. Median duration of response was 16.8 months (range, 3.5-26.7). Hematologic, symptomatic, pathologic, and molecular responses were observed. These data indicate that idasanutlin is a promising novel agent for PV; it is currently being evaluated in a global phase 2 trial. This trial was registered at www.clinicaltrials.gov as #NCT02407080.

Essential thrombocythemia (ET) and polycythemia vera (PV) are myeloproliferative neoplasms (MPNs) characterized by an increased risk of developing venous and arterial thromboses and of evolution to myelofibrosis or acute leukemia (1). MPNs are recognized as a major cause of splanchnic vein thromboses (SVT), which include hepatic, splenic, portal and mesenteric vein thromboses (2). Patients with SVT are at an increased risk of developing bleeding events and arterial thrombotic events (3), as well as recurrent SVT and the use of anticoagulation and cytoreduction do not clearly modify this risk (3–5). Management of SVT in MPN patients remains a challenge and most therapeutic recommendations are based on retrospective analyses (6). Recently, De Stefano reported that hydroxyurea failed to prevent recurrent thromboses in the splanchnic vasculature in patients with a prior SVT (7). We conducted a prospective, open-label, multi-center phase II clinical trial of Pegylated Interferon Alfa-2a (PEG) in 20 subjects with SVT and an MPN, who represented a cohort of patients who participated in the Myeloproliferative Disorders - Research Consortium (MPD-RC) 111 trial (). MPD-RC 111 was a prospective study of patients with high-risk ET/PV who were resistant or intolerant to hydroxyurea (HU), but prior HU therapy was not a requirement for patients to enter the SVT cohort. Here we report the outcomes of the 20 SVT patients who were treated with PEG.

Objectives Patients with lung cancer have high symptom burden and diminished quality of life. Electronic patient-reported outcome (PRO) platforms deliver repeated longitudinal surveys via web or telephone to patients and alert clinicians about concerning symptoms. This study aims to determine feasibility of electronic PRO monitoring in lung cancer patients receiving treatment in community settings. Methods Adults receiving treatment for advanced or metastatic lung cancer at 26 community sites were invited to participate in a prospective trial of weekly electronic PRO symptom monitoring for 12 months (NCT03249090). Surveys assessing patients’ satisfaction with the electronic PRO system were administered at 3 months. Descriptive statistics were generated for demographics, survey completion rates, symptom occurrence, and provider PRO alert management approaches. Pairwise relationships between symptom items were evaluated using intra-individual repeated-measures correlation coefficients. Results Lung cancer patients (n = 118) participating in electronic PROs were older (mean 64.4 vs 61.9 years, p = 0.03), had worse performance status (p = 0.002), more comorbidities (p = 0.02), and less technology experience than patients with other cancers. Of delivered weekly PRO surveys over 12 months, 91% were completed. Nearly all (97%) patients reported concerning (i.e., severe or worsening) symptoms during participation, with 33% of surveys including concerning symptoms. Pain was the most frequent and longest lasting symptom and was associated with reduced activity level. More than half of alerts to clinicians for concerning symptoms led to intervention. The majority (87%) would recommend using electronic PRO monitoring to other lung cancer patients. Conclusions Remote longitudinal weekly monitoring of patients with lung cancer using validated electronic PRO surveys was feasible in a multicenter, community-based pragmatic study. A high symptom burden specific to lung cancer was detected and clinician outreach in response to alerts was frequent, suggesting electronic PROs may be a beneficial strategy for identifying actionable symptoms and allow opportunities to optimize well-being in this population.

PURPOSE: To compare efficacy and safety of capecitabine and lapatinib with or without IMC-A12 (cituxumumab) in patients with HER2-positive metastatic breast cancer (MBC) previously treated with trastuzumab. PATIENTS AND METHODS: Following an initial safety run-in cohort, patients were randomized 1:2 to Arm A (capecitabine and lapatinib) or to Arm B (capecitabine, lapatinib, and cituxumumab). Given the frequency of non-hematologic grade ≥3 adverse events in those receiving the three-drug combination in the safety cohort, lapatinib and capecitabine doses were reduced in Arm B only. The primary objective was to determine if the addition of cituxumumab to capecitabine and lapatinib improved progression-free survival (PFS) compared with capecitabine and lapatinib. Secondary objectives included a comparison between arms of other clinical endpoints, safety, change in overall quality of life (QOL) and self-assessed fatigue, rash, diarrhea, and hand-foot syndrome. RESULTS: From July 2008 to March 2012, 68 patients (out of 142 planned) were enrolled and 63 were evaluable, including 8 for the safety run-in and 55 for the randomized cohort. Study enrollment was stopped early due to slow accrual. The addition of cituxumumab to capecitabine and lapatinib did not improve PFS (HR 0.93, 95% CI: 0.52-1.64). Furthermore, no difference in objective response rate or overall survival (OS) was observed. No difference between arms was observed in grade ≥3 adverse events, overall QOL change from baseline after 4 cycles of treatment. CONCLUSION: The addition of cituxumumab to lapatinib and capecitabine did not improve PFS or OS compared with lapatinib and capecitabine in patients with HER2-positive MBC.

Background: Although the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-PAN26 is widely used to assess health-related quality of life (HRQoL), its group-level minimal important difference (MID) and individual-level responder definition (RD) are not established; we calculated MID and RD using HRQoL data from the APACT trial in patients with surgically resected pancreatic cancer who received adjuvant chemotherapy. Methods: HRQoL was assessed using EORTC QLQ-C30 and QLQ-PAN26 at baseline, during treatment, at end of treatment, and during follow-up. Distribution-based MIDs were estimated using 0.5 × baseline standard deviation (SD) and reliability-based (intraclass correlation) standard error of measurement (SEM). Anchor-based MIDs and RDs (anchor, QLQ-C30 overall health) were estimated using a linear mixed model. Results: Overall, 772 patients completed the baseline assessment. Distribution-based MIDs (0.5 × SD) for QLQ-PAN26 scales ranged from 12 to 13, except hepatic symptoms (≈8), pancreatic pain (≈10), and sexual dysfunction (≈17); those for stand-alone items ranged from 12 to 16. The SEM values were similar. Among scales/items sufficiently correlated (r>0.30) with the anchor, MIDs ranged from 5 to 9. Within-patient QLQ-PAN26 RD estimates varied by direction (deterioration vs. improvement) and scale/item, but all values were lower than the true possible within-patient change (e.g. 16.7 points for a two-item scale) given a one-category change on the raw scale. Conclusions: Compared with distribution-based MIDs, anchor-based MIDs were twice as sensitive in detecting group-level changes in QLQ-PAN26 scales/items. For interpreting clinically meaningful change, RDs cannot be less than the true minimum of the scale. The group-level MID may help clinicians/researchers interpret HRQoL changes. Trial registration: ClinicalTrials.gov NCT01964430; Eudra CT 2013-003398-91.

Background Patients with Philadelphia-negative Myeloproliferative Neoplasms (MPN) suffer from numerous symptoms and decreased quality of life. Smoking is associated with an increased symptom burden in several malignancies. The aim of this study was to analyze the association between smoking and MPN-related symptom burden and explore MPN patients’ opinions on smoking. Methods A total of 435 patients with MPN participated in a cross-sectional internet-based survey developed by the Mayo Clinic and the Myeloproliferative Neoplasm Quality of Life Group. Patients reported their demographics, disease characteristics, tobacco use, and opinions on tobacco use. In addition, MPN-related symptoms were reported via the validated 10-item version of the Myeloproliferative Neoplasms Symptom Assessment Form. Results Current/former smokers reported worse fatigue (mean severity 5.6 vs. 5.0, p = 0.02) and inactivity (mean severity 4.0 vs. 3.4, p = 0.03) than never smokers. Moreover, current/former smokers more frequently experienced early satiety (68.5% vs. 58.3%, p = 0.03), inactivity (79.9% vs. 71.1%, p = 0.04), and concentration difficulties (82.1% vs. 73.1%, p = 0.04). Although not significant, a higher total symptom burden was observed for current/former smokers (mean 30.4 vs. 27.0, p = 0.07). Accordingly, overall quality of life was significantly better among never smokers than current/former smokers (mean 3.5 vs. 3.9, p = 0.03). Only 43.2% of the current/former smokers reported having discussed tobacco use with their physician, and 17.5% did not believe smoking increased the risk of thrombosis. Conclusion The current study suggests that smoking may be associated with increased prevalence and severity of MPN symptoms and underscores the need to enhance patient education and address tobacco use in the care of MPN patients.

Context This is the first in human Phase 1 dose escalation trial of oncolytic Vesicular Stomatitis Virus (VSV) incorporating interferon beta and sodium iodine symporter transgenes (VSV-IFNβ-NIS) to be administered intravenously in patients with relapsed and refractory hematologic malignancies. Objective The primary objective was to determine the maximum tolerated dose of VSV-IFNβ-NIS as a single agent. The secondary objectives were to determine safety and efficacy of VSV-IFNβ-NIS. Correlative objectives included monitoring viremia and virus shedding. Design This was a 3+3 phase 1 clinical trial from April 2017 to August 2020 including adult patients (pts) with relapsed refractory multiple myeloma (MM), T-cell lymphoma (TCL), or acute myeloid leukemia (AML). Results Fifteen patients received VSV-IFNβ-NIS: MM (7), TCL (7), and AML (1); median age was 64 years, 60% male, and median prior lines of systemic cancer therapies was 5 (range, 2 to 11). Three patients were treated at each dose level (DL) 1 through 3 (respectively 0.05, 0.17, and 0.5 x 1011 TCID50), and 6 at DL 4 (1.7x1011 TCID50). There were no dose-limiting toxicities. Hematologic AEs, particularly lymphopenia (73%) were the predominant grade 3 and 4 AEs. Non-hematologic AE of interest were grade 1 (6.7%) and 2 (46.6%) cytokine release syndrome, of which only 1 patient required transient norepinephrine support. Objective responses were seen in patients with TCL. There was a 3-month partial response (PR) in a patient treated at DL 2 after 11 prior systemic therapies. However, compelling responses were seen at DL 4 with a deepening 6-month PR in a patient with PTCL and ongoing CR, even 14 months after VSV in another patient with cutaneous relapse of PTCL; both patients received 5 prior lines of therapy. Viremia rapidly declined after infusion, and there was no significant viral shedding. Neutralizing anti-VSV antibodies developed by day 29. IFNβ appeared to indicate intratumoral amplification with TCL patients mounting the highest levels. Conclusions A single intravenous dose of VSV-IFNβ-NIS up to 1.7x1011 is safe in heavily pre-treated patients with hematologic malignancies and appears to be most effective as a single agent at DL 4, especially in patients with TCL. Future trials of combination strategies with immune-modulatory drugs are currently being planned. Grant Acknowledgements Mayo Clinic Multiple Myeloma Specialized Program of Research Excellence (SPORE), Grohne gifts, Phillips gift, and Liu gift.

Myeloproliferative neoplasms (MPN) that have evolved into accelerated or blast phase disease (MPN-AP/BP) have poor outcomes with limited treatment options and therefore represent an urgent unmet need. We have previously demonstrated in a multicenter, phase 1 trial conducted through the Myeloproliferative Neoplasms Research Consortium that the combination of ruxolitinib and decitabine is safe and tolerable and is associated with a favorable overall survival (OS). In this phase 2 trial, 25 patients with MPN-AP/BP were treated at the recommended phase 2 dose of ruxolitinib 25 mg twice daily for the induction cycle followed by 10 mg twice daily for subsequent cycles in combination with decitabine 20 mg/m2 for 5 consecutive days in a 28-day cycle. Nineteen patients died during the study follow-up. The median OS for all patients on study was 9.5 months (95% confidence interval, 4.3-12.0). Overall response rate (complete remission + incomplete platelet recovery + partial remission) was 11/25 (44%) and response was not associated with improved survival. We conclude that the combination of decitabine and ruxolitinib was well tolerated, demonstrated favorable OS, and represents a therapeutic option for this high-risk patient population. This trial was registered at www.clinicaltrials.gov as #NCT02076191.

Purpose: Little is known about the use of trastuzumab or trastuzumab + lapatinib in older patients. We have performed a sub-analysis of the Adjuvant Lapatinib And/Or Trastuzumab Treatment Optimisation (ALTTO) trial focused on toxicity and treatment completion of both regimens in older patients (≥ 65 years old) Methods: The ALTTO trial randomised 8381 patients with early HER2-positive BC in 4 arms. Eligible patients for this study were those having received at least one dose of assigned treatment in either the trastuzumab or trastuzumab + lapatinib arms. Treatment completion was evaluated through the rate of temporary treatment interruptions, permanent treatment discontinuations and lapatinib dose reductions. Toxicity was evaluated via a selected subset of adverse events of interest (AEI). Risk factors for both treatment completion outcomes and toxicity were investigated, including comorbidities and use of 5 or more co-medications at randomization. Results: A total of 430 patients ≥ 65 year were eligible. Median age was 68 (range 65–80). In comparison with the younger cohort, older patients had a significantly higher number of comorbidities at randomization (p < 0.001). Treatment completion outcomes were worse, particularly in the trastuzumab + lapatinib arm. Adverse events of interest were likewise more common in the trastuzumab + lapatinib arm with higher AEI rates (63.4% in younger vs 78.0% in older, p < 0.001). Concomitant chemotherapy was associated with worse treatment completion outcomes among older patients. Conclusion: Trastuzumab plus lapatinib was significantly more toxic among older patients and had worse treatment completion. Trastuzumab was generally well tolerated., SCOPUS: ar.j, info:eu-repo/semantics/published

Background Prior comparisons of chemotherapy adverse events (AEs) by age and performance status (PS) are limited by the traditional maximum grade approach, which ignores low-grade AEs and longitudinal changes. Materials and Methods To compare fatigue and neuropathy longitudinally by age ( Results Older patients had on average a 0.17-point (95% confidence interval [CI], 0.00–0.34; p = .049) higher mean fatigue grade longitudinally compared with younger patients. PS 2 was associated with earlier development of grade ≥2 fatigue (hazard ratio [HR], 1.56; 95% CI, 1.07–2.27; p = .02). For neuropathy, older age was associated with earlier development of grade ≥2 neuropathy (HR, 1.41; 95% CI, 1.00–1.97; p = .049). Patients with PS 2 had a 1.30 point lower neuropathy AUC (95% CI, −2.36 to −0.25; p = .02) compared with PS 0–1. In contrast, maximum grade analyses only detected a higher percentage of older adults with grade ≥3 fatigue and neuropathy at some point during treatment. Conclusion Our comparison of complementary but distinct aspects of chemotherapy toxicity identified important longitudinal differences in fatigue and neuropathy by age and PS that are missed by the traditional maximum grade approach. Clinical trial identification number: NCT00003117 (CALGB 9730) Implications for Practice The traditional maximum grade approach ignores persistent low-grade adverse events (AEs) and changes over time. This toxicity over time analysis of fatigue and neuropathy during chemotherapy for advanced non-small cell lung cancer demonstrates how to use longitudinal methods to comprehensively characterize AEs over time by age and performance status (PS). We identified important longitudinal differences in fatigue and neuropathy that are missed by the maximum grade approach. This new information about how older adults and patients with PS 2 experience these toxicities longitudinally may be used clinically to improve discussions about treatment options and what to expect to inform shared decision making and symptom management.

Background Cardiotoxicity is the most significant adverse event associated with trastuzumab (T), the main component of HER2-positive breast cancer (BC) treatment. Less is known about the cardiotoxicity of dual HER2 blockade with T plus lapatinib (L), although this regimen is used in the metastatic setting. Methods This is a sub-analysis of the ALTTO trial comparing adjuvant treatment options for patients with early HER2-positive BC. Patients randomised to either T or concomitant T + L were eligible. Cardiac events (CEs) rates were compared according to treatment arm. Results With 6.9 years of median follow-up (FU) and 4190 patients, CE were observed in 363 (8.6%): 166 (7.9%) of patient in T + L arm vs. 197 (9.3%) in T arm (OR = 0.85 [95% CI, 0.68–1.05]). During anti-HER2 treatment 270 CE (6.4%) occurred while 93 (2.2%) were during FU (median time to onset = 6.6 months [IQR = 3.4–11.7]). While 265 CEs were asymptomatic (73%), 94 were symptomatic (26%) and four were cardiac deaths (1%). Recovery was observed in 301 cases (83.8%). Identified cardiac risk factors were: baseline LVEF 64%, OR 3.1 [95% CI 1.54–6.25]), diabetes mellitus (OR 1.85 [95% CI 1.25–2.75]), BMI > 30 kg/m2 (vs 2, OR 2.21 [95% CI 1.40–3.49]), cumulative dose of doxorubicin ≥240 mg/m2 (OR 1.36 [95% CI 1.01–1.82]) and of epirubicin≥ 480 mg/m2 (OR 2.33 [95% CI 1.55–3.51]). Conclusions Dual HER2 blockade with T + L is a safe regimen from a cardiac perspective, but cardiac-focused history for proper patient selection is crucial. Trial registration number ClinicalTrials.gov Identifier: NCT00490139 (registration date: 22/06/2007); EudraCT Number: 2006–000562–36 (registration date: 04/05/2007); Sponsor Protocol Number: BIG2–06 /EGF106708/N063D.

Background Bladder cancer (BC) patients with advanced disease have poor outcomes. The use of patient‐reported outcomes (PROs) could lead to improvements in symptom management and hence quality of life (QoL). The aim of this study is to report correlations between selected PROs and QoL and thus to present symptoms that influence QoL. Identification of these symptoms during treatment can lead to earlier symptom management and thus secure improvements in QoL. Methods BC patients in chemo‐ or immunotherapy for locally advanced or metastatic disease reported weekly PROs for the duration of their treatment. The PROs included EORTC QLQ‐C30 and QLQ‐BLM30 and 45 selected PRO‐CTCAE items. Spearman's correlation analysis was performed for all PRO‐CTCAE items and QLQ‐C30 global QoL and subdomains. Results In this study, 78 BC patients reported 724 questionnaires. Spearman's analysis showed significant correlations between almost all PRO‐CTCAE items and the expected domain of QoL. The PRO‐CTCAE items with the strongest correlations with QoL were anxiety (F, frequency item) and emotional function (r s = −0.603, P, For bladder cancer patients, psychological items have a strong impact on the quality of life while urinary items have a weak impact on the quality of life. Toxicity reporting from clinical trials and supportive care in daily practice may be incomplete and not reflective of the full picture of symptomatology for bladder cancer patients.

Background: How can a clinician and patient incorporate survival and toxicity information into a single expression of comparative treatment benefit? Sloan et al. recently extended the ½ standard deviation concept for judging the clinical importance of findings from clinical trials to survival and tumor response endpoints. A new method using this approach to combine survival and toxicity effect sizes from clinical trials into a quality-adjusted effect size is presented. Methods: The quality-adjusted survival effect size (QASES) is calculated as survival effect size (ESS) minus the calibrated toxicity effect sizes (EST) (QASES=ESS-EST). This combined effect size can be weighted to adjust for the relative emphasis placed by the patient on survival and toxicity effects. Results: As an example, consider clinical trial NCCTG 89–20-52 which randomized patients to once-daily thoracic radiotherapy (ODTRT) versus twice-daily treatment of thoracic radiotherapy (TDRT) for the treatment of lung cancer. The ODTRT vs. TDRT arms had median survival time of 22 vs. 20 months (p=0.49) and toxicity rate of 39% vs. 54%, (p

Microsatellitosis (mS) in melanoma has been considered a marker of unfavorable tumor biology, leading to the current American Joint Committee on Cancer staging of IIIB/C/D disease, despite few investigative studies of this entity limited by the small sample sizes and incomplete nodal microstaging. We sought to better characterize outcomes and prognostic factors in a multi-institutional cohort of patients with mS and nodal microstaging. The Sentinel Lymph Node Working Group cohort included 414 mS patients who underwent sentinel lymph node (SLN) biopsy. Cox regression analysis was used to evaluate the prognostic significance of established clinicopathologic characteristics. Melanoma-specific survival (MSS) of patients with mS was compared with 3002 similarly staged patients from the Surveillance, Epidemiology, and End Results (SEER) Program registry. The median age of the mS cohort was 64.9 years; 39.6% were female. Median thickness was 3 mm, 40.6% of cases were ulcerated, and the SLN positivity rate was 46.7%. Increasing thickness, male sex, and SLN positivity were significantly associated with poorer MSS. Stage IIIB/C/D 5-year MSS rates were 86.3% (95% confidence interval [CI] 79.4–93.3%), 54.1% (95% CI 45.4–59.7%), and 44.2% (95% CI 25.4–63.0%), respectively. MSS survival for the stage IIIB mS cohort was significantly better than a similarly staged SEER cohort (5-year MSS of 70.1%, 95% CI 66.0–74.2%), while no significant difference was observed for the stage IIIC or D cohorts. SLN metastases are common and are a significant prognostic factor in patients with mS. Survival in stage IIIB patients with mS was considerably more favorable than their stage would otherwise suggest, which has important implications for decisions regarding adjuvant therapy for patients with mS.

In this phase 2 trial, we sought to evaluate the efficacy and safety of rituximab, cyclophosphamide, bortezomib, and dexamethasone (R-CyBorD) in patients with low-grade NHL. The regimen included rituximab on day 1 with weekly cyclophosphamide, dexamethasone, and bortezomib 1.3 mg/m

MAJIC is a phase II trial of Ruxolitinib (RUX) vs Best Available Therapy (BAT) in polycythemia vera (PV) patients with resistance/intolerance to Hydroxycarbamide (HC). This analysis involved a primary comparison between the RUX and BAT arms for quality of life (QOL) durability over 60 months, with secondary comparisons of best QOL response within first year in complete hematologic responders (CR) vs a group of partial or no response (NR/PR). This is a unique analysis due to cross-over nature of prior studies. Patients were stratified by treatment arm with either RUX or BAT. QOL was assessed over 0-60 months using the Myeloproliferative Neoplasms Symptom Assessment Form (MPN-SAF). MPN-SAF Total Symptom Score (TSS) was computed as the average of all completed items multiplied by 10 (scale 0-100, higher score represents higher symptom burden). Estimates of change from baseline and between arm differences in change by timepoint were made using a linear mixed model with compound symmetry covariance structure, which included covariates for categorical time point, treatment arm, and the interaction between time point and treatment arm. The difference between arms in proportion of patients with best post-baseline TSS response of 50% or greater was testing using a Chi-square test. In this study, 147 of the 190 trial patients had started treatment and completed at least their baseline assessment and were included in the analysis with 39 patients completing through 60 months. Groups were comprised of 76 patients in the RUX group (31 females, 45 males, mean age 64.2 [SD 11.4]) and 71 patients in the BAT group (29 females, 42 males, mean age 64.6 [SD 11.5]). Symptom scores at baseline were similar between arms, with MPN-SAF weight loss the only statistically significant difference (BAT 0.7 [SD 1.71] vs RUX 1.7 [SD 2.83], p=0.02). Significant, durable improvements in TSS were noted in RUX patients with symptom improvements lasting a mean of 52 months. BAT patients experienced a worsening of their symptom burden with improvements back to baseline notable at 56 months (Figure 1). MPN-SAF TSS there were significant differences between treatment arms in change from baseline to months 2-32, 44, and 48 (all p Comparing MPN-SAF TSS in Complete Response (CR n=51) vs Non-Responder/Partial Responders (NR/PR) (n=96) there was no difference at baseline in any of the measures at any time point. A possible limitation of this study is the potential for bias in which the patients who were lost to follow up could be different then the patients who remained in the study through all 60 months which would affect generalization, particularly at time points at the later years. The novel findings of this investigation demonstrate that Ruxolitinib ameliorates the PV symptom burden in patients resistant or intolerant to HC in a robust durable manner over at least four years, while patients receiving BAT have worsening of their symptom burden over this same time period. Figure 1 Figure 1. Disclosures Mead: Novartis: Consultancy, Honoraria, Speakers Bureau; Celgene/BMS: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria. Yap: Celgene: Honoraria; Faron Pharmaceuticals: Honoraria. Scherber: Incyte Corporation: Current Employment, Current holder of stock options in a privately-held company. Knapper: Novartis: Consultancy, Research Funding, Speakers Bureau; Astellas: Ended employment in the past 24 months, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau. Drummond: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI: Membership on an entity's Board of Directors or advisory committees. McMullin: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: clinical trial support, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AOP Orphan: Research Funding, Speakers Bureau. Mesa: CTI: Research Funding; AOP: Consultancy; Celgene: Research Funding; Novartis: Consultancy; Gilead: Research Funding; Pharma: Consultancy; Promedior: Research Funding; Constellation Pharmaceuticals: Consultancy, Research Funding; CTI: Research Funding; Samus: Research Funding; Sierra Oncology: Consultancy, Research Funding; Genentech: Research Funding; Incyte Corporation: Consultancy, Research Funding; Abbvie: Research Funding; La Jolla Pharma: Consultancy. Harrison: CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Geron: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Constellation Pharmaceuticals: Research Funding; Galacteo: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte Corporation: Speakers Bureau; Sierra Oncology: Honoraria; Promedior: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AOP Orphan Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

The myeloproliferative neoplasms (MPN) polycythaemia vera (PV) and essential thrombocythaemia (ET) are associated with significant symptom burden with impaired quality of life (QoL). In the MAJIC study patients refractory/intolerant to hydroxycarbamide (HC), were randomised to treatment with ruxolitinib (Rux) or best available therapy (BAT). In this unique and comprehensive analysis we explore quality of life (QoL) outcomes in the MAJIC study using the MPN10 Self-Assessment Form (SAF) in particular using this unique dataset to explore for the first time differences between JAK2 ET vs PV, and JAK2 ET vs CALR ET at baseline and 12 months of therapy with Rux or BAT. Methods 306 patients were randomised, (190, PV and 116 ET arm) and followed for 5 years, no cross over was permitted. MPN10 SAF was assessed at baseline, 2, 4, 8 and 12 months in both arms. Equal variance two sample t-tests were used to test differences between diagnosis groups (JAK2 ET vs PV & JAK2 ET vs CALR ET) in baseline scores and 12-month change from baseline scores, here negative change from baseline indicates improvement. QoL data was also collected using MD Anderson Symptoms Inventory (MDASI) and 5 level EQ5D at the same time points as the MPN10 SAF. Results JAK2 ET vs PV 110 participants with JAK2 mutation were included in the analysis for JAK2 ET vs PV. 81 (74%) had PV and 29 (26%) had JAK2 ET; 44 patients (54.3%) with PV and 18 (62.1%) patients with ET were randomised to Rux, and 37 (45.6%) patients with PV and 11 (37.9%) with ET to BAT. Baseline mean total symptom score (TSS) was similar (JAK2 ET: 18.9. SD 18.4 and PV: 23.7, SD 17.81 (p=0.27). Mean for pruritus was 1.9 (SD 2.47) in JAK2 ET and 3.5 (SD 2.99) in PV (p=0.03). Other baseline scores were comparable: mean scores for fatigue was 3.3 (SD 3.07) for JAK2 ET vs 4.7 (SD 2.68) for PV, for early satiety was 2.6 (SD 2.78) for JAK2 ET vs 2.1 (SD 2.40) for PV, for abdominal discomfort 3.0 (SD 3.34) for JAK2 ET vs 2.0 (SD 2.78) for PV, for inactivity was 2.4 (SD 2.86) for JAK2 ET vs 3.2 (SD 2.72) for PV; for concentration problems was 2.2 (SD 2.51) for JAK2 ET vs 2.9 (SD 3.11) for PV, for night sweats was 1.6 (SD 2.20) for JAK2 ET vs 2.1 (SD 2.66) for PV, for bone pain was 1.8 (SD 2.97) for JAK2 ET vs 2.0 (SD 2.86) for PV, for fever was 0.5 (SD 1.46) for JAK2 ET vs 0.5 (SD 1.70) for PV and for weight loss was 0.3 (SD 0.73) for JAK2 ET vs 1.0 (SD 2.15) for PV (p>0.05 for all). Concerning change at 12 months, mean (SD) change in TSS was -0.5 (SD 10.86) for JAK2 ET (n=21) vs -0.8 (SD 13.32) for PV (n=66) (P=0.93). Mean for individual symptom scores at 12 months were also not significantly different between the two phenotypic disease group (P>0.05 for all parameters). (Fig 1, top panels). CALR vs JAK2 ET Exploring symptoms for CALR vs JAK2 ET: 45 patients were included; 9/16 (56.3%) CALR and 18/29 (62.1%) JAK2 patients were assigned to Rux (p=0.70). 10/16 (62.5%) CALR ET and 19/29 (65.5%) JAK2 ET. Baseline mean total symptom score (TSS) was similar (JAK2 ET: 18.9, SD 18.4 and CALR ET: 18.8, SD 16.99 (p=0. 0.98). All other baseline scores were comparable in this intolerant/ refractory population (p>0.05 for all. Concerning change at 12 months, mean (SD) change in TSS was -0.5 (SD 10.86) for JAK2 ET vs -2.8 (SD 9.96) for CALR ET (P=0.56). Mean for individual symptom scores at 12 months were also not significantly different between the two phenotypic disease group (P>0.05 for all parameters); the mean change in night sweats approached but did not reach significance similar (JAK2 ET: 0.2 (SD 1.89) and CALR ET: 1.8 (SD 3.07) (p=0. 0.06). (Fig 1, lower panels). Preliminary analysis of the MDASI and EQ5D-5L data at baseline and at 12 months shows similar results and will be presented. Conclusion This first analysis of its kind compared the symptom burden and other parameters of QoL of patients with PV and ET, resistant/intolerant to HC shows that with the exception of pruritus at baseline there were no substantial differences between JAK2 ET or PV. Equally changes in symptom burden across 12 months did not substantially differ between JAK2 ET or PV. A second analysis of JAK2 vs CALR ET also failed to show substantial differences. This data should be expanded in a larger cohort but supports a symptom continuum of JAK2 ET and PV and also JAK2 vs CALR ET. Figure 1 Figure 1. Disclosures Mead: Abbvie: Consultancy, Honoraria; Celgene/BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau. Yap: Faron Pharmaceuticals: Honoraria; Celgene: Honoraria. Knapper: Novartis: Consultancy, Research Funding, Speakers Bureau; Astellas: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau. Drummond: CTI: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mesa: Pharma: Consultancy; CTI: Research Funding; Abbvie: Research Funding; Genentech: Research Funding; Gilead: Research Funding; AOP: Consultancy; Incyte Corporation: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Novartis: Consultancy; La Jolla Pharma: Consultancy; Samus: Research Funding; Promedior: Research Funding; Constellation Pharmaceuticals: Consultancy, Research Funding; Celgene: Research Funding; CTI: Research Funding. Scherber: Incyte Corporation: Current Employment, Current holder of stock options in a privately-held company. McMullin: Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AOP Orphan: Research Funding, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: clinical trial support, Research Funding. Harrison: CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Promedior: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AOP Orphan Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sierra Oncology: Honoraria; Constellation Pharmaceuticals: Research Funding; Incyte Corporation: Speakers Bureau; Geron: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Galacteo: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Background:Adherence to and tolerability of oral agents for the treatment of hormone receptor positive (HR+) breast cancer in the adjuvant setting may be challenging and can limit drug exposure. Palbociclib (P) is an oral CDK4/6 inhibitor; P in combination with endocrine therapy (ET) has demonstrated efficacy in HR+/HER-2 negative (HER2-) metastatic breast cancer (MBC). The global PALLAS study (NCT02513394) was designed to determine if the addition of P to adjuvant ET improves outcomes over ET alone in early breast cancer. The goal of this analysis is to describe P exposure and discontinuation in PALLAS, and explore any impact on study endpoints. Methods:Pts with stage II-III HR+/HER2- disease were randomized to receive 2 years of P (starting dose 125 mg daily, 3 weeks on, 1 week off) in combination with adjuvant ET (Arm A) or ET alone (Arm B). The primary objective was to compare invasive disease-free survival (iDFS) between arms; secondary endpoints included safety, quality of life, adherence, and translational science. Dose adjustments were defined per protocol in the setting of emergent toxicity. Continuous monitoring of toxicity, dose modifications, and early discontinuations was performed throughout the trial. Statistical analysis included tabulation of dose levels/reductions and reasons for treatment discontinuation, as well as landmark analysis comparing iDFS between those receiving > 12 months (mo) vs < 12 mo of P. Ongoing analyses include exploration of relative dose intensity and modeling of P dose intensity/duration and impact on iDFS. Results:A total of 5760 pts were randomized; 83% had received prior chemotherapy; 68% initiated aromatase inhibitor and 33% tamoxifen, with or without ovarian suppression. Grade 3/4 neutropenia was more common in Arm A vs B (62% vs 0.4%); febrile neutropenia was uncommon (1%). Other all-grade adverse events (AEs) more common in Arm A included other hematologic toxicity, fatigue, upper respiratory infection, nausea, diarrhea, and alopecia. A total of 55% of pts required P dose reduction to 100mg, and 34% to 75 mg, at some point during treatment. At a median follow-up of 23.7 mo at the second interim analysis, no significant difference in iDFS was observed between the arms (3-year iDFS of 87.9% vs 88.4%, HR 0.93, 95% CI 0.76, 1.15); consequently, pts in Arm A stopped P, and all pts moved to long-term follow-up. At time of data cut-off, 32% had completed the planned 2 years of P, 26% were still receiving P, and 42% had discontinued P prematurely. P discontinuation was 18% at 6 mo, 30% at 12 mo, 38% at 18 mo, and 45% projected at 24 mo. A total of 27% of Arm A pts (770 of 2840) discontinued therapy due to AEs, primarily neutropenia (460, 16%) and fatigue (71, 3%). Other reasons for P discontinuation included non-compliance (128, 5%), recurrent disease or second malignancy (104, 4%), or withdrawal of consent (100, 3%). Last observed dose level was 125mg, 100mg, and 75mg for 45%, 22%, and 33% pts, respectively. Among those discontinuing due to AEs, dose level at time of discontinuation was 75mg for 62%, suggesting some discontinuations occurred without maximum dose reduction. Pts who received > 12 mo of P had a 2-year iDFS of 96.6%; those receiving Citation Format: Erica L. Mayer, Christian Fesl, Amylou Dueck, Michael Gnant, Angela DeMichele, on behalf of the PALLAS study team. Treatment exposure and discontinuation in the PALLAS trial: PALbociclib CoLlaborative Adjuvant Study of palbociclib with adjuvant endocrine therapy for HR+/HER2- early breast cancer [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 PD2-03.

Myelofibrosis is a myeloproliferative neoplasm that is characterized by splenomegaly, profound symptom burden, and cytopenias. JAK inhibitor therapy offers improvements in splenomegaly, symptom burden, and potentially survival; however, cytopenias remain a significant challenge. Danazol has previously demonstrated improvements in myelofibrosis-associated anemia. We conducted a phase II clinical trial evaluating the efficacy and tolerability of combination therapy with ruxolitinib, an oral JAK inhibitor, and danazol. Fourteen intermediate or high-risk MF patients were enrolled at 2 institutions. Responses per IWG-MRT criteria were stable disease in 9 patients (64.2%) clinical improvement in 3 (21.4%) all of which were spleen responses, partial response in 1 (7.1%) and progressive disease in 1 (7.1%). Despite limited IWG-MRT response, stabilization of anemia and thrombocytopenia was demonstrated. In JAK inhibitor naïve patients, 4/5 (80%) had stable or increasing hemoglobin. Of the 9 patients on prior JAK inhibitor, 5 patients (55.5%) and 8 patients (88.9%) had stable or increasing hemoglobin or platelet levels, respectively. Adverse events possibly related included grade 3 or greater hematologic toxicity in ten patients (71.4%) and non-hematologic toxicity in two patients (14.3%). Although combination therapy did not lead to increased hematologic response per IWG-MRT criteria, hematologic stabilization was observed and may be clinically useful.

Background: Preclinical evidence indicates that increased insulin-like growth factor receptor-1 (IGF1R) signaling interferes with the action of trastuzumab suggesting a possible mechanism of trastuzumab resistance. Thus, we evaluated IGF1R prevalence, relationship with demographic data, and association with disease-free survival (DFS) of patients randomized to chemotherapy alone (Arm A) or chemotherapy with sequential (Arm B) or concurrent trastuzumab (Arm C) in the prospective phase III HER2+ adjuvant N9831 trial. Experimental Design: IGF1R protein expression was determined in tissue microarray sections (three cores per block; N = 1,197) or in whole tissue sections (WS; N = 537) using IHC (rabbit polyclonal antibody against IGF1R β-subunit). A tumor was considered positive (IGF1R+) if any core or WS had ≥1+ membrane staining in >0% invasive cells. Median follow-up was 8.5 years. Results: Of 1,734 patients, 708 (41%) had IGF1R+ breast tumors. IGF1R+ was associated with younger age (median 48 vs. 51, P = 0.007), estrogen receptor/progesterone receptor positivity (78% vs. 35%, P < 0.001), nodal positivity (89% vs. 83%, P < 0.001), well/intermediate grade (34% vs. 24%, P < 0.001), tumors ≥2 cm (72% vs. 67%, P = 0.02) but not associated with race or tumor histology. IGF1R did not affect DFS within arms. Between Arms A and C, patients with IGF1R+ and IGF1R− tumors had DFS HRs of 0.48 (P ≤ 0.001) and 0.68 (P = 0.009), respectively (Pinteraction = 0.17). Between Arms A and B, patients with IGF1R+ and IGF1R− tumors had DFS HRs of 0.83 (P = 0.25) and 0.69 (P = 0.01), respectively (Pinteraction = 0.42). Conclusions: In contrast to preclinical studies that suggest a decrease in trastuzumab sensitivity in IGF1R+ tumors, our adjuvant data show benefit of adding trastuzumab for patients with either IGF1R+ and IGF1R− breast tumors. Clin Cancer Res; 23(15); 4203–11. ©2016 AACR.

Background: Cholecystokinin (CCK) is an important satiety factor, acting at type 1 receptors (CCK1Rs) on vagal afferent neurons; however, CCK agonists have failed clinical trials for obesity. We postulated that CCK1R function might be defective in such patients due to abnormal membrane composition, such as that observed in cholesterol gallstone disease.Objective: Due to the challenges in directly studying CCK1Rs relevant to appetite control, our goal was to develop and apply a method to determine the impact of a patient's own cellular environment on CCK stimulus-activity coupling and to determine whether CCK sensitivity correlated with the metabolic phenotype of a high-risk population.Design: Wild-type CCK1Rs were expressed on leukocytes from 112 Hispanic patients by using adenoviral transduction and 24-h culture, with quantitation of cholesterol composition and intracellular calcium responses to CCK. Results were correlated with clinical, biochemical, and morphometric characteristics.Results: Broad ranges of cellular cholesterol and CCK responsiveness were observed, with elevated cholesterol correlated with reduced CCK sensitivity. This was prominent with increasing degrees of obesity and the presence of diabetes, particularly when poorly controlled. No single standard clinical metric correlated directly with CCK responsiveness. Reduced CCK sensitivity best correlated with elevated serum triglycerides in normal-weight participants and with low HDL concentrations and elevated glycated hemoglobin in obese and diabetic patients.Conclusions: CCK responsiveness varies widely across the population, with reduced signaling in patients with obesity and diabetes. This could explain the failure of CCK agonists in previous clinical trials and supports the rationale to develop corrective modulators to reverse this defective servomechanism for appetite control. This trial was registered at www.clinicaltrials.gov as NCT03121755.

Purpose Randomized trials have shown that honey is effective for the prevention of radiation-induced mucositis in head and neck cancer patients. Because there is no efficacious preventative for radiation esophagitis in lung cancer patients, this trial compared liquid honey, honey lozenges, and standard supportive care for radiation esophagitis. Methods The patients were stratified by percentage of esophagus receiving specific radiation dose (V60 Gy esophagus Results 53 patients were randomized to supportive care, 54 were randomized to liquid honey, and 56 were randomized to lozenge honey. There was no significant difference in the primary endpoint of change in the NRPS at 4 weeks between arms. There were no differences in any of the secondary endpoints except for opioid use at 4 weeks during treatment between the supportive care and liquid honey arms, which was found to be significant ( P =.03), with more patients on the supportive care arm taking opioids. Conclusion Honey as prescribed within this protocol was not superior to best supportive care in preventing radiation esophagitis. Further testing of other types of honey and research into the mechanisms of action are needed.

Background: Oncolytic virotherapy is a novel immunomodulatory therapeutic approach for relapsed refractory hematologic malignancies. The Indiana strain of Vesicular Stomatitis Virus (VSV) has been engineered to encode interferon beta (IFNβ) and sodium iodine symporter (NIS) to produce VSV-IFNβ-NIS. The virally encoded IFNβ serves as an index of viral proliferation and enhances host anti-tumor immunity. The NIS is inserted as a reporter gene into the viral genome to enable noninvasive monitoring of viral spread using PET/CT imaging. Here we present results of Arm A (patients with low tumor burden) of the Phase I clinical trial (NCT03017820) of intravenous administration of VSV-IFNβ-NIS for patients (pts) with relapsed refractory hematological malignancies: MM, AML, and TCL. Methods: This was a classical 3+3 phase I trial, starting at 5x10^9 TCID50 (50% tissue culture infectious dose) level 1 through 1.7x10^11 TCID50 dose level 4 given as a single IV dose. The primary objective was determining the maximum tolerated dose of VSV-IFNβ-NIS alone; secondary objectives include estimating the safety profile and preliminary efficacy. Correlative objectives include monitoring the pharmacodynamics of viral replication through SPECT/CT imaging with NIS gene, viremia, virus shedding and changes in the immune profile of peripheral blood leukocytes. Adverse events (AEs) are reported based on CTCAE v4; cytokine release syndrome (CRS) grading was based on Lee (Blood 2014; 124(2):188-195) criteria. Results: From April 2017, 12 pts have received IV VSV-IFNβ-NIS in Arm A: MM (7), TCL(4) and AML(1); 3 pts were treated at each dose level (DL) 1 to 4. At DL1, there were five grade 3 hematologic AEs (leukopenia [1], neutropenia [1], lymphopenia [3]) and no grade 3+ non-hematologic AEs. At DL2, three grade 3 hematologic AEs (anemia [2], lymphopenia [1]), four grade 4 hematologic AEs (neutropenia [1], leukopenia [1], lymphopenia [1] and thrombocytopenia [1]). There was 1 event of grade 2 CRS at DL2, two grade 3 non-hematologic AEs (nausea [1], dehydration [1]). At DL3, there was one grade 4 hematologic AE (neutropenia [1]), three grade 3 hematologic AEs (lymphopenia [2], leukopenia [1]), and one grade 3 non-hematologic AE (vasovagal reaction [1]). One grade 2 and grade 1 CRS by Lee criteria were observed. At DL4, there were three grade 3 hematologic AEs (lymphopenia [1], neutropenia [1], thrombocytopenia [1]), and three grade 3 non-hematologic AEs (AST increase [1], skin infection [1], soft tissue infection [1])and two grade 2 CRS. There were no dose limiting toxicities. There was one partial response (DL2) and one complete response (DL4); 3 pts had stable disease, 7 pts progressed. The MM pts receiving VSV-IFNβ-NIS at DL4 had stable disease. Six of the 7 MM pts demonstrated transient reduction in serum level of involved free light chain (LC) after VSV-IFNβ-NIS infusion, with median 20.4% reduction of the involved LC within 48 hrs. Viremia was detectable in all pts at the end of infusion, to varying levels at 30 mins, 1, 2, 4, 24, 48h or 72 hrs post infusion. No persistent viremia was observed. No infectious virus was recovered in buccal swabs or urine and neutralizing anti-VSV antibodies were present by day 29. The IFN levels were detectable within 30 minutes of infusion and peaked between 4 and 48 hrs. The pts with a diagnosis of TCL mounted higher hIFNβ levels within 48 hrs. Remarkably, the TCL pt with CR (DL4) mounted a peak hIFNβ response of 18213.3pg/ml at 48 hrs post infusion, approximately 15-fold higher than any other pt enrolled in the study; and highest neutralizing antibody titer (1:40960). Conclusion: VSV-IFNβ-NIS can be safely administered by intravenous infusion in pts with hematological malignancies, up to a dose level of 1.7 x 1011 TCID50, without dose limiting toxicities and no CRS higher than grade 2. In this small phase 1 study, pts with T-cell lymphoma demonstrated the strongest signal of response, with one confirmed partial response at DL2 and one complete response at DL4. IFNβ is an early biomarker of tumor susceptibility; the magnitude of IFNβ elevation appears to correlate with treatment response. There were no confirmed responses in pts with MM, but the 20.4% transient reduction in LC suggests that combination strategies with VSV-IFNβ-NIS may result in deeper and sustained responses in MM. Future trials investigating combination strategies with immune modulatory drugs are being planned. Disclosures Peng: Imanis: Other: Equity Ownership. Witzig:Karyopharm Therapeutics: Research Funding; Immune Design: Research Funding; Spectrum: Consultancy; Incyte: Consultancy; Acerta: Research Funding; MorphSys: Consultancy; AbbVie: Consultancy; Celgene: Consultancy, Research Funding. Dispenzieri:Intellia: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Alnylam: Research Funding; Janssen: Research Funding; Celgene: Research Funding. Gertz:Celgene: Consultancy; Annexon: Consultancy; Sanofi: Consultancy; Appellis: Consultancy; Amgen: Consultancy; Medscape: Consultancy, Speakers Bureau; Physicians Education Resource: Consultancy; Data Safety Monitoring board from Abbvie: Membership on an entity's Board of Directors or advisory committees; NCI SPORE MM: Research Funding; Johnson and Johnson: Speakers Bureau; Springer Publishing: Patents & Royalties; Amyloidosis Foundation: Research Funding; Advisory Board for Proclara: Membership on an entity's Board of Directors or advisory committees; Alnylam: Consultancy; Ionis/Akcea: Consultancy; Spectrum: Consultancy, Research Funding; Prothena: Consultancy; DAVA oncology: Speakers Bureau; i3Health: Consultancy; Advisory Board for Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; International Waldenstrom Foundation: Research Funding. Dingli:Rigel: Consultancy; Bristol Myers Squibb: Research Funding; Janssen: Consultancy; Alexion: Consultancy; Apellis: Consultancy; Karyopharm Therapeutics: Research Funding; Millenium: Consultancy; Sanofi-Genzyme: Consultancy. Kapoor:Cellectar: Consultancy; Celgene: Honoraria; Janssen: Research Funding; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; GlaxoSmithKline: Research Funding. Lin:Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Legend BioTech: Consultancy; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Merck: Research Funding; Takeda: Research Funding; Gamida Cells: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vineti: Consultancy. Kumar:Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Cellectar: Other; Carsgen: Other, Research Funding; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Merck: Consultancy, Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Sanofi: Research Funding; Dr. Reddy's Laboratories: Honoraria; Adaptive Biotechnologies: Consultancy; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Kite Pharma: Consultancy, Research Funding; Novartis: Research Funding; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; MedImmune: Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Karyopharm: Consultancy; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; BMS: Consultancy, Research Funding; Genecentrix: Consultancy; Tenebio: Other, Research Funding. Russell:Imanis: Other: Equity Ownership. OffLabel Disclosure: This describes of administration of Vesicular Stomatitis Virus Genetically Engineered to Express NIS and human interferon, in Patients with Relapsed or Refractory Hematologic malignacies

Literature regarding impact of genetic testing is wide ranging. For BRCA testing, findings suggest temporary impact on psychological state or quality of life (QOL) [1]. While some report perceived ...

Context: In planning oncology phase II and phase III clinical trials, the size of the expected effect for endpoints such as tumor response and overall survival are key parameters driving the sample size. We applied the empirical rule effect size approach, also known as the ½ standard deviation (SD) method, to define clinically significant effect sizes for overall survival and tumor response endpoints in a series of clinical trials. Methods: The observed effect size was calculated for 12 phase II and 27 phase III completed cancer clinical trials identified by experts as being notable. Results: The effect sizes of the phase II and phase III clinical trials ranged from -0.32 to 0.84 and 0.01 to 0.44 SDs respectively. Effect sizes for all but four of the phase II trials were less than a ½ SD. For phase III studies, the effect sizes for all but one study were below 0.4 SD and roughly 67% of them had an effect size smaller than 0.2 SDs. There were no differences across disease sites, although colorectal and breast trials did have slightly larger effect sizes. Conclusions: Even highly noteworthy existing phase II and phase III oncology clinical trials rarely achieve the ½ SD level of clinical significance. This method allows for more ready interpretation of the clinical significance of overall survival and tumor response endpoints. It allows for cross-study comparison across different endpoints. The method also facilitates study design as it directly builds clinical significance into the study.

Symptom monitoring during chemotherapy via web-based patient-reported outcomes (PROs) was previously demonstrated to lengthen survival in a single-center study. A multicenter randomized clinical trial comparedweb-based monitoring vs standard scheduled imaging to detect symptomatic recurrence in patients with lung cancer following initial treatment. A planned interim analysis (9-month follow-up) founda significant survival benefit (19-month survival in the PRO group vs 12 months in the control group). We now present the final overall survival analysis.

BACKGROUND Patients with myeloproliferative neoplasms (MPNs) including polycythemia vera, essential thrombocythemia, and myelofibrosis, are faced with oppressive symptom profiles that compromise daily functioning and quality of life. Among these symptoms, sexuality-related symptoms have emerged as particularly prominent and largely unaddressed. In the current study, the authors evaluated how sexuality symptoms from MPN relate to other patient characteristics, disease features, treatments, and symptoms. METHODS A total of 1971 patients with MPN (827 with essential thrombocythemia, 682 with polycythemia vera, 456 with myelofibrosis, and 6 classified as other) were prospectively evaluated and patient responses to the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ C30) were collected, along with information regarding individual disease characteristics and laboratory data. Sexuality scores were compared with an age-matched, healthy control population. RESULTS Overall, patients with MPN were found to have greater sexual dysfunction compared with the healthy population (MPN-SAF score of 3.6 vs 2.0; P 65 years and in those with cytopenias and transfusion requirements, and those receiving certain therapies such as immunomodulators or steroids. Conclusions The results of the current study identify the topic of sexuality as a prominent issue for the MPN population, and this area would appear to benefit from additional investigation and management. Cancer 2016. © 2016 American Cancer Society.

Background Lapatinib (L) plus trastuzumab (T) improves outcomes for metastatic human epidermal growth factor 2–positive breast cancer and increases the pathologic complete response in the neoadjuvant setting, but their role as adjuvant therapy remains uncertain. Methods In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial, patients with centrally confirmed human epidermal growth factor 2–positive early breast cancer were randomly assigned to 1 year of adjuvant therapy with T, L, their sequence (T→L), or their combination (L+T). The primary end point was disease-free survival (DFS), with 850 events required for 80% power to detect a hazard ratio (HR) of 0.8 for L+T versus T. Results Between June 2007 and July 2011, 8,381 patients were enrolled. In 2011, due to futility to demonstrate noninferiority of L versus T, the L arm was closed, and patients free of disease were offered adjuvant T. A protocol modification required P ≤ .025 for the two remaining pairwise comparisons. At a protocol-specified analysis with a median follow-up of 4.5 years, a 16% reduction in the DFS hazard rate was observed with L+T compared with T (555 DFS events; HR, 0.84; 97.5% CI, 0.70 to 1.02; P = .048), and a 4% reduction was observed with T→L compared with T (HR, 0.96; 97.5% CI, 0.80 to 1.15; P = .61). L-treated patients experienced more diarrhea, cutaneous rash, and hepatic toxicity compared with T-treated patients. The incidence of cardiac toxicity was low in all treatment arms. Conclusion Adjuvant treatment that includes L did not significantly improve DFS compared with T alone and added toxicity. One year of adjuvant T remains standard of care.

Introduction: FDA approval of JAK2-inhibitors for myelofibrosis (MF) has changed the landscape for treatment introducing possible increased complexity of clinical trial designs in MF. Many patients with MF will have insufficient response or intolerance to ruxolitinib, opening an opportunity for testing of novel agents alone or in combination. Novel trial designs exist for early stage (phase 1 and 2) studies. The Myeloproliferative Neoplasms Research Consortium (MPN-RC) is an NCI-funded academic group of laboratory and clinical scientists working to develop and evaluate treatments that will improve the survival of patients with MPNs focused on early stage trials in MF. This review was undertaken to understand the landscape of MF clinical trials and improve our approach to trial design. Methods: Studies with "myelofibrosis" as a condition were abstracted from clinicaltrials.gov using an application programming interface from 2010-2019 and reviewed for phase, trial design features, and endpoints. Trial design review captured such features as presence of dose escalation and approach (rule-based versus model-based/assisted) in the phase 1 setting. Observational and behavioral based studies were excluded. A total of 165 treatment interventional studies including MF patients (either MF as the primary cohort, or MF along with other MPN, myelodysplastic syndrome, or hematologic malignancies related cohorts) were reviewed. Primary and secondary endpoints were reviewed for quality of life, symptoms, or other patient-reported outcomes (PRO). Results: A median of 16.5 (range 13-20) trials were initiated per year; 92 (56%) phase 2, 54 (33%) phase 1; 17 (10%) phase 3 and 2 (1%) phase 4, with 77 (47%) industry sponsored (Figure 1). Among phase 1 trials, 41/54 (76%) included dose escalation, the majority employing a standard 3+3 design (or other rule-based design) or not specifically detailing the dose escalation schema. Less than 5 dose escalation trials were explicitly described as model-based or model-assisted. Almost half of the phase 1 trials (23/54; 43%) included combination treatment, with 17/23 (74%) using ruxolitinib or fedratinib. Among phase 2 trials, 82 (89%) were non-randomized and 10 (11%) randomized trials; 35/92 (38%) involved combination treatment and 57 (62%) single agent. Median actual/target enrollment for the phase 3 trials (n=16) was 192 patients (range 49-2233 patients); only 2 phase 3 trials were > 500 patients. Median number of total outcomes was 6.0 (range 1-28) across all studies with a median of 5.5 (range 1-28) for 2010-2014 versus 7.0 (range 1-22) for 2015-2019 (p=0.09). Overall 63/165 (38%) studies included at least one PRO endpoint; 15 (28%) phase 1, 33 (36%) phase 2 and 14 (82%) phase 3. Inclusion of PRO endpoints for years 2010-2014 was similar to studies started in years 2015-2019 [31/82 (38%) and 32/83 (39%)]. Industry sponsored studies included PRO endpoints more frequently [46/77 (60%) versus 17/88 (19%); p Conclusions: For phase 1 trials in MF, few dose-escalation trials included model-based or model-assisted methods. These designs are encouraged in order to maximize therapeutic benefits in MF, a rare cancer. Clinical trial designs in myelofibrosis have shifted in recent years as evidenced by an increase in number of endpoints, likely to accommodate new challenges in the post JAK2-inhibitors approval era. Use of patient-reported outcomes including quality of life and symptom assessment was high in the phase 3 setting, and continued use should be encouraged as endpoint assessments in MF clinical trial designs. Disclosures Mascarenhas: Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy; Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution). Mesa:LaJolla Pharma: Consultancy; Novartis: Consultancy; Sierra Onc: Consultancy; Abbvie: Research Funding; Celgene: Research Funding; CTI: Research Funding; Genetech: Research Funding; Incyte: Research Funding; Promedior: Research Funding; Samus: Research Funding. Hoffman:Dompe: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Forbius: Consultancy; Protagonist: Consultancy.

Background: Myelofibrosis (MF) is a clonal bone marrow disorder characterized by a constitutional symptoms, splenomegaly, anemia, elevated WBC and bone marrow fibrosis. Ruxolitinib is a JAK2 inhibitor approved for patients with Intermediate-2 (INT-2) or high risk disease based on dynamic international prognostic scoring system (DIPSS), however, there are limited options for patients with early disease. Interferon alpha (IFNa) is a cytokine therapy that has been used in treatment of chronic myelogenous leukemia and polycythemia vera (PV). In these diseases, there can be a reduction in the clonal burden in addition to a hematologic response. Therefore, we sought to use this therapy in patients with MF. Methods: Patients who had MF were enrolled on an IRB approved clinical protocol in a single arm, single institution study. Patients were stratified to either an early disease arm (characterized by intermediate 1 (INT-1) risk or advanced disease (Int-2 or high-risk disease based on DIPSS). Patients were started on ropeginterferon (interferon-alpha 2b) at 50 ug every two weeks, and the dose was titrated up to either 300 ug every other week, or until unacceptable toxicity. Patients were monitored for response based on IWG criteria. Results: Ten patients with MF have been enrolled on the study to date (Early: 3, Int/High: 7). Median age was 69.5 (39 - 88), four patients were female. Five patients had primary MF (PMF), 4 had post-essential thrombocythemia and 1 post PV MF. Five patients had previous treatment for their disease. Four patients continue to receive active treatment (2 early disease, and 2 advanced disease). Reasons for stopping include disease progression (3), toxicity (1), alternate treatment (1) and lack of benefit (1). The median number of cycles for those who ended treatment was 7.5 (4-47), and for those who remain on treatment, they range from 16 - 46 cycles. Five patients achieved a clinical improvement, 3 had a spleen response, and 2 had a symptom response. A grade 3 adverse event (AE) potentially attributable to the treatment occurred in 6 patients (60%), 4 (40.0%) patients had anemia, and 2 (20.0%) patients had lymphopenia. Only one patient discontinued therapy due to AEs (dizziness, atrial fibrillation). One death has occurred to date, due to an unrelated cause. Discussion: Ropeginterferon is a well-tolerated therapy that results in clinical improvement in half the patients, and appears to be well tolerated. These results, along with historic data suggesting possible reduction in clonal burden, suggest that ongoing studies are warranted to further understand the clinical benefit of ropeginterferon. Disclosures Zimmerman: Pharmaessentia: Current Employment. Mesa:Incyte: Research Funding; AbbVie: Research Funding; Sierra Oncology: Consultancy; CTI BioPharma: Research Funding; Promedior: Research Funding; Genentech: Research Funding; Novartis: Consultancy; Samus Therapeutics: Research Funding; LaJolla Pharmaceutical Company: Consultancy; Bristol Myers Squibb: Research Funding. OffLabel Disclosure: Clinical trial

1016 Background: The ph III EMBRACE trial of E vs physician’s choice of tx led to FDA approval of E as ≥3rd-line tx for MBC pts with prior exposure to anthracyclines/taxanes. The ph III BOLD 301 trial of E vs capecitabine in advanced BC treated with anthracyclines/taxanes showed a nonsignificant trend to improved median OS for all pts; pre-planned analysis by HER2 status revealed a nominally significant benefit for HER2- pts. Methods: RU011201I is an investigator initiated ph III trial with 1:1 randomization to E (1.4 mg/m2 D1,8 q21days) vs P (90 mg/m2 D1,8,15 q28days) within strata defined by (neo)adjuvant taxanes (yes/no), HR status (+/-), and line of tx (1st/2nd). Pts had measurable or non-measurable disease by RECIST v1.1; new or progressive mets; peripheral neuropathy (PN) gr3 mos were allowed. (Neo)adjuvant taxanes were allowed if >12 mos between tx completion and disease recurrence. Radiographic studies occur q12wks. Survival data are collected q12wks after the Off-Tx Visit. Pts reported side effects weekly; post-baseline symptomatic AE rates worse than baseline were compared between arms using Fisher’s exact tests. We report clinical outcomes and the primary objective related to PRO-CTCAE use. Results: 201 pts enrolled 3/2014 - 5/2018 with 33.8 mos median f/u; 3 are on tx as of 2/20/20 (1E, 2P). Pt characteristics were the same between E vs P: median age 62 yrs (range 27-85); 42% prior taxane; 78% ER+; 70% starting 1st line tx. Baseline lesion distribution was similar except for lung mets (37E, 53P). No difference was seen between E vs P in PFS (5.7 vs 5.9 mos; P=0.72), OS (18.1 vs 16.4 mos; P=0.75), TTF (5.3 vs 4.9 mos; P=0.82), DOR (10.8 vs 12.3 mos; P=0.84), or number of metastatic events (55 vs 54). 37E and 36P pts required ≥1 dose reduction. Hematologic toxicities ≥ gr 3 were higher with E (40 vs 22%). PN events were similar: 56 vs 58 total, 4 vs 7 motor, 52 vs 51 sensory. Median duration of PN and median time to 1st PN event were 74 vs 140 and 56 vs 41 days. Worsened numbness/tingling severity and other pt-reported AE rates were similar, but worsened numbness/tingling interference (63% vs 78%, P=0.04) and vomiting frequency (35% vs 57%, P=0.005) were lower with E. Conclusions: Clinical outcomes were equivalent with E vs P as 1st/2nd line tx for HER2- advanced BC. The nature and severity of PN were similar between arms, but time of onset, duration, and interference with daily living favor E. E may be a suitable treatment option in this setting. Clinical trial information: NCT02037529 .

e24176 Background: Decision aids for prostate cancer treatment can improve knowledge, but the relative effect of pre-consultation and within-consultation DAs is not known. Methods: We conducted a parallel design, 2-by-2 factorial, 4-arm, cluster-RCT in urology practices affiliated with the NCI’s Alliance research base. We compared patient knowledge immediately after consultation (%12-item% correct) intervention arms compared to usual care. We used mixed effects regression modeling to assess effect of interventions on knowledge adjusting for site-clustering, race/ethnicity (non-Hispanic White; Other), age (years), clinical stage (T1-3), PSA, and Gleason score. Results: 15 of 21 randomized centers accrued 158 pts from Nov 2017 to June 2019. The arm delivering both DAs (n = 3 sites) recruited 25 pts. The pre-consultation DA arm (n = 4 sites) recruited 39 pts. The within-consultation DA arm (n = 4 sites) recruited 44 pts. The no DA arm (n = 4 sites) accrued 50 pts. Overall, mean age was 64; 54% were AA; 73% had T1 stage; median Gleason = 7; and median PSA = 7. The combined DAs group, followed by pre-consultation reported higher median knowledge (75% and 67%, respectively). The within-consultation and no DA arms both reported median knowledge scores (58%). Within arm, inter-site standard deviations in mean knowledge scores ranged from 0.164 in in the pre-consultation arm to 0.232 in the usual care arm. Neither pre-consultation nor within-consultation DAs had statistically significant effects (p = .15 and p = .99, respectively). Pre-specified adjusted difference [97.5% CIs], comparing the pre-consultation DA and the within-consultation DA with the control was 9.4% [-7.3%, 26.2%] and -0.4% [-16.9%, 16.1%], respectively. Intra-cluster correlation (ICC) coefficient was high (.24). No interaction effects were identified (p = .98). A post-hoc analysis comparing any DA vs usual care found a mean adjusted difference [95% CI] of 5.6% [-8.5%, 19.8%] (p = 0.40), 63.9% for any DA and 58.3% for usual care. Conclusions: Possible knowledge gains associated with some DAs for early prostate cancer were obscured by larger-than-expected intra-cluster correlation effects associated with the primary outcome. How interventions were used was not measured. Support:UG1CA189823; https://acknowledgments.alliancefound.org ; R01 MD008934-06. Clinical trial information: NCT03103321 .

7018 Background: Standard reporting of symptomatic adverse events (AEs) in oncology relies on clinicians to rate patient (pt) experience using CTCAE; each symptom is represented by a single graded item. To capture direct pt experience, NCI developed PRO-CTCAE to supplement CTCAE. In PRO-CTCAE, the pt answers up to 3 questions per AE about a symptom’s frequency, severity and interference with daily activities. To align PRO-CTCAE with CTCAE, we developed an algorithm for mapping sets of questions for an AE to a single composite numerical grade. Methods: We used a 5-step process. (1) All 187 possible PRO-CTCAE score permutations were presented to clinical investigators to subjectively map permutations to single numerical grades (range 0-3). (2) Permutations with < 75% agreement were presented to investigator committees at a National Clinical Trials Network meeting to gain majority consensus via anonymous voting. (3) The resulting algorithm was refined via graphical and tabular approaches to assure directional consistency. (4) Validity, reliability and sensitivity were assessed in a national study dataset. (5) Accuracy for delineating AEs between study arms was measured in 2 phase III clinical trials (Alliance for Clinical Trials in Oncology A091105 and Exelixis COMET-2). Results: (1) 12/187 score permutations had < 75% initial agreement. (2) Majority consensus was reached for all permutations. (3) 5 mappings were adjusted to assure directional consistency. (4) Composite grades for 46/59 (78%) AEs were higher in pts with ECOG performance status 2-4 vs 0-1 (median effect size 0.23 [range -0.49-0.73]; 32/59 effect size ≥0.2; 25/59 p< 0.05), similar to when conducting analysis on individual unmapped items. The test-retest reliability for 24 selected composite grades ranged from 0.57-0.96 (median intraclass correlation coefficient [ICC] 0.77) with 18/24 (75%) grades having ICC ≥0.7. Median (range) standardized response means in pts reporting worsening, no change, and improvement were 0.20 (0.03-0.34), -0.06 (-0.20-0.03) and -0.12 (-0.32-0.06). (5) Pattern, directionality and statistical significance of between-arm differences in both trials were preserved with composite grades as compared to individual unmapped items. Conclusions: A composite grading algorithm for PRO-CTCAE was rigorously developed and validated. PRO-CTCAE composite grades may be useful in analyses to provide a single metric for each pt-reported AE for trial and real-world reporting. Support: UG1CA189823; U01CA233046; HHSN261200800043C; Bayer (A091105); https://acknowledgments.alliancefound.org .

7044 Background: There is growing interest to implement electronic patient-reported outcomes in oncology practices for symptom monitoring. It is not well known what nurse, physician, and patient impressions of benefits, acceptability, and challenges are in routine care use. Methods: PRO-TECT is an ongoing U.S. national trial including 26 community oncology practices across 15 states that implemented PRO symptom monitoring [NCT03249090]. Patients complete weekly PROs between visits, nurses receive alerts for severe/worsening symptoms, and oncologists review PROs at office visits. Interviews were conducted with 147 stakeholders including nurses (N = 46), oncologists (N = 27), data managers (N = 15), and patients (N = 59). Each stakeholder group had different interview guides with overlapping topics to explore experiences with the PRO system. Interviews lasted 15-60 minutes, were digitally recorded, transcribed, and entered into a qualitative analysis software program. A codebook was developed from the research questions, interview guides, and discussions with the project team. Standardized coding methods were applied, with transcripts double coded for thematic analysis. Feedback surveys were also completed by nurses (N = 57), oncologists (N = 38), and patients (N = 435). Results: Key benefits perceived across stakeholder groups included increased patient self-awareness of symptoms; improved direct communication of patients with care teams; more open and honest conveying of symptom experiences; ability to track symptoms over time; and increased involvement of patients in their own care. Most stakeholders felt PRO symptom monitoring had a positive impact on quality of care delivery, and believed benefits of PROs outweighed necessary staff efforts. Challenges included additional work by nurses to review and respond to alerts, staff turnover requiring retraining, and limited time of oncologists. In the survey, 39/56 (70%) nurses felt the PRO system improved quality of care; 27/33 (82%) oncologists noted PROs were useful for team discussions and care delivery; and 320/434 (74%) patients agreed that weekly PRO reporting improved discussions with their care team. Conclusions: Clinicians and patients perceived weekly PRO symptom monitoring between visits to be valuable despite added staff effort. Results of additional analyses are forthcoming. Clinical trial information: NCT03249090 .