Musculoskeletal Events Research Articles

Prevalence of Non-psychiatric Comorbidities in Pre-symptomatic and Symptomatic Huntington's Disease Gene Carriers in Poland.

Huntington's disease (HD) is monogenic neurodegenerative disorder caused by CAG expansions within the Huntingtin gene (Htt); it has a prevalence of 1 in 10,000 worldwide and is invariably fatal. Typically, healthy individuals have fewer than 35 CAG repeats, while the CAG expansions range from 36 to ~200 in HD patients. The hallmark of HD is neurodegeneration, especially in the striatal nuclei, basal ganglia and cerebral cortex, leading to neurological symptoms that involve motor, cognitive, and psychiatric events. However, HD is a complex disorder that may also affect peripheral organs, so it is possible that HD patients could be affected by comorbidities. Hence, we investigated the prevalence of comorbid conditions in HD patients (pre-symptomatic and symptomatic groups) and compared the frequency of those conditions to a control group. Our groups represent 65% of HD gene carriers registered in Poland. We identified 8 clusters of comorbid conditions in both HD groups, namely: musculoskeletal, allergies, cardiovascular, neurological, gastrointestinal, thyroid, psychiatric, and ophthalmologic. We found that HD patients have a significantly higher percentage of co-existing conditions in comparison to the control group. Among the 8 clusters of diseases, musculoskeletal, psychiatric, and cardiovascular events were significantly more frequent in both pre- and symptomatic HD patients, while neurological and gastrointestinal clusters showed significantly higher occurrence in the HD symptomatic group. A greater recognition of comorbidity in HD might help to better understand health outcomes and improve clinical management.

Abstract GS4-04: Ten year results of the international breast cancer intervention study II

Abstract Background: Two large clinical trials have shown the benefit of aromatase inhibitors in healthy women to reduce the risk of developing breast cancer (MAP.3 and IBIS-II). Here, we report blinded 10-year median follow-up efficacy data for the IBIS-II trial, which compared anastrozole to placebo in women at increased risk of developing breast cancer. Material and Methods: 3864 postmenopausal women at increased risk of developing breast cancer were recruited into a double-blind trial of anastrozole (N=1920) versus matching placebo (N=1944) for 5 years. The primary objective of this study was to determine the efficacy of anastrozole in preventing breast cancer (both invasive and ductal carcinoma in situ (DCIS)), overall and particularly for the post 5-year time period. Secondary endpoints included prevention of oestrogen receptor positive breast cancer, breast cancer mortality, non-breast cancer deaths, other cancers, cardiovascular disease, fractures, and musculoskeletal events. Results: After a median follow-up of 10.9 years (IQR 8.8-13.0), a total of 241 breast cancers have been reported (HR=0.50 (0.38-0.65), P<0.0001) (Table). The reduction was larger in the first 5 years (HR=0.39 (0.27-0.58), P<0.0001), but still significant after 5 years (117 (49%) new cases; HR=0.63 (0.43-0.91), P=0.015) (Table). The effects in the two time periods were not significantly different (P=0.11). Invasive oestrogen receptor (ER) positive breast cancer was reduced by 54% with anastrozole (HR=0.46 (0.33-0.65), P<0.0001), with a continued significant effect observed in the post treatment follow-up period (Table). A non-significant effect was observed in invasive ER-negative breast cancer (HR=0.76 (0.39-1.45), P=0.4). A reduction in DCIS overall was observed (Table), with a very large reduction in those known to be ER-positive (HR=0.23 (0.08-0.69), P<0.0001). A total of 129 deaths have been reported, with no significant difference in all-cause mortality between the two treatment arms (63 vs. 66; HR=0.93 (0.66-1.32), P=0.7). Only 5 deaths from breast cancer (2 vs. 3) were reported, but number of events are very small and longer follow-up is needed. 321 cancers other than breast were reported, with a significant decrease observed with anastrozole (129 vs. 192, OR=0.66 (0.52-0.83), P=0.0004). Specifically, fewer endometrial cancers (4 vs. 8), ovarian cancers (5 vs. 9), lung cancers (5 vs. 12), and melanomas (9 vs. 18) were observed with anastrozole. A comprehensive adverse event profile will be reported. Conclusion: This updated analysis of the IBIS-II trial confirms the significant reduction in breast cancer occurrence with anastrozole in the post-treatment follow-up period. These results indicate a long-term preventive benefit with anastrozole for ER-positive breast cancer in postmenopausal women. Table: Number of events and Hazard Ratios (95% CI) according to follow-up period.Number of eventsHR (95% CI)P-valueOverall241 (81 vs. 160)0.50 (0.38-0.65)<0.00010-5 years124 (35 vs. 89)0.39 (0.27-0.58)<0.00015+ years117 (46 vs. 71)0.63 (0.43-0.91)0.015Invasive ER-positive151 (48 vs. 103)0.46 (0.33-0.65)<0.00010-5 years72 (20 vs. 52)0.38 (0.23-0.64)<0.00015+ years79 (28 vs. 51)0.53 (0.34-0.84)0.007All DCIS42 (13 vs. 29)0.44 (0.23-0.85)0.0150-5 years22 (5 vs. 17)0.29 (0.11-0.80)0.0115+ years20 (8 vs. 12)0.65 (0.26-1.59)0.34 Citation Format: Jack Cuzick, Ivana Sestak, John Forbes, Mitchell Dowsett, Simon Cawthorn, Robert Mansell, Sibylle Loibl, Bernardo Bonanni, Anthony Howell, IBIS-II investigators. Ten year results of the international breast cancer intervention study II [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 GS4-04.

HALO 109-301: A randomized, double-blind, placebo-controlled, phase 3 study of pegvorhyaluronidase alfa (PEGPH20) + nab-paclitaxel/gemcitabine (AG) in patients (pts) with previously untreated hyaluronan (HA)-high metastatic pancreatic ductal adenocarcinoma (mPDA).

638 Background: HA is a major component of the tumor microenvironment (TME) in PDA. PEGPH20 degrades tumor HA, remodeling the TME. In PDA models, PEGPH20 has shown antitumor activity and increased TME delivery of anticancer agents to improve efficacy. A randomized phase 2 study showed promising results for PEGPH20+AG (PAG) in mPDA and identified HA accumulation as a biomarker. We present results from a phase 3 study (NCT02715804) of PAG for pts with HA-high mPDA. Methods: Pts ≥18 years with untreated HA-high mPDA were randomized (stratified by geographic region) 2:1 to PAG or placebo+AG (AG). HA status was prospectively determined with VENTANA HA RxDx Assay, with HA-high defined as ≥50% staining of a tumor sample. Treatment was administered IV in 4-wk cycles (3 wks on, 1 wk off) until progression or intolerable adverse events (AEs): PEGPH20 3.0 µg/kg twice wkly for Cycle 1 and once wkly (QW) thereafter, A 125 mg/m2 QW and G 1000 mg/m2 QW. Prophylactic enoxaparin 1 mg/kg was given daily for thromboembolism (TE) risk. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), objective response rate (ORR) and safety. Response was independently assessed per RECIST v1.1. The estimated sample size was ~500 pts to detect a hazard ratio (HR) for OS of 0.67 (93% power, 2-sided α = 0.05) after 330 deaths. Results: As of 20 May 2019, 494 pts were randomized with 492 (327 for PAG and 165 for AG) included in ITT analyses (2 pts excluded due to site violations). Baseline characteristics were balanced for PAG vs AG. After 330 deaths, median OS for PAG vs AG was 11.2 vs 11.5 mo (HR 1.00, 95% CI 0.80–1.27; P = 0.97); median PFS was 7.1 vs 7.1 mo (HR 0.97, 95% CI 0.75–1.26); confirmed ORR was 34% vs 27%. Grade (G) 3+ AEs (PAG vs AG) included neutropenia (44% vs 47%), thrombocytopenia (21% vs 16%) and fatigue (16% vs 10%); G3+ rates were 6% vs 7% for TE events, 5% vs 2% for bleeding events and 13% vs 5% for musculoskeletal events. Conclusions: PAG did not improve clinical outcomes vs AG. The PAG safety profile was consistent with that of previous studies. Clinical trial information: NCT02715804.

Imatinib in Children with Chronic Myeloid Leukemia in Chronic Phase: Long-Term Results of the French National Phase IV Trial

Because of the rarity of Chronic Myeloid Leukemia (CML) in children and adolescents, only few studies reported on efficacity and tolerance of imatinib in the pediatric population and scant data are available regarding long-term follow-up. The aim of our analysis was to assess, the long-term efficacity and safety of imatinib in children with CML in early chronic phase included in the French multicentric prospective Glivec Phase IV trial (Millot et al, J Clin Oncol 2011). Methods: Children aged 0 to 18 years with newly diagnosis CML in chronic phase were eligible to received daily imatinib 260 mg/m² according the trial. Long-term analysis included overall survival (OS), progression-free survival (PFS), response to treatment and adverse events. Results: Between March 2004 and December 2008, 44 patients (median age 13.4 years; range 0.8 - 16.7 years) were included in the trial. As of April 2019, with a median follow-up of 10.6 years (range 1.8 - 13.4 years), 2 patients (pts) progressed to blastic crisis and only one death was recorded. The median age was 21.8 years (range 9.3 - 28.8 years) at the last follow-up. The median duration of imatinib therapy was 10.5 years (range 0.2 - 12.5 years) for the entire cohort. To date, 13 pts (29.5%) are still treated with imatinib. Thirty-one pts (70.5%) had discontinued first line treatment with imatinib after a median time of treatment of 2.4 years (range 0.2 - 10.6 years) for the following reasons: 10 pts did not achieve major molecular response (MMR), 1 pt developed blast crisis, 2 pts had unsatisfactory level of molecular response (MR) according to the clinician, 10 pts lost their response (loss of complete hematological response n=1, complete cytogenetic response [CCR] n=6 and MMR n=3), 4 pts attempted treatment free remission (TFR), 3 pts were intolerant to imatinib and 1 pt stopped because of pregnancy. Among these 31 pts who discontinued imatinib, 2 pts are still in TFR, and 29 pts switched to a second line therapy: second generation tyrosine kinase inhibitors (2TKI) (n=25), allogeneic hematopoietic stem cell transplantation (HSCT) (n=3), polychemotherapy (n=1). Sixteen of these 31 pts (51.6%) required subsequent lines of therapy including a second pt who transformed to blastic crisis under a second line therapy with dasatinib. Overall 11 pts (25%) underwent HSCT. Overall, regarding the best response, during the study follow-up 11 pts (25%) achieved MMR after a median time of 2.3 years (range 0.8-5.1), 7 pts (13.6%) achieved MR4 after a median time of 5.1 years (range 2.5-7.8), 25 pts (56.8%) achieved MR4.5 after a median time of 2.92 years (range 1.1-10.4) and 1 pt (2.3%) achieved CCR only. At last follow-up, 43 out the 44 pts were alive : 3 pts (7%) were in CCR, 12 pts (27.9%) in MMR, 6 pts (13.9%) in MR4 and 22 pts (51.2%) in MR4.5. Among the 13 pts still treated with imatinib, 1 pt (7.7%) was in CCR, 6 pts (14%) in MMR, 3 pts (23.1%) were in MR4 and 3 pts (23.1%) in MR4.5. Among the 11 transplanted patients, all pts except one are alive, in at least MR4.5. The death was related to post transplant infection. On an intention to treat basis, the 10-year OS of 44 patients treated was 97.7% (CI 95% 93.3-100). The 10-year PFS was 95.5% (CI 95% 89.3-100). We collected also the long-term safety of imatinib in the 25 pts who have received this therapy for more than 4 years. Newly occurring or worsening grade 3 or 4 hematologic or biochemical adverse events were infrequent after 4 years of imatinib. There is a decrease in the frequency of hematologic and extra hematologic sides effects reported during the first year and those reported after the fourth year of treatment with imatinib: musculoskeletal events 80 vs 24% (p<0,0001), abdominal pain 44% vs 16% (p=0,03), nausea 48% vs 16% (p=0,02), diarrhea 24% vs 0% (p=0,01) and neutropenia 84% vs 28% (p<0,0001), respectively. Conversely, the incidence of lymphopenia appeared with duration of imatinib treatment (p=0,04). Conclusion: With more than 10 years of follow-up, we showed that imatinib remains effective in one third of children included in the Glivec phase IV study with acceptable adverse effects and a low impact over time. Despite the notable proportion of switches, the OS and the PFS remain satisfactory in this pediatric cohort. Disclosures No relevant conflicts of interest to declare.

2515. Clinical Relevance of Immune Non-Response Among Virally Suppressed Adults Living with HIV in Africa and the United States

BackgroundImmune non-response (INR) for people living with HIV (PLWH) is the inability to regain healthy CD4 counts despite viral suppression (VS) on antiretroviral therapy (ART). We identified factors associated with INR in two methodologically similar but demographically diverse cohorts with open access to care and assessed the relationship between INR and incident serious non-AIDS event (SNAE).MethodsThe US Military HIV Natural History Study (NHS) and the African Cohort Study (AFRICOS) are multisite, open cohort studies enrolling PLWH. Participants with 2 years of VS < 400 copies/mL on ART were evaluated for INR, defined as CD4 < 350 cells/µL at 2 years VS. Logistic regression was used to estimate adjusted odds ratios (aOR) and 95% confidence intervals (CI) for factors associated with INR. Cox proportional hazards regression produced adjusted hazard ratios (aHR) and 95% CIs for factors associated with incident SNAE (first non-AIDS cancer, cardiovascular, gastrointestinal, genitourinary, liver, musculoskeletal or respiratory event) after 2 years of VS.Results10.8% of the 1,784 NHS and 25.8% of the 984 AFRICOS subjects had INR. The AFRICOS cohort was older and had a higher proportion of females. In both cohorts, immune non-responders were significantly older and had a significantly lower CD4 at ART initiation. Those with INR also took longer to reach 2 years of VS since starting ART. Odds of INR decreased by over 60% for every 100 cell increase in baseline CD4 in both cohorts (NHS aOR = 0.31 [95% CI 0.26, 0.37]; AFRICOS aOR = 0.36 [95% CI 0.21, 0.86]). In the NHS, hazard of incident SNAE was 61% higher for those with INR (aHR = 1.61 [95% CI 1.12, 2.33]). Probability of SNAE-free survival at 15 years since 2 years of VS was approximately 20% lower comparing those with and without INR; nearly equal to the differences observed by 15-year age groups.ConclusionINR was common in two diverse cohorts with open access to care and treatment. The association with SNAEs suggests early identification of and interventions to prevent or reverse INR may improve clinical outcomes, but further study is needed. The clinical relevance of INR highlights the value of early HIV identification and treatment, and suggests CD4 monitoring at ART initiation and post-VS is important in settings where INR is prevalent. Disclosures All authors: No reported disclosures.

Systematic Review for the 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.

The 2013 American College of Cardiology/American Heart Association guidelines for the treatment of blood cholesterol found little evidence to support the use of nonstatin lipid-modifying medications to reduce atherosclerotic cardiovascular disease (ASCVD) events. Since publication of these guidelines, multiple randomized controlled trials evaluating nonstatin lipid-modifying medications have been published. We performed a systematic review to assess the magnitude of benefit and/or harm from additional lipid-modifying therapies compared with statins alone in individuals with known ASCVD or at high risk of ASCVD. We included data from randomized controlled trials with a sample size of >1 000 patients and designed for follow-up >1 year. We performed a comprehensive literature search and identified 10 randomized controlled trials for intensive review, including trials evaluating ezetimibe, niacin, cholesterol-ester transfer protein inhibitors, and PCSK9 inhibitors. The prespecified primary outcome for this review was a composite of fatal cardiovascular events, nonfatal myocardial infarction, and nonfatal stroke. The cardiovascular benefit of nonstatin lipid-modifying therapies varied significantly according to the class of medication. There was evidence for reduced ASCVD morbidity with ezetimibe and 2 PSCK9 inhibitors. Reduced ASCVD mortality rate was reported for 1 PCSK9 inhibitor. The use of ezetimibe/simvastatin versus simvastatin in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) reduced the primary outcome by 1.8% over 7 years (hazard ratio: 0.90; 95% CI: 0.84-0.96], 7-year number needed to treat: 56). The PSCK9 inhibitor evolocumab in the FOURIER study (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) decreased the primary outcome by 1.5% over 2.2 years (hazard ratio: 0.80; 95% CI: 0.73-0.88; 2.2=year number needed to treat: 67). In ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab), alirocumab reduced the primary outcome by 1.6% over 2.8 years (hazard ratio: 0.86; 95% CI: 0.79-0.93; 2.8-year number needed to treat: 63). For ezetimibe and the PSCK9 inhibitors, rates of musculoskeletal, neurocognitive, gastrointestinal, or other adverse event risks did not differ between the treatment and control groups. For patients at high risk of ASCVD already on background statin therapy, there was minimal evidence for improved ASCVD risk or adverse events with cholesterol-ester transfer protein inhibitors. There was no evidence of benefit for the addition of niacin to statin therapy. Direct comparisons of the results of the 10 randomized controlled trials were limited by significant differences in sample size, duration of follow-up, and reported primary outcomes. In a systematic review of the evidence for adding nonstatin lipid-modifying therapies to statins to reduce ASCVD risk, we found evidence of benefit for ezetimibe and PCSK9 inhibitors but not for niacin or cholesterol-ester transfer protein inhibitors.

Assessment of the Safety of Pembrolizumab in Patients With HIV and Advanced Cancer—A Phase 1 Study

Anti-PD-1 (anti-programmed cell death 1) and anti-PD-L1 (anti-programmed cell death ligand 1) regimens are preferred therapies for many cancers, including cancers associated with HIV. However, patients with HIV were excluded from most registered trials. The primary objective was to evaluate the safety of pembrolizumab in people with HIV and advanced cancer; the secondary objective was to evaluate tumor responses. Open-label, nonrandomized, phase 1 multicenter study conducted at 7 Cancer Immunotherapy Trials Network sites. Patients with HIV and advanced cancer as well as a CD4 count greater than or equal to 100 cells/μL, antiretroviral therapy (ART) for 4 or more weeks, and an HIV viral load of less than 200 copies/mL were eligible. Exclusion criteria included uncontrolled hepatitis B or C infection, active immunosuppressive therapy, or a history of autoimmune disease requiring systemic therapy. Pembrolizumab, 200 mg, administered intravenously every 3 weeks for up to 35 doses in 3 CD4 count-defined cohorts. Participants continued ART. Safety and tolerability were assessed using current NCI Common Terminology Criteria for Adverse Events. Immune-related adverse events grade 2 or higher were considered immune-related events of clinical interest (irECI). Tumor responses were evaluated using standard tumor-specific criteria. Thirty participants (28 men and 2 women; median [range] age, 57 [39-77] years) were enrolled from April 2016 through March 2018; 6 had Kaposi sarcoma (KS), 5 had non-Hodgkin lymphoma (NHL), and 19 had non-AIDS-defining cancers. Safety was observed over 183 cycles of treatment with pembrolizumab. Most treatment-emergent adverse events at least possibly attributed to pembrolizumab were grade 1 or 2 (n = 22), and 20% (n = 6) were grade 3. The irECI included hypothyroidism (6 participants), pneumonitis (3 participants), rash (2 participants), an elevated aminotransferase/alanine aminotransferase level (1 participant), and a musculoskeletal event (1 participant). One participant with pretreatment KS herpesvirus (KSHV) viremia developed a polyclonal KSHV-associated B-cell lymphoproliferation and died. HIV was controlled in all participants. Increases in CD4 count were not statistically significant (median increase, 19 cells/μL; P = .18). Best tumor responses included complete response (lung, 1 patient), partial response (NHL, 2 patients), stable disease for 24 weeks or more (KS, 2 patients), stable disease for less than 24 weeks (15 patients), and progressive disease (8 patients); 2 patients were not evaluable. Pembrolizumab has acceptable safety in patients with cancer, HIV treated with ART, and a CD4+ T-cell count of greater than 100 cells/μL but may be associated with KSHV-associated B-cell lymphoproliferation. Clinical benefit was noted in lung cancer, NHL, and KS. Anti-PD-1 therapy is appropriate for US Food and Drug Administration-approved indications and clinical trials in this population. ClinicalTrials.gov identifier: NCT02595866.

PS1195 TIME TO HEALTH‐RELATED QUALITY OF LIFE IMPROVEMENT IN THE PHASE 3 BFORE TRIAL: FIRST‐LINE BOSUTINIB VS IMATINIB IN CHRONIC PHASE CHRONIC MYELOID LEUKEMIA

Background:Bosutinib showed improved efficacy vs imatinib for newly diagnosed chronic phase chronic myeloid leukemia (CP CML) in the ongoing BFORE trial (NCT02130557). Gastrointestinal events and transaminase increases were more frequent with bosutinib; musculoskeletal events and edema were more common with imatinib. Improvement or preservation of health‐related quality of life (HRQoL) was seen in both treatment arms after 12 months.Aims:In post hoc analyses, we examined time to improvement of HRQoL with bosutinib or imatinib.Methods:HRQoL was assessed at study visits with the patient‐reported Functional Assessment of Cancer Therapy–Leukemia (FACT‐Leu) questionnaire. Nonparametric models (with SAS Proc Lifetest) were used to estimate median times to transient improvement (any increase in a FACT‐Leu domain score from baseline) and sustained improvement (any increase for 2 consecutive visits) of HRQoL.Results:Median times to transient improvement of FACT‐Leu scores were similar with bosutinib and imatinib (Table). Median time to sustained improvement was numerically shorter with bosutinib for FACT‐Leu total, FACT‐General (FACT‐G) total, emotional well‐being and leukemia subscale scores. Differences between treatment arms for both models (transient or sustained events) were not statistically significant (P&gt;0.05).Summary/Conclusion:Median time to HRQoL improvement was comparable with bosutinib and imatinib, suggesting differences in rates of specific side effects of individual tyrosine kinase inhibitors for CP CML do not necessarily translate into measurable differences in patient‐reported HRQoL.image

Abstract P1-11-24: Aromatase inhibitors and bone health in women 75 and older treated for early stage breast cancer

Abstract Introduction: Breast cancer is the most common cancer in women. In estrogen receptor positive breast cancers aromatase inhibitors (AI) are a common treatment option. AIs are associated with a reduction in bone mineral density, and patients with osteopenia at baseline have a higher risk of developing subsequent osteoporosis while on AI therapy. Women age 75 and older are a fast growing subset of breast cancer patients and commonly have osteopenia or osteoporosis at time of breast cancer diagnosis. Studies of long-term effects of AI on bone density in these older women who are at higher risk of osteoporosis and musculoskeletal events are lacking at this time. Objective: To evaluate the objective change in bone density in women over the age of 75 diagnosed with early stage breast cancer and treated with AI. Methods: A retrospective chart review of 49 patients ages 75 to 95 diagnosed with early stage breast cancer and treated with AI. Pretreatment DEXA scan results were recorded as well as prevalence of bone targeted therapy at the time of breast cancer diagnosis. Incidence of bone targeted therapy initiated subsequent to cancer diagnosis and changes in T score on follow up DEXA scans were collected as well. Incidence of musculoskeletal events and osteonecrosis of the jaw were recorded. Results: 40/49 (81.6%) of study women were found to have osteopenia (23/49 [46.9%]) or osteoporosis (17/49 [34.7%]) on pre-treatment DEXA scans. Only 16/49 (32.7%) of patients were on bone-targeted treatment prior to breast cancer diagnosis. Of the patient with baseline osteoporosis, only 4/17 (23.5%) were on bone targeted treatment prior to breast cancer diagnosis. 25/49 (51%) of women were initiated on bone targeted therapy subsequent to breast cancer diagnosis and following review of pretreatment DEXA scan results. 5/49 (10.2%) of women were started on bisphosphonates and 7/49 (14.3%) were started on Denosumab. On the first subsequent DEXA scan at a median follow up of 2 years, 14/21(66.7%) of women were noted to have stable DEXA findings (defined as change in T score less than 0.5). 7/21 (33.3%) had a worsening T score on repeat DEXA. Of those patients with worsening T score, 3/7 (42.9%) changed categories (either from normal density to osteopenia or from osteopenia to osteoporosis. 3/49 (6%) of patients sustained a fracture while on AI therapy. There were no reported events of osteonecrosis of the jaw. Subsequent DEXA showing stabilitySubsequent DEXA showing worsening T scoreFractureBaseline Normal bone density1 (n=3)2 (n=3)1 (n=9)Baseline Osteopenia9 (n=12)3 (n=12)0 (n=12)Baseline Osteoporosis4 (n=6)2 (n=6)2 (n=17) Conclusion: Many elderly women are found to have osteopenia or osteoporosis at the time of breast cancer diagnosis and AI initiation. Most elderly patients had stable findings on subsequent bone density testing. Women with known osteoporosis initiated on bone-targeted therapy and AI did not have significant worsening in bone health. With appropriate treatment and monitoring elderly women with baseline decreased bone density can be treated safely with aromatase inhibitors. Citation Format: Baer L, Chaudhry B, Kudelka A, Cohen J, Stopeck AT. Aromatase inhibitors and bone health in women 75 and older treated for early stage breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-11-24.

Delayed immune-related adverse events in assessment for dose-limiting toxicity in early phase immunotherapy trials

BackgroundImmunotherapy (IO) agents can cause late-onset immune-related adverse events (irAEs). In phase I trials, observation for dose-limiting toxicities (DLTs) is typically limited to the first cycle. The incidence of delayed-onset DLTs and their potential impact on dose determination have not been fully elucidated. Patients and methodsConsecutive patients enrolled in early phase IO trials at Princess Margaret Cancer Centre between August 2012 and September 2016 were retrospectively reviewed, applying trial-specific definitions for DLTs. A clinically significant AE (csAE) was defined as a treatment-related adverse event requiring corticosteroids, hormone replacement, IO delay or discontinuation. ResultsA total of 352 consecutive trial enrolments in 21 early phase clinical trials were included. Two-hundred seventy-eight patients (79%) received monotherapy and 74 (21%) received combination IO. Two hundred sixty (74%) patients experienced irAEs. There were two protocol-defined DLTs. Twenty (5.7%) patients had 24 csAEs qualifying as DLTs except for occurrence after the protocol-specified DLT period. One-hundred and six (10%) of irAEs were csAEs, including endocrine (26%), respiratory (14%), gastrointestinal (11%), general (10%), dermatological (8%), hepatic (8%), musculoskeletal (6%), pancreatic (6%), haematological, metabolic, neurological, cardiac (each 2%), infective and ocular (each 1%) events. The highest risk of first-onset csAE was during the first 4 weeks compared with the period from 4 weeks to end of treatment (odds ratio 3.13, 95% confidence interval 1.95–5.02). The median time to first onset csAE was significantly shorter with combination than monotherapy IO (32 vs. 146 days, P < 0.001). ConclusionsIn our series of early phase IO trials, the risk of csAE was highest during the initial 4 weeks on IO treatment, supporting the use of the conventional DLT period for dose escalation decision. However, there were 24 clinically significant late-onset DLTs in 5.7% of patients. Combination IO was associated with greater risk of and also earlier onset for csAE, which may need to be considered for early phase trial design.

Clinical and Cardiac Safety of Long-term Levofloxacin in Children Treated for Multidrug-resistant Tuberculosis.

Safety concerns persist for long-term pediatric fluoroquinolone use. Seventy children (median age, 2.1 years) treated with levofloxacin 10-20 mg/kg once daily for multidrug-resistant tuberculosis (median observation time, 11.8 months) had few musculoskeletal events, no levofloxacin-attributed serious adverse events, and no Fridericia-corrected QT interval >450 ms. Long-term levofloxacin was safe and well tolerated.

The effect of eicosapentaenoic and docosahexaenoic acids on physical function, exercise, and joint replacement in patients with coronary artery disease: A secondary analysis of a randomized clinical trial

Poor physical function impairs fitness and exercise and is associated with worse cardiovascular outcomes and all-cause mortality. Joint pain and stiffness limit physical function. To determine if eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) supplementation improves physical function and exercise in coronary artery disease (CAD) patients. A total of 291 subjects with stable CAD were randomized to either Lovaza (1.86g of EPA and 1.5g of DHA daily) or no Lovaza (control) for 1year. Change in pain, stiffness, and physical function was assessed by the Western Ontario and McMaster Universities Arthritis Index. Minutes of exercise per week were recorded, and musculoskeletal events were reported. Mean age (standard deviation) was 63.3 (7.6) years. In the intention-to-treat analysis, compared with controls, those on Lovaza had better physical function (mean difference, -11.0%, 95% confidence interval [CI] -18.5% to -3.5%, P=.004), better total Western Ontario and McMaster Universities Arthritis Index scores (mean difference, -9.8%, 95% CI -16.6% to -3.0%, P=.005), more exercise per week (135minutes vs 197minutes, respectively, P=.028), and less joint replacement (11 vs 1, respectively, P=.002). Pain and stiffness showed a trend toward significance (P=.06). The per-protocol analysis also showed less stiffness compared with controls (mean difference, -11.5%, 95% CI -22.9% to -0.1%, P=.048). High-dose EPA and DHA may benefit CAD patients by preserving physical function, increasing amount of exercise, and reducing joint replacement. EPA and DHA may be a safe preventative strategy against musculoskeletal symptoms in CAD patients.

Adjuvant anastrozole versus exemestane versus letrozole, upfront or after 2 years of tamoxifen, in endocrine-sensitive breast cancer (FATA-GIM3): a randomised, phase 3 trial

Uncertainty exists about the optimal schedule of adjuvant treatment of breast cancer with aromatase inhibitors and, to our knowledge, no trial has directly compared the three aromatase inhibitors anastrozole, exemestane, and letrozole. We investigated the schedule and type of aromatase inhibitors to be used as adjuvant treatment for hormone receptor-positive early breast cancer. FATA-GIM3 is a multicentre, open-label, randomised, phase 3 trial of six different treatments in postmenopausal women with hormone receptor-positive early breast cancer. Eligible patients had histologically confirmed invasive hormone receptor-positive breast cancer that had been completely removed by surgery, any pathological tumour size, and axillary nodal status. Key exclusion criteria were hormone replacement therapy, recurrent or metastatic disease, previous treatment with tamoxifen, and another malignancy in the previous 10 years. Patients were randomly assigned in an equal ratio to one of six treatment groups: oral anastrozole (1 mg per day), exemestane (25 mg per day), or letrozole (2·5 mg per day) tablets upfront for 5 years (upfront strategy) or oral tamoxifen (20 mg per day) for 2 years followed by oral administration of one of the three aromatase inhibitors for 3 years (switch strategy). Randomisation was done by a computerised minimisation procedure stratified for oestrogen receptor, progesterone receptor, and HER2 status; previous chemotherapy; and pathological nodal status. Neither the patients nor the physicians were masked to treatment allocation. The primary endpoint was disease-free survival. The minimum cutoff to declare superiority of the upfront strategy over the switch strategy was assumed to be a 2% difference in disease-free survival at 5 years. Primary efficacy analyses were done by intention to treat; safety analyses included all patients for whom at least one safety case report form had been completed. Follow-up is ongoing. This trial is registered with the European Clinical Trials Database, number 2006-004018-42, and ClinicalTrials.gov, number NCT00541086. Between March 9, 2007, and July 31, 2012, 3697 patients were enrolled into the study. After a median follow-up of 60 months (IQR 46-72), 401 disease-free survival events were reported, including 211 (11%) of 1850 patients allocated to the switch strategy and 190 (10%) of 1847 patients allocated to upfront treatment. 5-year disease-free survival was 88·5% (95% CI 86·7-90·0) with the switch strategy and 89·8% (88·2-91·2) with upfront treatment (hazard ratio 0·89, 95% CI 0·73-1·08; p=0·23). 5-year disease-free survival was 90·0% (95% CI 87·9-91·7) with anastrozole (124 events), 88·0% (85·8-89·9) with exemestane (148 events), and 89·4% (87·3 to 91·1) with letrozole (129 events; p=0·24). No unexpected serious adverse reactions or treatment-related deaths occurred. Musculoskeletal side-effects were the most frequent grade 3-4 events, reported in 130 (7%) of 1761 patients who received the switch strategy and 128 (7%) of 1766 patients who received upfront treatment. Grade 1 musculoskeletal events were more frequent with the upfront schedule than with the switch schedule (924 [52%] of 1766 patients vs 745 [42%] of 1761 patients). All other grade 3-4 adverse events occurred in less than 2% of patients in either group. 5 years of treatment with aromatase inhibitors was not superior to 2 years of tamoxifen followed by 3 years of aromatase inhibitors. None of the three aromatase inhibitors was superior to the others in terms of efficacy. Therefore, patient preference, tolerability, and financial constraints should be considered when deciding the optimal treatment approach in this setting. Italian Drug Agency.

Effect of High-Intensity Treadmill Exercise on Motor Symptoms in Patients With De Novo Parkinson Disease

Parkinson disease is a progressive neurologic disorder. Limited evidence suggests endurance exercise modifies disease severity, particularly high-intensity exercise. To examine the feasibility and safety of high-intensity treadmill exercise in patients with de novo Parkinson disease who are not taking medication and whether the effect on motor symptoms warrants a phase 3 trial. The Study in Parkinson Disease of Exercise (SPARX) was a phase 2, multicenter randomized clinical trial with 3 groups and masked assessors. Individuals from outpatient and community-based clinics were enrolled from May 1, 2012, through November 30, 2015, with the primary end point at 6 months. Individuals with idiopathic Parkinson disease (Hoehn and Yahr stages 1 or 2) aged 40 to 80 years within 5 years of diagnosis who were not exercising at moderate intensity greater than 3 times per week and not expected to need dopaminergic medication within 6 months participated in this study. A total of 384 volunteers were screened by telephone; 128 were randomly assigned to 1 of 3 groups (high-intensity exercise, moderate-intensity exercise, or control). High-intensity treadmill exercise (4 days per week, 80%-85% maximum heart rate [n = 43]), moderate-intensity treadmill exercise (4 days per week, 60%-65% maximum heart rate [n = 45]), or wait-list control (n = 40) for 6 months. Feasibility measures were adherence to prescribed heart rate and exercise frequency of 3 days per week and safety. The clinical outcome was 6-month change in Unified Parkinson's Disease Rating Scale motor score. A total of 128 patients were included in the study (mean [SD] age, 64 [9] years; age range, 40-80 years; 73 [57.0%] male; and 108 [84.4%] non-Hispanic white). Exercise rates were 2.8 (95% CI, 2.4-3.2) days per week at 80.2% (95% CI, 78.8%-81.7%) maximum heart rate in the high-intensity group and 3.2 (95% CI, 2.8-3.6; P = .13) days per week at 65.9% (95% CI, 64.2%-67.7%) maximum heart rate in the moderate-intensity group (P < .001). The mean change in Unified Parkinson's Disease Rating Scale motor score in the high-intensity group was 0.3 (95% CI, -1.7 to 2.3) compared with 3.2 (95% CI, 1.4 to 5.1) in the usual care group (P = .03). The high-intensity group, but not the moderate-intensity group, reached the predefined nonfutility threshold compared with the control group. Anticipated adverse musculoskeletal events were not severe. High-intensity treadmill exercise may be feasible and prescribed safely for patients with Parkinson disease. An efficacy trial is warranted to determine whether high-intensity treadmill exercise produces meaningful clinical benefits in de novo Parkinson disease. clinicaltrials.gov Identifier: NCT01506479.

Randomized phase 2 therapeutic equivalence study of abiraterone acetate fine particle formulation vs. originator abiraterone acetate in patients with metastatic castration-resistant prostate cancer: The STAAR study

BackgroundThis multicenter, randomized, open-label, active-controlled study evaluated therapeutic equivalence, steady-state pharmacokinetics, and safety of a novel abiraterone acetate fine particle formulation (AAFP) 500mg plus methylprednisolone vs. the originator AA (OAA) 1000mg plus prednisone in men with metastatic castrate-resistant prostate cancer (mCRPC). The primary endpoint was a comparison of average of serum testosterone levels on treatment days 9 and 10 between groups. MethodsMen with progressive mCRPC, receiving gonadotropin-releasing hormone agonist or antagonist therapy, and with a serum testosterone level of <50ng/dl were randomized 1:1 to either AAFP 500mg daily plus 4mg methylprednisolone orally twice daily (BID), or OAA 1000mg daily plus 5mg prednisone BID for 84 days. Serum testosterone, serum prostate-specific antigen (PSA), steady-state (trough) abiraterone pharmacokinetics, and safety were evaluated. ResultsFifty-three patients were enrolled (n = 24, AAFP; n = 29, OAA). Mean age was 75.1 years and 54.7% had Gleason>7. Over 90% of patients in each group achieved absolute testosterone levels of ≤1ng/dl during the study. The averaged absolute testosterone levels ≤0.1ng/dl were achieved in 25% of AAFP-treated patients and 17% of OAA-treated patients. A PSA-50 response was observed in>65% of patients in both groups on days 28, 56, and 84 (P = NS, all timepoints). Days 9 and 10 averaged rounded-up least squares (LS) mean (SE) serum testosterone levels were comparable (1.05ng/dl [0.04], AAFP; 1.02ng/dl [0.03], OAA; P = 0.4703 for LS mean difference). The geometric mean ratio between groups was 1.021 (90% CI: 0.965–1.081); the 90% CI fell within 80.0% to 125.0% equivalence limits. The LS mean differences in abiraterone trough plasma concentrations were not statistically significant at any visit. Adverse event frequency was comparable between arms (75.0%, AAFP; 82.8%, OAA). Musculoskeletal events were more common among OAA-treated patients (37.9% vs. 12.5%). ConclusionTherapeutic equivalence between AAFP 500mg daily and OAA 1000mg daily based on serum testosterone levels was confirmed in mCRPC patients. Both agents led to similar PSA-50 response rates. Abiraterone trough levels were similar between treatments. No new safety concerns were observed.

Estimating global treatment toxicity burden from adverse-event data.

A summary measure that reflects the global toxicity burden of a treatment is essential for comparing therapies. Current toxicity summaries are ad hoc and do not distinguish among the severities and types of toxicities. Here a clinically feasible method for estimating the toxicity burden, based on a prospective evaluation of the toxicity profile of a randomized clinical trial of 746 prostate cancer patients conducted by SWOG, is proposed. For 308 patients who experienced severe toxicities, 2 physicians randomly selected from 14 physicians evaluated each toxicity profile and assigned a visual analogue scale score (0-10) based on their impression of the global burden of toxicities. With mixed-effects models, severity scores and a 10-point toxicity burden score (TBS) were derived from 27 predictors accounting for severe (grade 3) and life-threatening (grade 4) toxicities for each organ class of the Common Terminology Criteria for Adverse Events. For most organ classes, grade 3 toxicities had a TBS of 4.14 (95% confidence interval [CI], 3.65-4.63), but infections, cardiovascular events, and pulmonary events had a higher TBS with differences of 0.87 (95% CI, 0.53-1.21), 0.88 (95% CI, 0.51-1.25), and 0.73 (95% CI, 0.22-1.24), respectively. Moreover, most grade 4 events had a higher TBS than grade 3 events, except for hemorrhaging, pain, metabolic events, and musculoskeletal events. The intrarater and interrater correlations were 0.91 and 0.59, respectively. The burden of toxicity grades differs with toxicity types. A TBS provides a toxicity burden summary that incorporates physicians' perspectives and differentiates between severe and life-threatening toxicities and organ classes. Cancer 2018;124:858-64. © 2017 American Cancer Society.

749P - Musculoskeletal Events (MSEs) with PEGPH20 treatment and management in patients with previously untreated metastatic pancreatic ductal adenocarcinoma (mPDA)

749P - Musculoskeletal Events (MSEs) with PEGPH20 treatment and management in patients with previously untreated metastatic pancreatic ductal adenocarcinoma (mPDA)

Lymphedema, musculoskeletal events and arm function in older patients receiving adjuvant chemotherapy for breast cancer (Alliance A171302).

Musculoskeletal events (MEs) resulting from breast cancer treatment can significantly interfere with the quality of life (QOL) of older adults. We evaluated the incidence of MEs in women 65years and older who had surgery and adjuvant chemotherapy for breast cancer, and the impact of treatment on MEs and arm function. Patient-reported data in Alliance/CALGB 49907 were collected using the EORTC QLQ-BR23 and physician-reported adverse events to characterize self-reported MEs and incidence of lymphedema. EORTC QLQ-BR23 items related to musculoskeletal events were analyzed in this study and data collected at study entry (post-operative) and 12 and 24months post-entry. Lymphedema, arm function, and ME data were available for 321 patients. One or more MEs were reported by 87% (median number=3) and 64% (median number=1) of patients post-operatively and at 24months. At 24months 2% had persistence of six MEs. Seventy-four percent experienced at least≥3/6 types of MEs over the 24-month period. Detection of lymphedema at any time during the study was noted in 7.5% of the patients and appeared to be associated with the type of chemotherapy given: CMF 16.4%, capecitabine 5.8%, and AC 4%. Mastectomy and axillary node dissection were associated with the most MEs. LROM correlated with poorer arm function at all time periods. Potentially debilitating MEs occur in three-fourths of elderly women undergoing standard therapy for breast cancer. Emphasis should be placed on prevention, identification, and treatment of these MEs to improve QOL.

Abstract 1240: Evaluating clinically relevant pharmacological agents in a rat ambulation model to ameliorate PEGylated recombinant hyaluronidase PH20 (PEGPH20)-mediated musculoskeletal adverse events

Abstract Some cancers accumulate high levels of the glycosaminoglycan hyaluronan (HA) within the tumor microenvironment (TME), and this HA accumulation is associated with rapid tumor progression and poor clinical outcomes. As preclinical data have demonstrated that enzymatic degradation of HA, via intravenous (IV) administration of PEGylated recombinant human hyaluronidase PH20 (PEGPH20), increases therapeutic efficacy in HA-accumulating tumors, several clinical trials evaluating PEGPH20 in combination with anti-cancer therapies are ongoing. The most advanced clinical trial (Phase 3) is evaluating PEGPH20 plus Abraxane® (nab-paclitaxel)/gemcitabine (AG) in patients with stage IV untreated pancreatic ductal adenocarcinoma (PDA)(NCT02715804). The safety profile of PEGPH20/Abraxane/gemcitabine (PAG) was generally similar to AG alone in an interim analysis of the Phase 2 data, with the exception of a potential imbalance of thromboembolic events (TEs), and an increased incidence of musculoskeletal events (MSEs) in the PAG arm, with the predominant MSE being muscle spasms (55.4% PAG vs. 1.6% AG, all grades)(Bullock, ASCO 2016). In an effort to find pharmacological agent(s) that might decrease MSEs in PAG-treated patients, a rat locomotor activity assay was developed. In brief, locomotor activity of male Sprague Dawley rats was measured with an automated infrared photobeam monitoring apparatus (Hamilton/Kinder®, San Diego) during the 12h dark cycle when rats are normally active. Any PEGPH20-mediated decrease in rat locomotor activity was interpreted as MSE-like effects. In response to PEGPH20 (1 mg/kg) the locomotor activity of male rats was reduced by ~75% for the first 2 dark cycles post-treatment (48h), and then gradually returned to vehicle baseline levels by days 4-5. FDA approved drugs used clinically to alleviate pain were subsequently tested for their ability to ameliorate the effects of PEGPH20 on locomotor activity. Agents included anti-inflammatories, anti-spasmodics, neuropathic pain medications, neuroleptics, diuretics, anti-hypertensives, anti-fibromyalgics and opioids. The steroid dexamethasone, currently being used in the Phase 2 and Phase 3 PDA clinical trials to manage MSEs, was the positive control. As a class, nonsteroidal anti-inflammatory drugs (NSAIDs), including ketorolac, ketoprofen, diclofenac, and piroxicam, increased rat ambulation by ~40% on the first night following PEGPH20 treatment compared to PEGPH20 alone. Mobility in rats treated with NSAIDs/PEGPH20 increased ~60% on the second night compared to PEGPH20 alone. No other drug classes increased rodent ambulation. These data suggest that NSAIDs may be useful in partially alleviating the MSEs experienced by patients receiving PEGPH20. Citation Format: Li Ma, Marc R. Azar, Michael Shepard, Ya Huang, Piet A. Vervaet, Daniel C. Maneval, Curtis B. Thompson, Rudy Paladini. Evaluating clinically relevant pharmacological agents in a rat ambulation model to ameliorate PEGylated recombinant hyaluronidase PH20 (PEGPH20)-mediated musculoskeletal adverse events [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1240. doi:10.1158/1538-7445.AM2017-1240

Abstract CT032: A Phase 1b study of PEGPH20 plus pembrolizumab in patients with selected hyaluronan-high solid tumors

Abstract Background: Hyaluronan (HA) accumulation in the tumor microenvironment increases tumor interstitial fluid pressure, promoting vascular collapse and limiting access of chemotherapy and immune cells to tumor sites. In animal models, HA-High tumors exhibit increased growth and metastasis, treatment resistance, and reduced survival. PEGPH20 is a PEGylated recombinant human hyaluronidase that enzymatically degrades tumor HA. Pembrolizumab (PEM) is a humanized monoclonal antibody targeting PD-1, demonstrating tolerability and activity in patients (pts) with non-small cell lung cancer (NSCLC). This study evaluates the safety and activity of PEGPH20 plus PEM in pts with NSCLC or gastric cancer. Methods: This Phase 1b study comprises dose escalation (up to 30 pts regardless of HA status) and cohort expansion (up to 51 pts with tumors accumulating high levels of HA). HA staining is performed using the VENTANA HA RxDX Assay, which indicates HA in the extracellular matrix. HA-High status (ie, patients who may achieve clinical benefit) was determined by Halozyme to be ≥50% staining based on clinical outcome data from a phase 2 study. For dose escalation, eligible pts (ECOG 0-1) had stage IIIB/IV NSCLC failing ≥1 prior platinum-based regimen or locally advanced or metastatic gastric adenocarcinoma failing ≥1 previous chemotherapy regimen. NSCLC pts known to be epidermal growth factor receptor (EGFR)- or anaplastic lymphoma kinase (ALK)-positive must have received an EGFR inhibitor or ALK inhibitor, respectively. For cohort expansion, previously treated or untreated NSCLC is allowed; gastric cancer pts must have failed 1-2 prior treatments. PEGPH20 (1.6, 2.2, 2.6, 3.0, 4.0 µg/kg) is administered IV on D1, 8, 15 of each 21-day cycle followed by PEM 200 mg IV on D1, 4 to 6 hours after PEGPH20. Due to increased thromboembolic risk in gastric cancer, these pts receive prophylactic enoxaparin. Additional prophylaxis with piroxicam (possible musculoskeletal events) and proton pump inhibitors are given to all patients. The primary endpoint for dose escalation is the recommended Phase 2 dose for PEGPH20 in combination with PEM. The primary endpoint for cohort expansion is objective response rate per RECIST v1.1. Secondary endpoints are duration of response, disease control rate, progression-free survival per RECIST and immune-related response criteria, pharmacokinetics, and adverse events. Exploratory endpoints include secondary efficacy endpoints by PD-LI status, plasma and tumor HA levels, and imaging parameters of tumor blood flow (dynamic contrast-enhanced magnetic resonance imaging [DCE-MRI]) and tumor metabolic activity (positron emission tomography/computed tomography [PET/CT] scans). ClinicalTrials.gov Identifier: NCT02563548. Citation Format: Lyudmila Bazhenova, Philip J. Gold, R. Donald Harvey, Alexander I. Spira, John Nemunaitis, Joaquina C. Baranda, Shirish Gadgeel. A Phase 1b study of PEGPH20 plus pembrolizumab in patients with selected hyaluronan-high solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT032. doi:10.1158/1538-7445.AM2017-CT032