Clinical Efficacy and Whole-Exome Sequencing of Liquid Biopsies in a Phase IB/II Study of Bazedoxifene and Palbociclib in Advanced Hormone Receptor-Positive Breast Cancer.

PURPOSE: Sensitivity to endocrine therapy (ET) is critical for the clinical benefit from the combination of palbociclib plus ET in hormone receptor-positive/HER2-negative (HR+/HER2-) advanced breast cancer. Bazedoxifene is a third-generation selective estrogen receptor (ER) modulator and selective ER degrader with activity in preclinical models of endocrine-resistant breast cancer, including models harboring ESR1 mutations. Clinical trials in healthy women showed that bazedoxifene is well tolerated. PATIENTS AND METHODS: We conducted a phase Ib/II study of bazedoxifene plus palbociclib in patients with HR+/HER2- advanced breast cancer who progressed on prior ET (N = 36; NCT02448771). RESULTS: The study met its primary endpoint, with a clinical benefit rate of 33.3%, and the safety profile was consistent with what has previously been seen with palbociclib monotherapy. The median progression-free survival (PFS) was 3.6 months [95% confidence interval (CI), 2.0-7.2]. An activating PIK3CA mutation at baseline was associated with a shorter PFS (HR = 4.4; 95% CI, 1.5-13; P = 0.0026), but activating ESR1 mutations did not impact the PFS. Longitudinal plasma circulating tumor DNA whole-exome sequencing (WES; N = 68 plasma samples) provided an overview of the tumor heterogeneity and the subclonal genetic evolution, and identified actionable mutations acquired during treatment. CONCLUSIONS: The combination of palbociclib and bazedoxifene has clinical efficacy and an acceptable safety profile in a heavily pretreated patient population with advanced HR+/HER2- breast cancer. These results merit continued investigation of bazedoxifene in breast cancer.

Clinical utility of vinblastine therapeutic drug monitoring for the treatment of infantile myofibroma patients: A case series.

Infantile myofibroma is a rare, benign tumour of infancy typically managed surgically. In a minority of cases, more aggressive disease is seen and chemotherapy with vinblastine and methotrexate may be used, although evidence for this is limited. Chemotherapy dosing in infants is challenging, and vinblastine disposition in infants is unknown. We describe the use of vinblastine therapeutic drug monitoring in four cases of infantile myofibroma. Marked inter- and intrapatient variability was observed, highlighting the poorly understood pharmacokinetics of vinblastine in children, the challenges inherent in treating neonates, and the role of adaptive dosing in optimising drug exposure in challenging situations.

Prospective Study Testing a Simplified Paclitaxel Premedication Regimen in Patients with Early Breast Cancer.

BACKGROUND: In early trials, hypersensitivity reactions (HSRs) to paclitaxel were common, thus prompting the administration of antihistamines and corticosteroids before every paclitaxel dose. We tested the safety of omitting corticosteroids after cycle 2 during the paclitaxel portion of the dose-dense (DD) doxorubicin-cyclophosphamide (AC)-paclitaxel regimen. PATIENTS, MATERIALS, AND METHODS: In this prospective, single-arm study, patients who completed four cycles of DD-AC for stage I-III breast cancer received paclitaxel 175 mg/m2 every 2 weeks for four cycles. Patients received a standard premedication protocol containing dexamethasone, diphenhydramine, and a histamine H2 blocker prior to the first two paclitaxel cycles. Dexamethasone was omitted in cycles three and four if there were no HSRs in previous cycles. We estimated the rate of grade 3-4 HSRs. RESULTS: Among 127 patients enrolled, 125 received more than one dose of protocol therapy and are included in the analysis. Fourteen (11.2%; 90% confidence interval, 6.9%-20.0%) patients had any-grade HSRs, for a total of 22 (4.5%; 3.1%-6.4%) HSRs over 486 paclitaxel cycles. Any-grade HSRs occurred in 1.6% (0.3%-5.0%), 6.5% (3.3%-11.3%), 7.4% (3.9%-12.5%), and 2.6% (0.7%-6.6%) of patients after paclitaxel cycles 1, 2, 3, and 4, respectively. Dexamethasone use was decreased by 92.8% in cycles 3 and 4. Only one patient experienced grade 3 HSR in cycles 3 or 4, for a rate of grade 3/4 HSR 0.4% (0.02%-2.0%) (1/237 paclitaxel infusions). That patient had grade 2 HSR during cycle 2, and the subsequent grade 3 event occurred despite usual dexamethasone premedication. A sensitivity analysis restricted to patients not known to have received dexamethasone in cycles 3 and 4 found that any-grade HSRs occurred in 2.7% (3/111; 0.7%-6.8%) and 0.9% (1/109; 0.05%-4.3%) of patients in cycle 3 and 4, respectively. CONCLUSION: Corticosteroid premedication can be safely omitted in cycles 3 and 4 of dose-dense paclitaxel if HSRs are not observed during cycles 1 and 2. IMPLICATIONS FOR PRACTICE: Because of the potential for hypersensitivity reactions (HSRs) to paclitaxel, corticosteroids are routinely prescribed prior to each dose, on an indefinite basis. This prospective study, including 125 patients treated with 486 paclitaxel cycles, demonstrates that corticosteroids can be safely omitted in future cycles if HSRs did not occur during cycles 1 and 2 of paclitaxel and that this strategy reduces the use of corticosteroids in cycles 3 and 4 by 92.8% relative to current standard of care.

A Phase 1 Dose-Escalation Trial of Radiation Therapy and Concurrent Cisplatin for Stage II and III Triple-Negative Breast Cancer.

PURPOSE: Patients with triple-negative breast cancer (TNBC) experience higher local-regional recurrence rates than those with luminal or HER2-positive tumors. This prospective, phase 1B trial was designed to assess the safety and to establish the maximum tolerated dose (MTD) of cisplatin with radiation therapy for women with early-stage TNBC. METHODS AND MATERIALS: Eligible patients had stage II or III TNBC. Cisplatin was initiated at 10 mg/m2 intravenously once weekly during radiation and then escalated in a 3 + 3 design by 10 mg/m2 at each dose level until 40 mg/m2, or the MTD, was reached. Patients undergoing breast-conserving therapy (BCT) or mastectomy were accrued in separate parallel cohorts during dose escalation, followed by a 10-patient expansion at the MTD. RESULTS: During 2013 to 2018, 55 patients were accrued. Four patients developed dose-limiting toxicity. In the BCT cohort, 1 patient receiving 40 mg/m2 developed tinnitus resulting in a cisplatin delay; therefore, this was the BCT cohort MTD. In the mastectomy cohort, 1 patient receiving 20 mg/m2 developed a grade 3 urinary infection, and 2 additional patients had dose-limiting toxicities at 40 mg/m2 (grade 3 neutropenia and grade 2 tinnitus), both resulting in cisplatin delay. Thus, 30 mg/m2 was the mastectomy cohort MTD. Median follow-up was 48.5 months. Three-year disease-free survival was 74.7% for the BCT cohort and 64.4% for the mastectomy cohort. CONCLUSIONS: Adjuvant radiation therapy with concurrent cisplatin is feasible with a recommended phase 2 dose of 30 mg/m2 and 40 mg/m2 intravenously weekly in mastectomy and BCT cohorts, respectively.

Avoiding Peg-Filgrastim Prophylaxis During the Paclitaxel Portion of the Dose-Dense Doxorubicin-Cyclophosphamide and Paclitaxel Regimen: A Prospective Study.

PURPOSE: The use of growth factors adds considerable expense and some toxicity to adjuvant breast cancer chemotherapy. We tested the feasibility and safety of omitting routine peg-filgrastim use during the paclitaxel portion of the dose-dense doxorubicin-cyclophosphamide-paclitaxel regimen. PATIENTS AND METHODS: This was a prospective, single-arm study in which patients 18 to 65 years of age who completed 4 cycles of dose-dense doxorubicin-cyclophosphamide for stage I-III breast cancer received paclitaxel 175 mg/m2 every 2 weeks. Peg-filgrastim was administered after paclitaxel only if patients had had febrile neutropenia in a prior cycle or at investigator discretion if patients had infections or treatment delays of > 1 week. Once a patient received peg-filgrastim, it was administered in all future cycles. The primary end point was the rate of paclitaxel completion within 7 weeks from cycle 1 day 1 to cycle 4 day 1. If ≥ 100 out of 125 patients completed 4 cycles of paclitaxel without dose delay, the regimen would be considered feasible. RESULTS: The enrollment goal of 125 patients was met. Median age was 46 years (range, 21-65 years), and 112 patients (90% [95% CI, 83% to 94%]) completed dose-dense paclitaxel within 7 weeks. Omission of peg-filgrastim was not causally related to noncompletion of paclitaxel in any patients. The most common reasons for dose reduction or delays were nonhematologic. One patient experienced febrile neutropenia but was able to complete paclitaxel on time. Eight patients (6.4%) received peg-filgrastim during the trial. Overall, peg-filgrastim was administered in only 4.3% of paclitaxel cycles. CONCLUSION: Omission of routine peg-filgrastim during dose-dense paclitaxel according to a prespecified algorithm seems to be safe and feasible and was associated with a 95.7% reduction in the use of peg-filgrastim relative to the current standard of care.

Ribociclib Plus Trastuzumab in Advanced HER2-Positive Breast Cancer: Results of a Phase 1b/2 Trial.

BACKGROUND: Signaling through the cyclin-dependent kinase 4 and 6 (CDK4/6) pathway can mediate therapeutic resistance in HER2-positive breast cancer. Preclinical studies have demonstrated that CDK4/6 inhibitors can resensitize resistant HER2-positive breast cancer to anti-HER2 therapies. PATIENTS AND METHODS: We conducted a phase 1b/2 study of ribociclib (400 mg per day on a continuous schedule) plus trastuzumab (6 mg/kg every 3 weeks) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine. There were no restrictions on the number of prior therapy lines. Primary objective was clinical benefit rate at 24 weeks, and secondary objectives included safety, objective response, rate and progression-free survival. The study was enrolled at ClinicalTrials.gov as NCT02657343. RESULTS: From March 2016 to March 2017, 13 patients were enrolled. One patient was found to have HER2-negative disease and did not receive treatment. Median number of prior lines in the metastatic setting was 5 (range, 0-14); 67% had hormone receptor-positive disease. No dose-limiting toxicities were observed during the safety run-in phase, and ribociclib was thus dosed at 400 mg per day continuously for the expansion cohort. Grade 3 adverse events were observed in 4 patients (33.3%) and included neutropenia (n = 2) as well as fatigue and pain in 1 patient each. No grade 4/5 adverse events or QTc prolongation were observed. One patient (8.3%) experienced stable disease > 24 weeks; no objective responses were observed, and median progression-free survival was 1.33 months (95% confidence interval, 0.92-2.57). CONCLUSION: Continuous low-dose ribociclib (400 mg) plus trastuzumab is safe, with no new safety concerns. The limited activity observed in this study suggests that further study of CDK4/6 inhibitor/anti-HER2 combinations should focus on a less pretreated population.

Appetite for change: a multidisciplinary team approach to behavioral modification for weight management in a community health group setting.

PURPOSE: Obesity is a growing issue in Australia with limited evidence for brief community based intervention. This preliminary study aimed to investigate the long term effects of a 4-week group based multidisciplinary behavior management program for weight loss in the community health setting. METHOD: A quasi-experimental study design was employed recruiting patients referred to two Community Health Centers. Participants completed a 4-week Appetite for change program, comprising four 2-h group sessions co-facilitated by a multidisciplinary team. The mindfulness self efficacy scale (MSES), quality of life scale (QoL), and self-reported knowledge and stages of change were measured pre-treatment, immediately post-treatment and, 6 and 12 months post-treatment. Weight and waist circumference were additionally measured at baseline, 6 and 12 months post-treatment. RESULTS: Eighty participants (mean age 63 ± 12.1 years) comprising 73 % women consented to participate. Statistically significant improvements (p ≤ 0.01) from pre-treatment were found at both 6 and 12 months, with a clinically significant mean percentage weight loss of approximately 4 %, and a mean improvement of 8.5 point on QoL at 12 months follow-up. Self-reported improvements in stages of change and knowledge were also maintained at 12 months. CONCLUSION: Clinically and statistically significant long term improvements in all outcomes were found following a multidisciplinary brief intervention program for overweight/obese adults in the community health setting. The promising results following the Appetite for Change program warrant further controlled investigation.