A phase Ib/II study of eribulin in combination with cyclophosphamide in patients with advanced breast cancer.

PURPOSE: We hypothesized that eribulin combined with cyclophosphamide (EC) would be an effective combination with tolerable toxicity for the treatment of advanced breast cancer (ABC). METHODS: Patients with histologically confirmed metastatic or unresectable ABC with any number of prior lines of therapy were eligible to enroll. In the dose escalation cohort, dose level 0 was defined as eribulin 1.1 mg/m2 and cyclophosphamide 600 mg/m2, and dose level 1 was defined as eribulin 1.4 mg/m2 and cyclophosphamide 600 mg/m2. Eribulin was given on days 1 and 8 and cyclophosphamide on day 1 of a 21-day cycle. In the dose expansion cohort, enrollment was expanded at dose level 1. The primary objective was clinical benefit rate (CBR), and secondary objectives were response rate (RR), duration of response (DOR), progression-free survival (PFS), and safety. RESULTS: No dose-limiting toxicities were identified in the dose escalation cohort (n = 6). In the dose expansion cohort, an additional 38 patients were enrolled for a total of 44 patients, including 31 patients (70.4%) with hormone receptor-positive (HR +)/HER2- disease, 12 patients (27.3%) with triple-negative breast cancer (TNBC), and 1 patient (2.3%) with HR + /HER2 + disease. Patients had a median age of 56 years (range 33-82 years), 1 prior line of hormone therapy (range 0-6), and 2 prior lines of chemotherapy (range 0-7). CBR was 79.5% (35/44; 7 partial response, 28 stable disease) and the median DOR was 16.4 weeks (range 13.8-21.1 weeks). Median PFS was 16.4 weeks (95% CI: 13.8-21.1 weeks). The most common grade 3/4 adverse event was neutropenia (47.7%, n = 21). Fourteen of 26 patients (53.8%) with circulating tumor cell (CTC) data were CTC-positive ([Formula: see text] 5 CTC/7.5 mL) at baseline. Median PFS was shorter in patients who were CTC-positive vs. negative (13.1 vs 30.6 weeks, p = 0.011). CONCLUSION: In heavily pretreated patients with ABC, treatment with EC resulted in an encouraging CBR of 79.5% and PFS of 16.4 weeks, which compares favorably to single-agent eribulin. Dose reduction and delays were primarily due to neutropenia. The contribution of cyclophosphamide to eribulin remains unclear but warrants further evaluation. NCT01554371.

Crofelemer for the Management of Neratinib-Associated Diarrhea in Patients With HER2+ Early-Stage Breast Cancer.

BACKGROUND: To evaluate the efficacy of crofelemer, a first in class anti-secretory anti-diarrheal agent, to manage neratinib-induced diarrhea in patients with early-stage breast cancer taking adjuvant neratinib. PATIENTS AND METHODS: This single center, open label trial enrolled patients with Stage 2 to 3 HER2+ breast cancer taking adjuvant neratinib. One cohort took prophylactic crofelemer 125 mg bid and loperamide in the first 2 cycles, and as needed in subsequent cycles. The second cohort took dose-escalated neratinib with loperamide as needed (DE cohort). The primary endpoint was incidence of grade ≥ 3 diarrhea in the first 2 cycles. RESULTS: Seven patients in the crofelemer cohort and 4 in the DE cohort were enrolled. In the first 2 cycles, 2 patients (29%) in the crofelemer cohort and 2 patients (50%) in the DE cohort experienced grade 3 diarrhea lasting 1 day on average. After cycle 2, no additional patients in either cohort had grade 3 diarrhea. Five of 7 patients controlled diarrhea with crofelemer alone. There were no grade 4 diarrhea events in either cohort. Three patients in the crofelemer cohort dose-reduced neratinib due to diarrhea in the first 2 cycles. Patients in the crofelemer cohort had an average of 0.58 diarrhea episodes/day. 82% experienced constipation, all grade 1. CONCLUSIONS: This is the first study to investigate crofelemer for neratinib-induced diarrhea and demonstrates crofelemer activity in this setting. Further investigation of crofelemer for diarrhea secondary to cancer treatment is needed.

Evaluation of the Pathways for Survivors Program to Address Breast Cancer Survivorship-Associated Distress: Survey Study.

BACKGROUND: Patients with breast cancer frequently experience escalation of anxiety after completing curative treatment. OBJECTIVE: This study evaluated the acceptability and psychological impact of a 1-day workshop to emphasize behavioral strategies involving intention and self-efficacy. METHODS: Breast cancer survivors who attended a 1-day Pathways for Survivors workshop provided feedback and completed electronic quality of life (QOL) questionnaires at baseline, 1 and 6 weeks, and 6 months after the workshop. Attendees' baseline QOL scores were compared to follow-up (FUP) scores. Scores from patients receiving routine FUP care were also compiled as a reference population. RESULTS: In total, 77 patients attended 1 of 9 workshops. The mean satisfaction score was 9.7 out of 10 for the workshop and 9.96 out of 10 for the moderator. Participants' baseline mean Patient-Reported Outcomes Measurement Information System (PROMIS) anxiety and depression scores were 57.8 (SD 6.9) and 55.3 (SD 7.5), respectively, which were significantly higher than those of patients receiving routine FUP care (49.1, SD 8.3 and 47.3 SD 8.0, respectively). PROMIS anxiety and depression scores decreased, and the Happiness Index Profile (HIP-10) score-measuring intention and resiliency-increased significantly at 1- and 6-week FUPs. CONCLUSIONS: The Pathways for Survivors program was favorably received. Anxiety and depression decreased significantly at 1- and 6-weeks after the workshop and remained below baseline at 6 months. Increased HIP-10 scores suggest that patients acquired and implemented skills from the workshop. A 1-day workshop led by a lay moderator significantly improved several psychological measures, suggesting that it may be a useful and time-efficient strategy to improve QOL in breast cancer survivors. We are investigating whether an abbreviated "booster" of the intervention at a later date could further improve and maintain QOL gains.

Fitbit Usage in Patients With Breast Cancer Undergoing Chemotherapy.

BACKGROUND: Many patients' activity levels decrease during chemotherapy. Wearable devices, such as Fitbits, track activity patterns and may encourage behavior change. This study aimed to determine the utility of using Fitbits to measure physical activity and sleep throughout chemotherapy. PATIENTS AND METHODS: Patients with early stage breast cancer were enrolled prior to starting chemotherapy. Patients received a Fitbit Charge HR and were instructed to wear it and sync at least weekly throughout chemotherapy and up to 6 months post therapy. Patients completed baseline surveys, and treatment information was collected from their medical records. Fitbit data was downloaded from the Fitabase data management platform. To assess utility, we evaluated how many days patients wore their Fitbit for at least 10 hours. RESULTS: Adherence to wearing the Fitbit was low, with 16.9% of patients never syncing their device. For those who did sync, the mean number of valid days (> 10 hours of use) across the 9-month study period was 44.5% (SD, 36.9%), and the median was 39.6%, with a range of 0% to 100% of the total study days. Adherence was higher among participants receiving adjuvant chemotherapy versus neoadjuvant chemotherapy (51.9% vs. 29.6% valid days, respectively [P = .037]). Baseline questions indicating positive attitudes toward technology were significantly correlated with higher adherence. CONCLUSIONS: Fitbit use during breast cancer chemotherapy was poor in the absence of prompts to encourage wear. Interventions including phone calls, texts, or other reminders to maintain adherence are likely necessary to increase wear in active treatment settings.

A phase 1b study of the Akt-inhibitor MK-2206 in combination with weekly paclitaxel and trastuzumab in patients with advanced HER2-amplified solid tumor malignancies.

PURPOSE: Akt plays a key role in the aggressive pathogenesis of HER2+ malignancies, suggesting that Akt-inhibitors may be of therapeutic value in the treatment of HER2+ tumors. Preclinical studies demonstrate synergy between MK-2206, a selective allosteric Akt-inhibitor, with paclitaxel and trastuzumab. We aimed to evaluate the safety of this combination in patients with HER2+ malignancies. METHODS: We conducted a phase 1b study of weekly MK-2206 in combination with weekly paclitaxel 80 mg/m(2) and trastuzumab 2 mg/kg in patients with HER2+ malignancies. Dose escalation was performed using a modified toxicity probability interval method. Molecular profiling of archived tissue samples and limited PK analyses were performed. RESULTS: 16 patients with HER2+ tumors were enrolled (12 breast, 3 gastric, 1 esophageal). 81 and 75 % had received prior trastuzumab and taxane chemotherapy, respectively. MK-2206 135 mg/week was determined to be tolerable. Three dose-limiting toxicities were observed including two grade 3 rashes and 1 grade 3 neutropenia resulting in a > 7 day delay in treatment. Grade 3/4 adverse events include neutropenia (44 %), rash (13 %), peripheral neuropathy (6 %), and depression (6 %). 10 patients (63 %) demonstrated tumor response (3 complete, 7 partial). Median duration of response was 6 months. Exploratory analyses identified STARD3, TM7SF2, and G3BP1 as potential biomarkers of response. CONCLUSIONS: MK-2206 at a dose of 135 mg/week in combination with weekly paclitaxel and trastuzumab is safe and well tolerated, and is the recommended phase 2 dose for this combination. Preliminary data indicate significant clinical activity in patients with HER2+ tumors despite prior HER2-directed therapy.