Erhan Berrak

A Post Hoc Sensitivity Analysis of Survival Probabilities in a Multinational Phase III Trial of Decitabine in Older Patients With Newly Diagnosed Acute Myeloid Leukemia

BACKGROUND In a multicenter, randomized, open-label phase III study, patients ≥ 65 years with newly diagnosed AML received decitabine 20 mg/m(2) once daily for 5 days every 4 weeks (n = 242) or treatment choice (supportive care or cytarabine 20 mg/m(2) once daily for 10 days every 4 weeks; n = 243). Decitabine use demonstrated greater response rates (P = .001) and OS data favored decitabine. PATIENTS AND METHODS In a post hoc sensitivity analysis of mature data of patients in the intent-to-treat population (N = 485), OS at 3, 6, 12, 18, and 24 months after randomization was estimated for each arm using Kaplan-Meier methods. Age, cytogenetic risk, and Eastern Cooperative Oncology Group performance status were used as stratification factors in the Cox regression model to estimate the hazard ratio. RESULTS A survival advantage was seen with decitabine at each cutoff time point; hazard ratios for OS for decitabine vs. treatment choice were 0.83, 0.71, 0.83, 0.80, and 0.79 at 3, 6, 12, 18, and 24 months, respectively. A trend toward improved OS with decitabine was observed at fixed time points over 2 years. CONCLUSION Decitabine should be considered as a treatment option for older patients with AML and poor prognostic risk factors.

Phase II, Multicenter, Single-Arm, Feasibility Study of Eribulin Combined With Capecitabine for Adjuvant Treatment in Estrogen Receptor-Positive, Early-Stage Breast Cancer

BACKGROUND The present phase II, open-label, multicenter study explored the feasibility, safety, and tolerability of eribulin, a novel non-taxane microtubule inhibitor, plus capecitabine as adjuvant therapy. PATIENTS AND METHODS Postmenopausal women with early-stage, human epidermal growth factor receptor 2 (HER2)-negative, estrogen-receptor (ER)-positive breast cancer received four 21-day cycles of treatment with eribulin mesylate (1.4 mg/m(2) intravenously on days 1 and 8 of each cycle) combined with capecitabine (900 mg/m(2) orally twice daily on days 1-14 of each cycle [standard schedule] or 1500 mg orally twice daily using a 7-days on/7-days off schedule [weekly schedule]). Feasibility was determined by the relative dose intensity (RDI) of the combination using prespecified criteria for 80% of patients achieving an RDI of ≥ 85%, with a lower 95% confidence boundary > 70%. RESULTS The mean RDI was 90.6%, and the feasibility rate was 81.3% among women (n = 67, mean age, 61.3 years) receiving the standard schedule and 95.6% and 100% among women (n = 10, mean age 62.3 years) receiving the weekly schedule. Dose reductions, missed doses, and withdrawals due to adverse events (most commonly hand-foot syndrome) ascribed to capecitabine led to a higher RDI (93.5% vs. 87.8%) and feasibility rate (82.8% vs. 71.9%) for eribulin than for capecitabine using the standard dosing schedule. The most common adverse events were alopecia and fatigue. CONCLUSION Eribulin plus capecitabine with standard or weekly dosing schedules is feasible in patients with early-stage, HER2-negative, ER-positive breast cancer. Full-dose eribulin (1.4 mg/m(2) on days 1 and 8) with capecitabine (1500 mg orally twice daily, 7 days on/7 days off) is recommended as a regimen for further evaluation.

Post hoc analysis of the relationship between baseline white blood cell count and survival outcome in a randomized phase iii trial of decitabine in older patients with newly diagnosed acute myeloid leukemia

Background In a Phase III trial, 485 patients (≥65 years) with newly diagnosed acute myeloid leukemia received decitabine 20 mg/m2 intravenously for 5 days every 4 weeks or a treatment choice (supportive care or cytarabine 20 mg/m2 subcutaneously for 10 days every 4 weeks). Materials and methods We summarized overall and progression-free survival by baseline white blood cell count using two analyses: <1, 1–5, >5×109/L; ≤10 or >10×109/L. Results There were 446 deaths (treatment choice, n=227; decitabine, n=219). Median overall survival was 5.0 (treatment choice) versus 7.7 months (decitabine; nominal P=0.037). Overall survival differences between white blood cell groups were not significant; hazard ratios (HRs) favored decitabine. Significant progression-free survival differences favored decitabine for groups 1–5×109/L (P=0.005, HR =0.67), greater than 5×109/L (P=0.027, HR =0.71), and up to 10×109/L (P=0.003, HR =0.72). Conclusion There was a trend toward improved outcome with decitabine, regardless of baseline white blood cell count.

Association between Treatment Response and Potential Indicators of Efficacy and Safety in a Phase III Trial of Decitabine in Older Patients with Acute Myeloid Leukemia

Objective: In a phase III trial, 485 patients aged 65 years or older with newly diagnosed acute myeloid leukemia received decitabine (20 mg/m2 intravenously for 5 days) or treatment of choice (supportive care or cytarabine 20 mg/m2 subcutaneously for 10 days) every 4 weeks. This post hoc analysis investigated potential efficacy and safety indicators and treatment response. Methods: Transfusions, intravenous antibiotics, and dose modifications were tabulated for responders (morphologic complete remission, complete remission with incomplete blood count recovery, or partial response) and nonresponders. Results: Median overall survival was significantly greater for treatment responders than for nonresponders (17.4 months vs 4.3 months; P<0.0001). Nonresponders had more intravenous antibiotic use (P=0.024), dose modifications per cycle (P=0.016), and platelet or red blood cell transfusions per cycle (P<0.0001). Conclusions: Response to decitabine or to treatment of choice may be associated with certain indicators in older patients with acute myeloid leukemia.

Safety and tolerability of eribulin mesylate in patients with pretreated metastatic breast cancer

PURPOSE The safety and tolerability of eribulin mesylate for the treatment of metastatic breast cancer (MBC) are examined. METHODS This retrospective analysis used pooled safety and tolerability data from three Phase II trials and one Phase III trial of eribulin in patients with MBC. In these studies, patients with pretreated MBC received eribulin mesylate 1.4 mg/m(2) as a two- to five-minute i.v. infusion on days 1 and 8 of a 21-day cycle. Adverse events were assessed according to the Common Terminology Criteria for Adverse Events, version 3.0. RESULTS Across the four trials, 908 patients received eribulin and were assessed for safety. Aside from anthracyclines and taxanes, the most common prior chemotherapy agents were capecitabine, vinorelbine, and gemcitabine. Patients had received a mean of 3.7 (range, 1-11) prior chemotherapeutic regimens. Dose delays, reductions, and interruptions due to treatment-emergent adverse events occurred in 35.0%, 17.3%, and 2.9% of patients, respectively. Treatment was discontinued in 12.3% of patients due to adverse events, regardless of whether the adverse event was considered treatment related. The most common grade 3 or 4 treatment-related adverse events were neutropenia (52.4%) and leukopenia (19.3%). Serious adverse events occurred in 26.1% of patients, with the most common being febrile neutropenia (3.6%) and pyrexia (2.3%). Peripheral neuropathy was seen in 30.6% of patients, with 6.6% experiencing grade 3 or 4 reactions. CONCLUSION Despite heavy pretreatment with anthracyclines, taxanes, and capecitabine, eribulin was well tolerated in this pooled analysis of patients with MBC.

Clinical effects of prior trastuzumab on combination eribulin mesylate plus trastuzumab as first-line treatment for HER2+ locally recurrent or metastatic breast cancer (MBC): Results from a phase 2, single-arm, multicenter study.

139 Background: Eribulin mesylate, a novel nontaxane microtubule dynamics inhibitor in the halichondrin class of antineoplastic drugs, is indicated for women with MBC who previously received ≥ 2 chemotherapy regimens in the metastatic setting. Primary data from a phase 2 trial on first-line combination eribulin + trastuzumab (TRAS) in HER2+ patients (pts) showed a 71% objective response rate (ORR) and tolerability consistent with the known profile of these agents. Here we present prespecified endpoint data for this study by prior TRAS use. METHODS Pts with HER2+ MBC who had not received prior chemotherapy for MBC received eribulin mesylate 1.4 mg/m2 IV on days 1 and 8 of each 21-day cycle and initial TRAS (8 mg/kg IV/day 1), followed by 6 mg/kg/day 1 of each subsequent cycle. Response, progression-free survival (PFS), and tolerability were assessed in patients who had and had not received prior TRAS treatment. RESULTS The 52 pts (median age, 59.5 years) received combination eribulin + TRAS, for a median treatment duration of ~30 weeks; 40% (n=21) were previously treated with TRAS in the neo-adjuvant/adjuvant setting. There was median of 23 months since completion of adjuvant treatment prior to retreatment with eribulin + TRAS for first-line MBC.Efficacy, assessed by ORR, clinical benefit rate (CBR), PFS, and duration of response (DOR), was largely consistent in pts who received prior TRAS relative to pts who had not received prior TRAS (see table). Overall, grade (G) 3-5 adverse events (AEs), treatment-related AEs (TRAEs), and discontinuations (d/c) were similar between groups (Table). CONCLUSIONS In this phase 2 single-arm trial in pts with HER2+ MBC, eribulin + TRAS demonstrated activity and was well tolerated as first-line treatment, irrespective of prior (neo) adjuvant TRAS treatment. CLINICAL TRIAL INFORMATION NCT01269346. [Table: see text].

Abstract P1-12-05: Phase 2 study of dose-dense doxorubicin and cyclophosphamide followed by eribulin mesylate with or without prophylactic growth factor for adjuvant treatment of early-stage breast cancer

Background : Eribulin has demonstrated antitumor activity and significantly improved overall survival (OS) in patients (pts) with heavily pretreated locally advanced/metastatic breast cancer (BC). This trial assessed the feasibility of eribulin as adjuvant therapy following dose-dense doxorubicin and cyclophosphamide (AC) for pts with human epidermal growth factor receptor 2 (HER2)-negative early-stage BC. Methods : Pts with HER2(-), stage I–III, invasive BC were enrolled. Pts received dose-dense AC (doxorubicin 60 mg/m2 IV and cyclophosphamide 600 mg/m2 IV) on D1 of each 14-day cycle for 4 cycles with pegfilgrastim, followed by 4 cycles of eribulin (1.4 mg/m2 IV) on D1 and D8 every 21 days. Pts were divided into 2 cohorts: Cohort 1 did not receive any prophylactic growth factor (GF); Cohort 2 received a short course of prophylactic GF (filgrastim) on days 3, 4, 10, and 11 of each eribulin cycle. Primary endpoint of feasibility was determined as %pts who completed eribulin portion of the regimen without a dose delay (>2 days) or reduction due to eribulin-related adverse event (AE). Based on similar previous studies, the target for feasibility was 80%. Relative dose intensity of eribulin and toxicities were also summarized by cohort. Exploratory objectives include efficacy endpoints of 3-yr disease-free survival and OS. Results : We report data from 81 pts (55 Cohort 1; 26 Cohort 2) enrolled in the study, of whom 88% completed study treatment. Pt characteristics include median age 49 yrs (range 26–69), ECOG status 0 (85%), BC stages 1/2/3 (21%/57%/22%). Of 90% (73/81) pts evaluable for feasibility, 27% and 40% of pts in Cohorts 1 and 2, respectively, had dose delay or reduction during eribulin treatment, indicating the primary endpoint was not met. Overall, results were similar between the 2 cohorts (Table). Median duration of treatment with eribulin was 10.14 weeks in both cohorts (vs 10 weeks planned). Most eribulin-related dose delays were due to grade 3 (n=18) or grade 4 (n=7) neutropenia. Non-fatal serious AEs were observed in 11% of pts in Cohort 1 and 15% in Cohort 2. Discontinuations due to AEs occurred in 6% of pts in Cohort 1 and 0 in Cohort 2. Neutropenia (all grades) was reported in 36% of pts in Cohort 1 and 42% in Cohort 2. Most common AEs (all grades) were fatigue (96%), nausea (75%), alopecia (73%), hot flush (63%), and constipation (57%). Conclusions : The primary study endpoint of >80% feasibility of planned dose delivery without any dose delays or reduction was not met. However, adjuvant treatment with dose-dense AC-eribulin was given safely, with two-thirds (67%) of pts achieving full dosing with no dose delay or reduction. Investigation into alternative dosing schedules or GF support is recommended. Citation Format: Cadoo K, Kaufman PA, Hudis C, Chang C, Berrak E, Song J, Seidman AD, Traina TA. Phase 2 study of dose-dense doxorubicin and cyclophosphamide followed by eribulin mesylate with or without prophylactic growth factor for adjuvant treatment of early-stage breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-12-05.

Clinical effects of prior trastuzumab on combination eribulin mesylate plus trastuzumab as first-line treatment for human epidermal growth factor receptor 2 positive locally recurrent or metastatic breast cancer: Results from a Phase II, single-arm, multicenter study

Eribulin mesylate, a novel nontaxane microtubule dynamics inhibitor in the halichondrin class of antineoplastic drugs, is indicated for the treatment of patients with metastatic breast cancer who previously received ≥2 chemotherapy regimens in the metastatic setting. Primary data from a Phase II trial for the first-line combination of eribulin plus trastuzumab in human epidermal growth factor receptor 2 positive patients showed a 71% objective response rate and tolerability consistent with the known profile of these agents. Here, we present prespecified analyses of efficacy of this combination based on prior trastuzumab use. Patients received eribulin mesylate 1.4 mg/m2 (equivalent to 1.23 mg/m2 eribulin [expressed as free base]) intravenously on days 1 and 8 plus trastuzumab (8 mg/kg intravenously/cycle 1, then 6 mg/kg) on day 1 of each 21-day cycle. Objective response rates, progression-free survival, and tolerability were assessed in patients who had and had not received prior adjuvant or neoadjuvant (neo/adjuvant) trastuzumab treatment. Fifty-two patients (median age: 59.5 years) received eribulin/trastuzumab for a median treatment duration of ~31 weeks; 40.4% (n=21) had been previously treated with neo/adjuvant trastuzumab prior to treatment with eribulin plus trastuzumab for metastatic disease (median time between neo/adjuvant and study treatment: 23 months). In trastuzumab-naïve patients (n=31) compared with those who had received prior trastuzumab, objective response rate was 77.4% versus 61.9%, respectively; duration of response was 11.8 versus 9.5 months, respectively; clinical benefit rate was 87.1% versus 81.0%, respectively; and median progression-free survival was 12.2 versus 11.5 months, respectively. The most common grade 3/4 treatment-emergent adverse events (occuring in ≥5% of patients) in patients who received prior trastuzumab versus trastuzumab naïve patients, respectively, were neutropenia (47.6% vs 32.3%), peripheral neuropathy (14.3% vs 25.8%), febrile neutropenia (14.3% vs 3.2%), fatigue (9.5% vs 6.5%), nausea (9.5% vs 0%), vomiting (9.5% vs 3.2%), and leukopenia (9.5% vs 3.2%). In patients with human epidermal growth factor receptor 2 positive metastatic breast cancer, first-line eribulin/trastuzumab treatment demonstrated substantial antitumor activity and was well tolerated, regardless of prior neo/adjuvant trastuzumab treatment.

Abstract P3-09-09: Eribulin mesylate plus capecitabine for adjuvant treatment in post-menopausal ER+ early-stage breast cancer: A phase 2, multicenter, open-label study using 2 different dosage regimens

Introduction: Eribulin mesylate is a novel non-taxane microtubule inhibitor. The primary objective of this study was to explore feasibility of administering eribulin plus capecitabine as adjuvant therapy in subjects with early-stage, estrogen receptor-positive (ER+) breast cancer. Methods: In this phase 2, open-label, multicenter study, 67 postmenopausal women with early HER2-normal/HER2-negative, ER+ breast cancer received four 21-day cycles of treatment with eribulin mesylate (1.4 mg/m 2 IV on day 1 and day 8 of each cycle) in combination with capecitabine (900 mg/m 2 orally twice daily on days 1 through 14 of each cycle). A second dosage regimen for capecitabine was initiated after dose reductions and treatment discontinuations were noted and attributed to capecitabine-related toxicities, such as grade 3/4 GI events and hand-foot syndrome. As a consequence, capecitabine was administered to an additional cohort of 10 subjects at a fixed dose of 1500 mg given orally twice daily on a 7 days on/7 days off schedule for the 4 cycles; eribulin mesylate was administered on the same dosage schedule as the original regimen (1.4 mg/m 2 IV on day 1 and day 8 of each cycle). The 7 days on/7 days off regimen for capecitabine was based on mathematical modeling and has been shown to have an acceptable toxicity profile, including minimal gastrointestinal toxicity, when given in combination with bevacizumab to patients with metastatic breast cancer. Feasibility was assessed based on relative dose intensity (RDI) of the combination using prespecified criteria of 80% of subjects achieving an RDI of at least 85% of the regimen with lower 95% confidence boundary >70%; safety and tolerability were also assessed. Results: Among subjects on the original eribulin plus capecitabine dosing schedule (n=64), the average (SD) RDI was 90.6% (11.94%) and the feasibility rate was 81.3% (95% lower CI: 71.4%), indicating that this dosage regimen is feasible. Dose reductions, missed doses, and withdrawals due to adverse events were ascribed more to capecitabine (36%, 85%, and 18%, respectively) than to eribulin (21%, 8%, and 12%, respectively), which led to higher RDI and feasibility rates for eribulin (93.5% and 82.8%, respectively) than for capecitabine (87.8% and 71.9%). Grade 3/4 hand-foot syndrome ascribed to capecitabine only, led to dose reductions in 11.9% of subjects under the original dosing schedule. The most common adverse events under the original dosing schedule were alopecia (77.6%), fatigue (58.2%), and nausea (52.2%). With the new dosing schedule (n=9), higher RDI and feasibility rates were achieved, the average RDI was 96% and the feasibility rate was 100%, indicating that this alternative regimen is also feasible, and probably better. (Detailed feasibility and safety data with new dosing regimen will be available at the time of the presentation.) Conclusions: Adjuvant use of the combination of eribulin plus capecitabine is feasible in patients with early, HER2-normal/HER2-negative, ER+ breast cancer. The combination had an acceptable safety profile under the original dosing schedule and has the potential to be improved by use of a 7 day on/7 day off regimen of capecitabine. Citation Format: John W Smith II, Svetislava Vukelja, Anthony Hoffman, Vicky Jones, Kristi McIntyre, Erhan Berrak, Angela Teng, David Cox, Joyce O9Shaughnessy. Eribulin mesylate plus capecitabine for adjuvant treatment in post-menopausal ER+ early-stage breast cancer: A phase 2, multicenter, open-label study using 2 different dosage regimens [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-09-09.

Abstract P5-17-02: Quality of life in patients receiving first-line eribulin mesylate for HER2- locally recurrent or MBC

Introduction: Eribulin mesylate is a nontaxane microtubule inhibitor approved to treat MBC in patients (pts) who previously received ≥2 chemotherapeutic regimens for MBC. A phase 2 study of first-line eribulin for HER2-negative (HER2-) MBC showed an overall response rate of 29%, median 6.8 m progression-free survival, and tolerability consistent with earlier studies. We present prespecified quality of life (QoL) results for this trial. Methods: Pts (N=56) received eribulin mesylate 1.4 mg/m 2 IV on days 1 and 8 of each 3-wk cycle (median: 7 cycles). QoL was assessed using the EORTC QoL assessment (QLQ-C30) and a breast-cancer specific questionnaire (QLQ-BR23) pretreatment (baseline) and on day 1 of every other cycle during treatment. Percentage of pts with at least ±10-point change from baseline was summarized descriptively. Linear mixed-effects models were used to evaluate changes over time and compare responders vs nonresponders controlling for baseline score and time effect. Time-to-event analysis was performed on time to deterioration, defined as time from 1st dose to 1st occurrence of worsening in QoL score that reached minimally clinically important difference (MID; eg, 10 points in global health status in QLQ-C30) from baseline without further improvement of at least MID. Results: For QLQ-C30 at cycle 6 (n=29), more pts had at least a 10-point improvement from baseline in role, emotional, and social functioning; fatigue, nausea/vomiting, pain, dyspnea, and insomnia item scores, than had worsening. More pts had worsening in global health status/QoL, cognitive functioning, and diarrhea (Table). Median time to deterioration in global health status/QoL was 5.06 m (responders, 8.54 m; nonresponders, 3.71 m; hazard ratio=0.60, P=0.22). In linear mixed models, responders (n=16) performed better than nonresponders (n=40) in role functioning (P=0.011), emotional functioning (P=0.031), fatigue (P=0.007), pain (P=0.047), insomnia (P=0.018), and appetite loss (P=0.032). Mean symptom scores were significantly correlated with corresponding adverse event rates for nausea and vomiting, dyspnea, appetite loss, constipation, and diarrhea; Spearman rank correlation coefficients ranged from 0.31 to 0.54. For QLQ-BR23 at cycle 6, symptom scores were mostly stable; more pts had worsening in body image and systemic therapy side effects than had improvement and more pts had improvement in breast and arm symptoms than had worsening. Responders also had longer time to symptom deterioration. Conclusions: In this study of first-line eribulin treatment for HER2- MBC, a majority of pts had stable or improvement in QoL scales. Responders to eribulin were more likely than nonresponders to have stable or improved QoL. Citation Format: Lee Schwartzberg, Kristi McIntyre, Joyce O9Shaughnessy, Stefan Gluck, Erhan Berrak, James Song, David Cox, Linda Vahdat. Quality of life in patients receiving first-line eribulin mesylate for HER2- locally recurrent or MBC [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-17-02.