Number Of Prior Chemotherapies Research Articles

Abstract PS08-09: Impact of HER2 expression dynamics on the real-world activity of trastuzumab deruxtecan for metastatic breast cancer (RELIEVE)

Abstract Background: trastuzumab deruxtecan (T-DXd) is a standard treatment for patients (pts) with HER2-positive (HER2+) and HER2-low metastatic breast cancer (MBC). HER2-low expression has been shown to be a highly unstable biomarker, and no data exists on the activity of T-DXd among pts with changes in HER2 status over time. Furthermore, limited data exists on the performance of regimens administered after progression on T-DXd. Methods: We analyzed data for pts with MBC receiving T-DXd at Dana-Farber Cancer Institute between 7/2017 - 2/2023 and at Duke Cancer Center between 3/2020 - 4/2022. The disease was categorized HER2+ if IHC 3+ or ISH-amplified at any time point; HER2-negative cases were categorized as HER2-low (IHC 2+/ISH- or IHC 1+) or HER2-0 (IHC 0) based on the last biopsy before T-DXd; the HER2 status for the primary tumor and at first metastatic diagnosis were also collected. We determined time to next treatment (TTNT), overall survival (OS), toxicities with T-DXd, TTNT based on dynamic HER2 status and TTNT with post-T-DXd regimens. Genomic data was available for 58 pts using an in-house NGS assay on archival tumor samples. Results: A total of 191 pts were included in the analysis (126 HER2+, 44 HER2-low, 21 HER2-0). Median age at metastatic diagnosis was 50.9 (range 21 - 78), 26% had de-novo MBC and 38% had history of brain metastases before T-DXd. The proportion of hormone receptor (HR)-positive tumors based on the last biopsy prior to T-DXd was 53% in HER2+, 68% in HER2-low and 57% in HER2-0; pts within each cohort had received a median of 2 prior lines of chemotherapy before T-DXd (range 0 - 9). With a median follow-up of 10.4 months, median TTNT was 10.4 months for HER2+, 7.6 months for HER2-low and 3.7 months for HER2-0 MBC (p < 0.001). Switch in HER2 status between primary tumor and pre-T-DXd biopsy significantly impacted outcomes, with the shortest TTNT observed in pts switching from HER2-low to HER2-0 (TTNT 3.0 months) compared with 5.6 months if switching from HER2-0 to HER2-low, and 9.4 months if having stable HER2-low status (p=0.006). Conversely, HER2 status switch within the metastatic setting did not impact outcomes (Table 1). No difference in TTNT was seen regardless of HR status (negative vs positive, 7.4 vs 10.2 months, p=0.25) or number of prior chemotherapies (≤2 vs >2, 10.1 vs 8.8 months, p=0.50). Median OS is shown in Table 1. At last follow-up, 55 pts remain on T-DXd (28.8%), 108 progressed (56.5%), 28 stopped due to toxicity (14.7%). A total of 22 pts (11.5%) developed interstitial lung disease (ILD, 6.2% grade [G]1, 3.1% G2, 1.6% G3, 0.5% G4, no G5). ILD occurred after a median of 8 months from T-DXd initiation and resolved in 63.6% of the cases, with a median time to resolution of 4 months (2 months for grade 1 events). 5 pts (2.6%) developed cardiotoxicity. T-DXd was dose reduced in 61 pts (31.9%), most often for fatigue (14.7%), nausea/vomiting (9.9%) or hematological toxicity (6.3%). Among 105 pts receiving post-T-DXd treatments, TTNT was 4 months for HER2+, 3.1 months for HER2-low and 4.3 months for HER2-0 MBC (p=0.62). Pts with HER2-negative tumors and ERBB2 hemizygous deletions (6/58, 10.3 %) had a TTNT with T-DXd of 4.1 months, vs 7.6 months without ERBB2 deletions (p=0.41). Additional biomarker data will be presented at the meeting. Conclusions: T-DXd showed promising real-world activity in pretreated pts with MBC, with the longest TTNT observed among pts with HER2+ disease or with stable HER2-low disease over time. Real world TTNT is relatively short post-T-DXd and further studies evaluating resistance mechanisms and optimal treatments in this setting are needed. Table 1 – TTNT and OS among patients with metastatic breast cancer receiving T-DXd and post-T-DXd regimens according to HER2 status The activity of T-DXd significantly differed according to the HER2 status of the disease, with the longest TTNT observed among patients with HER2+ disease (at any timepoint in time) and among patients with stable HER2-low disease over time. Regimens administered immediately after T-DXd achieved a similar performance irrespective of the HER2 status of the disease, with a TTNT ranging between 3.1 and 4.3 months. Citation Format: Paolo Tarantino, Melissa Hughes, Ross Kusmick, Laura Alder, Alyssa Pereslete, Laura Noteware, Heather Moore, Amanda Van Swearingen, Tianyu Li, Hersh Gupta, Kalie Smith, Stefania Morganti, Janet Files, Kerry Sendrick, Simone Buck, Deborah Dillon, Rinath Jeselsohn, Yvonne Li, Andrew Cherniack, Aleix Prat, Nay Nwe Nyein Chan, David Rimm, Giuseppe Curigliano, Sarah Sammons, Carey Anders, Nancy Lin, Sara Tolaney. Impact of HER2 expression dynamics on the real-world activity of trastuzumab deruxtecan for metastatic breast cancer (RELIEVE) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS08-09.

Event-free survival in relapsed and refractory rhabdomyosarcoma treated on cooperative group phase II trials: A report from the Children's Oncology Group.

Novel therapies are needed for relapsed and refractory rhabdomyosarcoma (RRMS). Phase II clinical trials in RRMS have typically utilized radiologic response as the primary activity endpoint, an approach that poses several limitations in RRMS. In this analysis, we aimed to estimate an event-free survival (EFS) endpoint for RRMS that could be used as a benchmark for future studies. We performed a retrospective study of patients with RRMS enrolling on 13 single-agent phase II Children's Oncology Group and legacy group trials from 1997 to 2016. All included trials used radiographic response as their primary activity endpoint. Six-month EFS was estimated from time of trial enrollment with 95% confidence intervals. Clinical characteristics, including trial of enrollment, sex, age, race, histology, number of prior chemotherapies, and radiographic response were evaluated for their impact on 6-month EFS. We identified 175 patients across 13 trials. The 6-month EFS was 16.8% (11.6%-22.8%). No differences were seen in 6-month EFS based on age, sex, race, or histology. There were nonsignificant trends toward improved 6-month EFS for patients with less than or equal to two prior lines of therapy versus higher than two, for patients enrolled on trials that achieved their primary radiographic response endpoint versus trials that did not, and for patients who achieved complete or partial response compared to those achieving stable disease. The prognosis of RRMS enrolled on single-agent phase II trials is poor. This pooled 6-month EFS of RRMS on single-agent trials may be used as a RRMS-specific benchmark for future single-agent phase II trials.

Impact of Lynch syndrome, BRAFV600E, and RAS mutations on outcomes in MSI/dMMR metastatic colorectal cancer (mCRC) treated with immune checkpoint inhibitors (ICI): Analysis of combined international cohorts.

171 Background: ICI have demonstrated efficacy in patients (pts) with MSI/dMMR mCRC . Lynch (LS) vs sporadic (Sp) status, BRAFV600E and RAS mutations (mt) are known factors of clinical and molecular heterogeneity in this population. We aimed to evaluate the prognostic value of these parameters in ICI-treated MSI mCRC pts. Methods: Pts are drawn from international cohorts (France, Italy, Spain, and USA). Pts were considered to have cancer linked to LS only in case of determined germline mutation and Sp in case of loss of MLH1/PMS2 protein expression associated with BRAF V600E mutation and/or hypermethylation of MLH1 promoter, or in case of biallelic somatic mutations of MMR genes. Survival analyses: progression-free survival (PFS) per iRECIST criteria and overall survival (OS) were adjusted on prognostic modifiers, selected on unadjusted analysis (p < 0.2) in case of limited number of events. Results: On the 466 pts included, 112 (24%) received ICI in first line, 305 (65%) received anti-PD1 alone, 161 (35%) anti-PD1 plus anti-CTLA4, 129 (29%) had BRAFV600Emt and 153 (34%) RASmt. Median follow-up was 24.0 months. In adjusted analysis of the whole population (n=466; 186 PFS events and 143 OS events), no association with PFS and OS was observed for BRAFV600E mt (PFS HR 1.20 [0.80 to 1.79], p=0.372; OS HR 1.06 [0.66 to 1.70], p= 0.811) and RASmt (PFS HR 0.93 [0.64 to 1.36], p= 0.712; OS HR 0.75 [0.48 to 1.17] p= 0.202). Adjusting factors were age, ECOG status, number of prior chemotherapies, treatment type (bi vs monotherapy), sidness (right vs left + rectum), primary tumor surgery. Concerning the population with determined Lynch status (n= 242; 83 PFS events and 54 OS events), PFS results are displayed. The analysis of impact of LS was not adjusted on BRAFV600E mutational status due to collinearity. In adjusted analysis, LS improved PFS compared with Sp (HR = 0.49, 95%CI (0.25 to 0.96), p = 0.036). Adjusted HR for OS was 0.56 without reaching significance 95%CI (0.25 to 1.22), p = 0.143. Conclusions: In this analysis of ICI-treated MSI/dMMR mCRC pts, RAS/BRAFV600E mutations are not associated with survival while Lynch syndrome pts demonstrated improved PFS. [Table: see text]

Abstract CT176: Phase 2 study of tazemetostat in Japanese patients with relapsed or refractory EZH2 mutation-positive B-cell Non-Hodgkin's Lymphoma

Abstract Background: Tazemetostat is a selective, reversible, small-molecule inhibitor of enhancer of zest homolog 2 (EZH2), a histone methyltransferase. EZH2 is the catalytic subunit of polycomb repressive complex 2, which methylates lysine 27 on histone 3 (H3K27). Recurrent gain-of-function alterations in EZH2 occur in approximately 30% of germinal center B-cell like diffuse large B-cell lymphoma (GCB-DLBCL) and 27% of follicular lymphoma (FL). The aim of this multicenter, open-label, Phase 2 study was to assess the efficacy and safety of tazemetostat in Japanese patients with relapsed or refractory B-cell Non-Hodgkin's Lymphoma (NHL) harboring the EZH2 mutation. Methods: Patients with histologically diagnosed FL (cohort 1) or DLBCL (cohort 2) were screened centrally for EZH2 mutation using the cobas EZH2 Mutation Test. Tazemetostat (800 mg BID) was administered orally for 28 days/cycle until disease progression, occurrence of unacceptable toxicity, or withdrawal of consent. The primary endpoint was the objective response rate (ORR) based on IWG-2007 by independent imaging review and safety was evaluated as the secondary endpoint. Results: Among the 20 eligible patients, 17 were enrolled in cohort 1, and 3 were enrolled in cohort 2. In cohort 1, the median number of prior chemotherapy was 2 (range 1-4) and the ORR was 76.5% , including 6 patients (35.3%) achieving a complete response and 7 patients (41.2%) achieving a partial response (PR) as of the data cutoff. The ORR in subjects who received prior treatment with bendamustine, rituximab, and CHOP was 87.5%, 76.9%, and 76.9%, respectively. All 3 patients in cohort 2 (100%) achieved PR. In cohort 1, 3 of the 17 subjects (17.6%) had progression-free survival (PFS) events. The median PFS was not reached. Estimated PFS rates at 12 and 15 months based on the Kaplan-Meier analysis were 94.1% and 73.2%, respectively. The median duration of response (DOR) was not reached, and the DOR rate at 9 and 12 months was 100% and 80.0%, respectively. The median time to response was 3.6 months. The most common grade-3 treatment emergent adverse event (TEAE) was lymphopenia (2 patients, 10.0%). Grade-4 TEAEs included hypertriglyceridemia and pneumonia aspiration (1 patient each, 5.0%). TEAEs leading to study drug discontinuation were reported by 4 of 20 (20.0%) patients, including fatigue (2 patients, 10.0%), atypical pneumonia, traumatic intracranial haemorrhage, non-small cell lung cancer, muscle spasticity, and dysgeusia (1 patient each, 5.0%), indicating that the safety profile was acceptable and manageable. Conclusion: Tazemetostat at a dose of 800 mg BID showed encouraging efficacy in patients with relapsed or refractory EZH2 mutation-positive FL with an acceptable safety profile in the overall population. Thus, tazemetostat may be a potential option for the treatment of relapsed or refractory EZH2 mutation-positive FL. Citation Format: Shinya Rai, Kiyoshi Ando, Akifumi Takaori-Kondo, Hirohiko Shibayama, Takanori Teshima, Junya Kuroda, Koji Kato, Yoshitaka Imaizumi, Kisato Nosaka, Rika Sakai, Tadashi Nakanishi, Seiichiro Hojo, Koji Izutsu. Phase 2 study of tazemetostat in Japanese patients with relapsed or refractory EZH2 mutation-positive B-cell Non-Hodgkin's Lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT176.

Rucaparib maintenance treatment for recurrent ovarian carcinoma: the effects of progression-free interval and prior therapies on efficacy and safety in the randomized phase III trial ARIEL3

IntroductionIn ARIEL3 (NCT01968213), the poly(adenosine diphosphate-ribose) polymerase inhibitor rucaparib significantly improved progression-free survival versus placebo regardless of biomarker status when used as maintenance treatment for recurrent ovarian cancer. The aim...

Romidepsin (HDACi) plus cisplatin and nivolumab triplet combination in patients with metastatic triple negative breast cancer (mTNBC).

1076 Background: Histone deacetylase inhibitors (HDACi) upregulate genes involved in antigen presentation machinery and increase expression of natural killer group 2, member D ligands (NKG2DL), thus resulting in enhanced tumor cell recognition and response to PD-1/CTLA-4 blockade. Cisplatin and HDACi combination synergistically induces cytotoxicity, apoptosis, and DNA damage. This phase I-II trial investigated combination of romidepsin (HDACi) plus cisplatin and nivolumab (PD-1 inhibitor) in mTNBC. Patients and Methods: Eligible patients had mTNBC with any number of prior chemotherapies. Phase I was 3+3 dose-escalation design with three dose levels of romidepsin (8, 10, 12mg/m2, D2, 9) plus cisplatin 75mg/m2 D 1 every 21 days. Phase II treatment included romidepsin plus cisplatin plus nivolumab 360mg every 21 days and was designed according to Simon’s two stage minimax design. Primary endpoints were recommended phase 2 dose (RP2D) and objective response rate (ORR). Additional endpoints included safety, PFS, and pharmacokinetics. Results: 51 patients were enrolled (N=13 phase I, N=38 phase II) between 2015-2020. 69% had received ≥1 prior metastatic chemotherapy, 47% had prior platinum, 53% had liver metastasis, 12% had BRCA1/2 mutation, and 11% had PD-L1 positive disease. There were no dose limiting toxicities in phase I. The RP2D was romidepsin 12mg/m2 D2,9 + cisplatin 75mg/m2 D1 + nivolumab 360mg D1 every 21 days. Thrombocytopenia (G3:27%, G4:0%), neutropenia (G3:25%, G4:0%), anemia (G3:22%, G4:0%), nausea (G3:22%, G4:0%), and vomiting (G3:20%, G4:0%) were the most common grade 3/4 adverse events. 21% of patients had immune AEs (G3-4:8%). Among 34 evaluable phase II patients, ORR was 44% (Table), median PFS was 4.4 months, and 1-year PFS was 23%. Median OS was 10.3 months and 1-year OS was 43%. No pharmacokinetic interactions were detected with co-administration of romidepsin-cisplatin-nivolumab. Conclusions: The triplet combination of romidepsin plus cisplatin and nivolumab was well tolerated and shows encouraging efficacy in pretreated mTNBC, including in patients with PD-L1 negative disease and in those with liver metastasis. Correlative biomarker work is ongoing. This combination warrants further evaluation in larger studies. Clinical trial information: NCT02393794 .[Table: see text]

IMMU-02. CHIMERIC ANTIGEN RECEPTOR (CAR) T CELL NEUROTOXICITY CORRELATES WITH PRETREATMENT AND ACUTE CSF NEUROFILAMENT LIGHT CHAIN (NFL) LEVELS

OBJECTIVEImmunotherapy for hematologic malignancies with CD19-directed CAR T cells is complicated by neurotoxicity in approximately 40% of patients. We have previously reported evidence of glial injury in pediatric patients with CAR T neurotoxicity by elevated CSF levels of GFAP and S100b. We now hypothesize that NFL is also a useful biomarker of neuronal injury related to abnormal blood-brain-barrier and glial function.METHODSWe used the Mesoscale Discovery platform to measure CSF and serum NFL levels in a consecutive cohort of 43 pediatric patients with B cell ALL who received CD19-directed CAR T cells. In addition, we will present expansion cohort measurements of NFL and GFAP (N=95).RESULTSCSF NFL levels prior to CAR T cell infusion positively correlated with the risk of subsequently developing severe neurotoxicity (no neurotoxicity, median 275pg/mL, mild 378pg/mL, severe 951pg/mL, P=0.0182 for severe vs none, P=0.0458 for severe vs mild). During neurotoxicity, mean CSF NFL levels increased to 1179pg/mL (mild neurotoxicity, P=0.0338) and 1345 pg/mL (severe neurotoxicity, P=0.0148), respectively. In serum, pretreatment NFL levels were highly abnormal in many patients (median 368pg/mL, range 10–56,321pg/mL; healthy control median 4pg/mL, range 1–7.5pg/mL). However, there was no correlation with neurotoxicity, history of CNS radiation, peripheral neuropathy, stem cell transplant, or number of prior chemotherapies. Day 7 serum NFL levels did not change significantly (median 439pg/mL, range 5–17,439pg/mL, P=0.3254).CONCLUSIONWe conclude that CSF NFL is promising biomarker of CAR T neurotoxicity risk and severity. The abnormal baseline serum NFL concentrations remain unexplained and require further study.

Bevacizumab-related gastrointestinal perforation in patients with three or more prior chemotherapy regimens: A real-world experience

ObjectiveAssociations between the number of prior chemotherapy (CT) regimens and gastrointestinal (GI) perforation in patients receiving bevacizumab treatment has not been fully investigated. The aim of the study was to investigate the impact of ≥3 prior CT regimens on GI perforation. Materials and methodsWe retrospectively investigated the medical records of 133 patients with gynecological cancer who received bevacizumab-containing treatment. Bevacizumab was intravenously administered at a dose of 15 mg/kg every 4 weeks. Incidence of GI perforation was compared between ≤2 and ≥3 prior CT groups. ResultsTwenty-three (17.3%) patients had a history of ≥3 CT; these patients received bevacizumab at 4-week intervals. The percentage of patients with prior surgery was significantly higher in the ≥3 prior CT group (95.7% vs. 70.0%, P = 0.008), while those with prior bowel resection was significantly higher in the ≥3 prior CT group (30.4% vs. 12.7%, P = 0.034). There was no significant difference in the mean number of bevacizumab cycles between the two groups (10.7 vs. 8.9, P = 0.19). While GI perforation was observed in three (2.7%) patients in the ≤2 prior CT group, no GI perforation was found in the ≥3 prior CT group (P > 0.99). ConclusionA history of ≥3 prior CT did not increase the risk for GI perforation when bevacizumab is administered at a dose of 15 mg/kg every 4 weeks in our cases.

Real-world efficacy and safety of eribulin in advanced and pretreated HER2-negative breast cancer in a Spanish comprehensive cancer center

BackgroundEribulin improves survival in pre-treated HER2-negative advanced breast cancer (ABC). However, limited data exist on co-morbidities and central nervous system (CNS) efficacy. The purpose of this study was to review eribulin’s efficacy and safety in everyday clinical practice with special focus on age, body mass index (BMI) and central nervous system (CNS) activity.MethodsAn observational study was conducted in a series of HER2-negative ABC patients treated from January’14-December’17 outside a clinical trial. Objective Response Rate (ORR), Progression Free Survival (PFS), Overall Survival (OS), and association of clinical and pathological variables with outcome were evaluated.ResultsNinety-five women were treated with at least one cycle of eribulin. Median age was 57 (33–83), and 18% were obese. Median number of prior chemotherapies for ABC was 3 (2–5) and 76% of patients had visceral metastases, including 21% with CNS involvement. Most tumors were estrogen receptor-positive (79%). ORR and stable disease (SD) at 6 months were 26.2 and 37.5%, respectively. Remarkably, relevant CNS efficacy was observed with eribulin: 20% of patients obtained partial response and 25% SD. Treatment was generally well tolerated and manageable, with 29% grade 3 and 10.9% grade 4 toxicities. Median PFS and OS were 4.1 months (CI95% 3.2–4.9) and 11.1 months (CI95% 9.5–14.7), respectively. Triple-negative disease, > 2organs involved and being younger than 70 years old were independent prognosis factors for worse OS in multivariate analysis. Most patients (75%) progressed in pre-existing metastases sites.ConclusionIn everyday clinical practice, eribulin’s efficacy seems similar to pivotal trials. CNS-efficacy was observed. TNBC, > 2 organs involved and being younger than 70 years old were independent prognosis factors for worse OS. Remarkably, less incidence of grade 4-toxicity compared to previous studies was found.

The elevation of eosinophils could prolong the time to the next treatment in patients with RRMM who are treated with lenalidomide

Lenalidomide (LEN) directly targets myeloma cells and stimulates an immunological response. Eosinophils (Eo) have a variety of immunological functions and play roles in the development of allergic diseases and asthma. Eo level elevations have been shown to represent immunological activity in patients with myeloma who are treated with LEN. The purpose of this study was to investigate the clinical significance of Eo level elevation in patients with relapsed or refractory multiple myeloma (RRMM) who were treated with LEN. We reviewed the medical records of patients with RRMM who were treated with LEN-containing regimens at the Jikei Kashiwa Hospital, between November 2010 and June 2018. The included patients were followed-up until March 2019, and the median follow-up period was 24.4 months. Fifty-nine patients with RRMM who were treated with LEN were analyzed, and median patient age was 73 years. An elevation of Eo was defined as an increase in Eo count of 250 /microL or more during the first cycle, compared to the level on day one of the first cycle. As salvage chemotherapy, 39, 8, 4, 3, 3, and 2 patients received LEN plus dexamethasone (Rd), elotuzumab plus Rd (ERd), daratumumab plus Rd (DRd), ixazomib plus Rd, bortezomib plus Rd, and LEN, melphalan, plus prednisone, respectively. The median time from diagnosis to the start of LEN was 25.9 months. The median number of prior regimens was two. The percentage of patients with the Eo elevation was 22.0%. There were no a significant relationships among Eo elevation and age, sex, M protein type, international staging system (ISS), serum lactate dehydrogenase level, serum C-protein level, number of prior chemotherapies, prior bortezomib, dose of lenalidomide, and dose of corticosteroid. The overall response rate (ORR) in the groups with Eo level elevation and non-elevation were 84.6% and 63.0%, respectively (P = 0.189). The elevation of Eo was not related to any grade of skin rash (P = 0.713). The median time to next treatment (TTNT) of the Eo elevation group was significantly longer than that of the Eo non-elevation group (40.3 vs 8.4 months, P = 0.017). In addition, the median TTNT in the Eo elevation group with partial response (PR) or better was significantly longer that of the Eo non-elevation group with a PR or better (40.3 vs 11.9 months, P = 0.021). In the multivariate analysis, the Eo elevation was a significant good prognostic factor for TTNT (hazard ratio 0.401, P = 0.043). The overall survival was similar between the Eo elevation and non-elevation groups (P = 0.334). From our findings, we conclude that Eo level elevations are common and can prolong TTNT in patients with RRMM who are treated with LEN.

Abstract CT171: Safety and efficacy of a whole-cell targeted immunotherapy for breast cancer: Preliminary findings

Abstract The purpose of this study is to evaluate the safety and preliminary efficacy of a targeted immunotherapy for breast cancer based on SV-BR-1-GM, a breast cancer cell line modified to secrete GM-CSF. The regimen used includes low dose cyclophosphamide (300 mg/m2) 2-3 days prior to inoculation to reduce immune suppression; irradiated SV-BR-1-GM (20,000 cGy) dosed intradermally (ID) in 4 sites (~20x106 cells total); and post-inoculation interferon-α (10,000 units ID into the SV-BR-1-GM inoculation sites) 2±1 and 4±1 days later. Dosing is every 2 weeks for the first month, then monthly for up to one year. This regimen was used in a prior study in 4 evaluable patients with advanced cancer (3 breast and 1 ovarian) and was safe and well tolerated. One patient, who had a partial response of widely metastatic breast cancer, was found to match SV-BR-1-GM at an MHC class II allele (HLA-DRB3*02:02). This regimen is being used in a clinical trial (NCT03066947 in ClinicalTrials.gov) in patients with advanced breast cancer. To date 7 patients with metastatic breast cancer have been recruited and 6 dosed with evidence of tumor response in 2 patients. Ages ranged from 46-73. Time from initial diagnosis ranged from 2 - 12 years. The number of prior chemotherapy or biological therapy regimens ranged from 3-7. Treatment was generally safe and well tolerated. The majority of adverse events were limited to local irritation at the injection sites. No serious adverse events related to SV-BR-1-GM treatment have been reported and no new or unexpected safety issues related to SV-BR-1-GM have been observed. Two patients dropped out after a single cycle of treatment. One patient with inflammatory breast cancer dropped out after 2 treatments due to worsening breast inflammation. One patient appeared to be responding in the breast after the first treatment, with regression of soft tissue lesions in the breast, but developed a worsening pleural and pericardial effusions shortly after the second treatment with the development of pulseless electrical activity and was unable to be resuscitated. One patient has received 5 cycles of therapy and is ongoing. One patient had a notable response. For this 73-year-old woman with breast cancer diagnosed in 1995 with liver and lung metastases and 7 prior rounds of chemotherapy, after 3 months of treatment her scans noted “a clear response in the multiple bilateral pulmonary nodules” indicating that several lung tumors had disappeared or decreased in size. This response was maintained after 6 months. The liver tumors were stable to slightly increased at 3 months, and then progressed after 6 months. This patient matched with SV-BR-1-GM at 2 HLA loci (HLA-A*24:02 and HLA-DRB3*02:02). The regimen used in this study has shown early evidence of activity in these patients with late stage, heavily pre-treated metastatic breast cancer. HLA matching may be useful in predicting those patients most likely to respond. Citation Format: Jarrod P. Holmes, Elizabeth Tan-Chiu, Charles L. Wiseman, Markus D. Lacher, George Peoples, William V. Williams. Safety and efficacy of a whole-cell targeted immunotherapy for breast cancer: Preliminary findings [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT171.

Platinum-Based Chemotherapy Plus Cetuximab in Patients With Recurrent or Metastatic Nasopharyngeal Cancer

Platinum-containing doublet chemotherapy regimens are generally considered the standard first-line systemic therapy for recurrent or metastatic (R/M) nasopharyngeal caner (NPC). Gemcitabine (GEM)+Cisplatin (CDDP) demonstrated significant improvement of both progression-free survival and overall survival over 5FU+CDDP for R/M NPC in a phase 3 study, leading to standard of care as first-line therapy for R/M NPC. Although the results of a phase 2 study of cetuximab (Cmab) in combination with carboplatin in patients with heavily pretreated NPC was reported, there was no available data for platinum-based chemotherapy plus Cmab as first-line therapy for R/M NPC. The objective of the currents study was to evaluate safety and efficacy of platinum-based chemotherapy plus Cmab in patients with R/M NPC. We conducted a retrospective review of patients with recurrent or metastatic NPC who were treated with platinum-based chemotherapy plus cetuximab during 2013 to 2017 at our institute. Treatment consisted of CDDP or carboplatin+5FU+Cmab(PFE) or paclitaxel+carboplatin+Cmab(PCE). Eleven patients were identified; patient characteristics were median age, 54.7 years (36-75); male /female 8/3; PS 0/1/2, 6/5/0; histology WHOI/II/III/ unknown, 2/3/3/3; number of prior chemotherapies 0/1/2/3 2/2/1; treatment regimen: PFE/PCE: 3/8. Of the 10 patients assessable for efficacy, 1 patient (10%) achieved complete response (CR), 3 patients (30%) with partial responses (PR), 5 patients (50%) with stable disease (SD), and 1 patient (10%) with progressive diseases (PD), in best response. Overall response rate (ORR) was 40% in all patients. The median progression-free survival (PFS) were 5.6 overall, 6.5 for patients treated with PFE, 5.4 months for patients treated with PCE, respectively. The median overall survival (OS) were 25.3 overall, 25.3 for patients treated with PFE, 25.8 months for patients treated with PCE, respectively. A patient who achieved CR has continued to receive Cmab maintenance for 42.3 months. Most common adverse events(AEs) were acne-like rash (81.8%), skin cracks (72.7%), and bone marrow suppression (54.5%). Most common grade 3 AEs were acne-like rash (1 patient) and althralgia (1 patient). Grade 4 AEs were infusion reaction (1 patient) and allergy due to carboplatin (1 patient). No treatment-related death was observed. Platinum-based chemotherapy plus Cmab demonstrated promising efficacy with ORR 40%, median PFS 5.6 months and OS of 25.3 months, with acceptable toxicities. Cmab in combination with gemcitabine plus CDDP, warrants further investigations.

Abstract P5-21-08: Tolerability of the combination of lapatinib and trastuzumab in older patients with HER2 positive metastatic breast cancer

Abstract Background: Older adults are less likely to be included in clinical trials leading to the approval of novel cancer treatments. The Institute of Medicine and ASCO have identified therapeutic phase II trials as a key research priority to increase the evidence base for older adults with cancer. While targeted therapies may represent a less toxic option for older patients, few trials have studied their tolerability and efficacy in older adults. Here, we present a phase II study (NCT01273610) of the combination of trastuzumab and lapatinib in older patients with HER2+ metastatic breast cancer (MBC), incorporating geriatric oncology principles in the study design. Methods: Patients age ≥ 60 years with MBC and any number of prior chemotherapy (CT) lines received trastuzumab (either 4mg/kg loading dose followed by 2mg/kg weekly or 8mg/kg followed by 6mg/kg q/3 weeks) plus lapatinib 1000 mg/m2 daily in 21-day cycles. Patients completed a pre-treatment geriatric assessment including measures of function, comorbidity, cognition, nutrition, and psychosocial status. A toxicity risk score developed for older adults receiving cytotoxic CT was calculated for each patient (Hurria et al. JCO 2011 & 2016). Relationships between tolerability (dose reductions and grade (G) ≥ 3 toxicity attributed to treatment) and risk score analyzed using a log2 transformation were assessed using generalized linear models, Student's t tests, and Fisher's exact test. Response rate (RR) and progression free survival (PFS) were evaluated. Results: 40 patients (mean age 72 [60-92]) were accrued from 04/11 to 05/15. 25% (n = 10) were ≥ 75 years of age. 65% of patients (n = 26) had HR+ tumors and 35% (n = 14) were receiving ≥ 3rd line treatment. Median number of cycles was 4 (0-28). RR was 23% (n = 9, 95% CI 11-38%; 1 complete, 8 partial). 23% (n = 9) achieved stable disease. PFS was 2.7 months (95% CI 2.5-12). Based on the toxicity risk score, 21% (n = 8), 54% (n = 21), and 26% (n = 10) were at low, intermediate, and high risk. 70% (n = 28) of patients had G ≥ 2 toxicities and 20% (n = 8) G ≥ 3 toxicities. G 2 and 3 diarrhea occurred in 28% (n = 11) and 5% (n = 2) respectively. 5% (n = 2) were hospitalized due to treatment-related toxicity. No G ≥ 3 cardiac toxicities were observed. 23% of patients (n = 9) had treatment delays, and 43% (n = 17) required a lapatinib dose reduction. The mean toxicity risk score was higher in patients who required dose reductions (Student's t: p = 0.02). No statistically significant relationship was found between toxicity risk scores and the presence of G ≥ 3 treatment toxicity (logistic regression: OR = 3.08, 95% CI [0.54, 21.2], p = 0.22). Conclusions: Among older patients with MBC (79% at intermediate or high risk of G ≥ 3 cytotoxic CT toxicity), trastuzumab and lapatinib were well tolerated, with only 20% experiencing G3 toxicities. The toxicity risk score was not found to be significantly related with treatment toxicity, which may be explained by the very low incidence of G3 events. Patients with a low toxicity risk score were not likely to require a lapatinib dose reduction. Citation Format: O'Connor T, Soto-Perez-de-Celis E, Blanchard S, Chapman A, Kimmick G, Muss H, Luu T, Waisman JR, Li D, Mortimer J, Yuan Y, Somlo G, Stewart D, Katheria V, Levi A, Hurria A. Tolerability of the combination of lapatinib and trastuzumab in older patients with HER2 positive metastatic breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-21-08.

Phase I study of the combination of balixafortide (CXCR4 inhibitor) and eribulin in HER2-negative metastatic breast cancer (MBC) patients (pts).

2555 Background: Balixafortide (POL6326) is a cyclic peptide and a potent, selective antagonist of the chemokine receptor CXCR4. Evidence suggests that CXCR4 inhibition interferes with the tumor-protective microenvironment and sensitizes tumor cells to chemotherapy. The combination of balixafortide (B) and eribulin (E) was safe with early signs of efficacy in the dose escalation part of this study. Methods: The expanded cohort of thisopen label phase I study was designed to assess the anti-tumor activity, safety and pharmacokinetics of the addition of the recommended phase 2 dose (RP2D) of B to E in pts with MBC and with any CXCR4 expression level at the tumor site. Patients received E (1.4 mg/m2) on days 2 and 9, flanked by B (5.5 mg/kg) on days 1-3, and 8-10 of 21-day cycles. Results: 24 pts with relapsed MBC (median age 59 [33-82]) were enrolled in the expanded cohort. Median number of prior chemotherapies for MBC was 2 (range 1-3). 20/24 (83%) pts were ER and/or PR positive; 3/24 (13%) pts had TNBC. Objective response rate (ORR) was 33%. 8/24 (33%) pts achieved a partial response and 4/24 (17%) pts had meaningful (≥ 6 months) stable disease for a Clinical Benefit Ratio of 50%. Median duration of treatment was 15.3 weeks (range 5-40) with 11 pts still on treatment. The most common Gr 3-4 adverse events were neutropenia (9/24, 38%) and leucopenia (3/24, 13%); 2 pts had febrile neutropenia and 1 patient died from sepsis. 15/24 (63%) pts experienced histamine-like infusion reactions related to B that were manageable with anti-histamines. Conclusions: The therapeutic activity of this treatment regimen appears promising with an ORR of 33% in patients with advanced MBC. B (5.5 mg/kg) can be combined safely with E (1.4 mg/m2) and the safety profile resembles E monotherapy as previously reported. This is the first study of the treatment combination of E with B in relapsed MBC pts. Further confirmatory studies are being considered. Clinical trial information: NCT01837095.

A phase-I study of lapatinib in combination with foretinib, a c-MET, AXL and vascular endothelial growth factor receptor inhibitor, in human epidermal growth factor receptor 2 (HER-2)-positive metastatic breast cancer

BackgroundThe mechanisms of resistance to anti-human epidermal growth factor receptor 2 (HER 2) therapies are unclear but may include the tyrosine-protein kinase Met (c-Met), vascular endothelial growth factor (VEGF) and AXL pathways. Foretinib is an inhibitor of c-Met, VEGF receptor 2 (VEGFR-2), platelet-derived growth factor receptor beta (PDGFRB), AXL, Fms-like tyrosine kinase 3 (FLT3), angiopoiten receptor (TIE-2), RET and RON kinases. This phase Ib study sought to establish the associated toxicities, pharmacokinetics (PK) and recommended phase II doses (RP2D) of foretinib and lapatinib in a cohort of HER-2-positive patients with metastatic breast cancer (MBC).MethodsWomen with HER-2 positive MBC, Performance status (PS 0-2), and no limit on number of prior chemotherapies or lines of anti-HER-2 therapies were enrolled. A 3 + 3 dose escalation design was utilized. Four dose levels were intended with starting doses of foretinib 30 mg and lapatinib 750 mg orally once a day (OD) on a 4-weekly cycle. Assessment of c-MET status from the primary archival tissue was performed.ResultsWe enrolled 19 patients, all evaluable for toxicity assessment and for response evaluation. Median age was 60 years (34–86 years), 95% were PS 0-1, 53% were estrogen receptor-positive and 95% had at least one prior anti-HER-2-based regimen. The fourth dose level was reached (foretinib 45 mg/lapatinib 1250 mg) with dose-limiting toxicities of grade-3 diarrhea and fatigue. There was only one grade-4 non-hematological toxicity across all dose levels. There were no PK interactions between the agents. A median of two cycles was delivered across the dose levels (range 1–20) with associated progression-free survival of 3.2 months (95% CI 1.61–4.34 months). By immunohistochemical assessment with a specified cutoff, none of the 17 samples tested were classified as positive for c-Met.ConclusionsThe RP2D of the combined foretinib and lapatinib is 45 mg and 1000 mg PO OD, respectively. Limited activity was seen with this combination in a predominantly unselected cohort of HER-2-positive patients with MBC.

Abstract OT2-01-11: Phase II of POSEIDON: A phase Ib / randomized phase II trial of tamoxifen plus taselisib or placebo in hormone receptor positive, HER2 negative, metastatic breast cancer patients with prior exposure to endocrine treatment

Abstract Background: The combination of PI3K-AKT-mTOR pathway inhibitors with endocrine therapy can improve clinical outcomes of hormone receptor positive (HR+) metastatic breast cancer (MBC) patients. Taselisib is a potent and selective PI3K inhibitor, with greater selectivity against mutant (MUT) PI3Kα isoforms than wild-type (WT) via a unique mechanism. Phase Ib data of POSEIDON with Taselisib + tamoxifen (TAM) demonstrated encouraging activity in patients with heavily pre-treated MBC, with an acceptable toxicity profile (Baird et al, ASCO 2016). The recommended phase II dose (RP2D) was Taselisib 4mg plus TAM 20mg, both administered on a daily continuous schedule. ctDNA monitoring may have value in drug development by (1) assessing predictive biomarkers to therapy, (2) providing an early indication of treatment response, and (3) shedding light on potential mechanisms of acquired drug resistance. In some patients included in phase Ib of POSEIDON, tumor response was preceded by a corresponding early change in plasma PIK3CA ctDNA levels. Methods: The phase II portion of the POSEIDON trial is a two-arm, randomized, double blind study of Taselisib plus TAM versus placebo (PLA) plus TAM in pre- and postmenopausal women with HR+/HER2- MBC. In the first part of the Phase II, 180 patients will be randomized (1:1) to receive continuous TAM with either Taselisib at the RP2D or PLA until disease progression, unacceptable toxicity or patient / physician decision. Crossover is allowed upon progressive disease in those patients receiving PLA plus TAM, after collection of tumor and blood samples for exploratory biomarker analysis. Stratification is based on menopausal status, histology [lobular breast cancer (LBC) vs. ductal/others], PIK3CA mutation (WT vs. exon 9 vs. exon 20), prior everolimus, timing of recurrence/progression after prior endocrine therapy, number of prior chemotherapy (CT) lines, and treatment center. After recruiting the initial 180 patients, trial will focus in LBC, until a total number of 110 patients with LBC are enrolled. Other key eligibility criteria include presence of measurable or evaluable disease (RECIST 1.1), prior progression to endocrine treatment, maximum of 5 prior CT lines in the metastatic setting, absence of diabetes under medical treatment, and absence of chronic inflammatory bowel disease. Primary endpoint is investigator-assessed PFS. Key secondary endpoints are PFS in LBC, objective response rate, clinical benefit rate, safety, and exploratory biomarker analysis (including ctDNA). The study has a 90% power at a two-sided log-rank test significance level of 0.2 to detect an HR of 0.64, which corresponds to an increase in median PFS from 4.5 months in the PLA plus TAM arm to 7 months in the Taselisib plus TAM arm. Enrollment to POSEIDON Phase II started in June 2016 (Clinicaltrials.gov NCT02285179). Citation Format: Oliveira M, Baird RD, van Rossum AGJ, Beelen K, Garcia-Corbacho J, Mandjes IAM, Vallier AL, van Werkhoven E, Garrigós L, Kumar S, van Tinteren H, Muñoz S, Linossi C, Rosing H, Miquel JM, Schrier M, de Vries Schultink A, Saura C, Gallagher WM, Bernards R, Tabernero J, Cortés J, Caldas C, Linn SC. Phase II of POSEIDON: A phase Ib / randomized phase II trial of tamoxifen plus taselisib or placebo in hormone receptor positive, HER2 negative, metastatic breast cancer patients with prior exposure to endocrine treatment [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-01-11.

Prognostic factors in recurrent glioblastoma patients treated with bevacizumab.

The value of bevacizumab (BEV) in recurrent glioblastoma is unclear. Imaging parameters and progression-free survival (PFS) are problematic endpoints. Few data exist on clinical factors influencing overall survival (OS) in unselected patients with recurrent glioblastoma exposed to BEV. We retrospectively analyzed 174 patients with recurrent glioblastoma treated with BEV at two German brain tumor centers. We evaluated general patient characteristics, MGMT status, pretreatment, concomitant oncologic treatment and overall survival. Karnofsky performance score, number of prior chemotherapies, number of prior recurrences and combined treatment with irinotecan (IRI) were significantly associated with OS in univariate analysis. We did not find differences in OS related to sex, age, histology, MGMT status, prior surgical treatment or number of prior radiotherapies. Combined treatment with IRI and higher KPS both remained significantly associated with prolonged survival in multivariate analysis, but patients receiving IRI co-treatment had less advanced disease. Grouping into clinically relevant categories revealed an OS of 16.9months from start of BEV in patients with first recurrence and KPS≥80% (n=25). In contrast, in patients with second recurrence and KPS<80%, OS was 3.6months (n=27). Our observational data support an early use of BEV in patients with good performance status. The benefit of co-treatment with IRI in our cohort seems to be the result of biased patient recruitment.

Survival of patients with advanced lung adenocarcinoma before and after approved use of gefitinib in China.

BackgroundTo compare the overall survival (OS) of patients with advanced lung adenocarcinoma in China before and after the approved use of gefitinib, and analyze clinical factors that may affect OS.MethodsClinical data of 558 patients with advanced lung adenocarcinoma who received chemotherapy from January 2002 to December 2010 were retrospectively analyzed. According to the matched-pair case-control study design, 255 patients who only received chemotherapy and 255 patients who received gefitinib treatment after its approval were stringently matched by age, gender, and smoking history and enrolled in the study. Clinical factors including age, gender, smoking history, Eastern Cooperative Oncology Group (ECOG) performance status (PS), tumor stage, organ metastasis, and the number of prior chemotherapies were analyzed to determine their correlations with OS.ResultsThe median survival time (MST) of the 510 enrolled patients with advanced lung adenocarcinoma was 22.8 months. The MST of the patients who received gefitinib treatment was significantly longer than that of patients who did not receive gefitinib treatment (33.5 vs. 14.1 months, P < 0.001). The OS in patients who received gefitinib treatment was significantly longer than in patients who did not receive gefitinib treatment in almost all clinical factor-based subgroups, including age, gender, smoking history, ECOG PS 0–1, tumor stage, the presence or absence of lung, pleural, bone, brain, adrenal gland and liver metastasis, and the number of prior chemotherapies (all P < 0.001), except in the ECOG PS ≥2 subgroup.ConclusionsGefitinib treatment significantly improved the survival of patients with advanced lung adenocarcinoma in China.

Abstract P6-06-45: Predictive significance of the mucocutaneous toxicities, but not dose intensity of capecitabine for the treatment of lapatinib plus capecitabine in patients with HER2 positive metastatic breast cancer

Abstract Background: There are no definitive predictive markers, except HER2 overexpression, for anti-HER2 therapeutic sensitivity of patients (Pts) with HER2-positive breast cancer. The aim of this study was to evaluate clinical predictive factors for lapatinib plus capecitabine (LAPCAP) in Pts with HER2 positive metastatic breast cancer (HER2MBC). Methods: This retrospective observational study was used data from our single institutional medical record system from June 2009 to March 2013. Evaluation of female Pts with HER2MBC who were treated with LAPCAP (LAP at 1250 mg/day continuously plus CAP at 2000 mg/m2 on days 1 through 14 of a 21-day cycle) included baseline clinical characteristics, dose modifications of LAPCAP, clinical efficacy, and incidence of adverse events (AEs). Dose-intensity was compared with reference standard regimens. The Kaplan Meier method was used to estimate time to progression free survival (PFS). Results: A total 76 Pts were included in this analysis. At a median follow-up of 20 months, median age was 56 years (range, 36 to 75) and 41 of 76 Pts had received prior (neo- or) adjuvant chemotherapy including 18 trastuzumab (Tmab) containing regimen. Visceral metastases (Mets) were identified in 49, bone Mets in 37, lymph nodes Mets in 36, brain Mets in 17, and chest wall Mets in 16. The median number of prior chemotherapy or hormonal therapy for MBC before LAPCAP was 2 (range, 0 to 13), and 66 of 76 Pts had previously received Tmab containing regimen with taxanes for 40 Pts, vinorelbine for 36, CAP for 29, and hormonal therapies for 15. In LAPCAP, the overall response rate was 21% including 2 CRs and 14 PRs, and the clinical-benefit rates which had more than 6-month SD was 60%. During initial 12 months observation, 93% of Pts had any AEs. The most common AEs were hand-foot syndrome (HFS) in 55 Pts. Those Pts who had HFS had better PFS than those who did not have (p = 0. 23×10−4). Since HFS was one of the well-known AEs associated with CAP, we sought whether CAP dose influenced PFS or not. However, we did not find any relationship between cumulative or relative dose intensity of CAP and PFS in Pts who treated with LAPCAP. Because several studies with EGFR-targeted agents showed a positive correlation between cutaneous toxicities and outcomes, we sought whether the incidence of any AEs other than HFS influenced PFS in 76 Pts. HFS, and diarrhea, as well as skin rash were statistically significant favorable factors (p = 0. 23×10−4, 0. 60×10−2, and 0. 28×10−1) in Log rank analysis. Furthermore, median PFS of Pts who had all 3 AEs (n = 21) were 377 days, while 84 days (n = 7) who had not (p = 0.58×10−8). We did not find any other clinical predictive factors except these 3 AEs. Furthermore, we compared 20 Pts with longer PFS who had more than 12-month to 26 Pts with shorter PFS that had less than 6-month. Longer PFS had more statistically significant incidence of diarrhea (p = 0. 49×10−2), HFS (p = 0. 49×10−2), and skin rash (p = 0.36×10−1) than shorter one. Conclusions: In LAPCAP, dose of CAP did not influence PFS, but EGFR inhibitor related toxicities might be alternative predicative markers for LAPCAP in HER2MBC. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-06-45.

Abstract PD3-4: A first-in-human phase I study of the tamoxifen (TAM) metabolite, Z-endoxifen hydrochloride (Z-Endx) in women with aromatase inhibitor (AI) refractory metastatic breast cancer (MBC) (NCT01327781)

Abstract Background: In AI refractory MBC, TAM anti-tumor activity is limited (median PFS 4.5 months). In patients (pts) receiving TAM in the adjuvant and metastatic setting, breast cancer recurrence has been shown to differ based upon CYP2D6 genotype and Endx exposure. In collaboration with NCI, Z-Endx (NSC #750393) was synthesized and preclinical pharmacology studies demonstrated that oral Z- Endx resulted in &amp;gt; 20 fold Endx exposure compared to an equivalent dose of TAM and significantly greater anti-tumor activity than TAM in AI sensitive and resistant MCF7 xenografts. We conducted a phase I study of Z-Endx in women with ER+, AI refractory MBC to identify dose-limiting toxicities (DLT), a maximum tolerated dose (MTD) and a dose associated with steady state concentrations (Css) of ≥ 2 uM, based on the IC50 of recently identified Endx substrates: PKC and PI3K. Methods: Pts were enrolled to an accelerated titration schedule (2 pts/dose level) until moderate toxicity or DLT, and then to a 3+3 design. Z-Endx was administered orally once daily (28 day cycle). Eye exams were performed at baseline, end of cycle 2, and after 6 cycles. PK was performed on days 1-2, 3, 7, 14, and 28, and prior to subsequent cycles. Results: 23 women with AI refractory MBC (median 56 yrs, range 41-83) received Z-Endx once daily encompassing 7 dose levels (Table 1). The median number of prior chemotherapies and hormonal therapies in the metastatic setting were 2 and 2, respectively. Dose escalation continues at 160 mg/day and the MTD has yet to be determined. Cmax and AUC increased in a dose-dependent manner. A 20 and 100 mg/day dose yields Css of 0.39 and 2.48 uM, respectively. Significant anti-tumor activity was observed including 1 pt (100 mg/day) with a PR lasting 225 days; 1 pt (80 mg/day) with a 30% reduction in tumor size (PFS 169 days) and 2 pts (60 and 80 mg/day) with stable disease for &amp;gt;270 days. No eye toxicity was observed. Conclusions: In women with AI refractory MBC, the MTD of Z-Endx HCl has not been determined but Endx Css concentrations of &amp;gt; 2 uM and substantial anti-tumor activity has been observed. Following completion of the 160 mg/day dose, expansion at 20 and 100 mg/day will commence to perform translational studies and further characterize Endx pk. A randomized phase II examining two different doses of Z-Endx is planned in AI refractory MBC. Supported in part by CA 133049, CA69912, CA15083, CA116201, and CA15083. Table 1Dose Level (mg/day)Number of Treatment CyclesModerate or Severe Toxicities ReportedTumor ResponseProgression-free Survival (days)28 day Z-Endx Css (uM) 20 (n = 2)2; 3Gr 2 hot flashes (1 pt)----60; 850.39 40 (n = 2)2; 6noneStable (1 pt)61; 1670.66 60 (n = 6)1; 2; 2; 5; 8; 14Gr 4 Triglycerides (1 pt);Gr 3 thromboembolic event (1 pt); Gr 2 hot flashes, anemia, and hypoalbuminemia (1 pt)Stable (3 pts)125+; 56; 57; 132; 232; 4331.01 80 (n = 3)4; 6; 10Gr 2 hot flashesStable (3 pts)113; 169; 2961.61 100 (n = 3)1; 2; 8Gr 2 nausea (1 pt); Gr 2 irritability (1 pt)PR (1 pt)30; 56; 2252.48 120 (n = 3)1; 2; 4Gr 2 hypersomnia, paresthesia, and peripheral sensory neuropathy (1 pt)—39; 54; 1082.18 * Bold face toxicities occurred during cycle 1 Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD3-4.