Prior Anthracycline Treatment Research Articles

The Mini-Teddi-R Treatment Demonstrated a High Rate of Remission in Patients with DLBCL Involving the CNS Who Had Previously Been Exposed to BTK Inhibitors

Background: Secondary CNS B-cell lymphomas (SCNSL) are aggressive lymphomas with a bleak prognosis. TEDDI-R has been successful in achieving lasting remission in relapsed/refractory primary DLBCL of the CNS (PCNSL), but the effectiveness of ibrutinib-responsive tumors in SCNSL remains unknown. This study presents initial findings from the use of mini-TEDDi-R in SCNSL. Methods: Efficacy and safety data of mini-TEDDi-R were retrospectively analyzed for patients with DLBCL involving the CNS. All patients experienced relapse in the CNS or/and peripheral region after initial therapy. Brain parenchyma involvement allowed for treatment with MTX, Ara-c, and/or BTK inhibitors. The dosage of the drugs used in the original regimen was reduced, leading to the adoption of the term “mini-TEDDi-R.” Each 21-day cycle involved the following treatments: intravenous rituximab at a dose of 375 mg/m 2/day on days 1-2, oral temozolomide at a dose of 150 mg/m 2/day on days 2-5, intravenous infusion of 30 mg/m 2/day etoposide on days 2-5, intravenous infusion of 25 mg/m 2 of pegylated liposomal doxorubicin on day 2, intravenous infusion of dexamethasone at a dose of 10 mg/m 2/BID on days 1-5, and oral zanubrutinib at a dose of 200mg/BID or oral orelabrutinib at a dose of 150mg/qd or oral ibrutinib at a dose of 560mg/qd from day 1 until neutrophil count <0.5*10^9/L or platelet count <30*10^9/L. Additionally, intrathecal administration of 70 mg of cytarabine occurred on days 1 and 5, All remissions observed on MRI were confirmed through FDG-PET and CSF analysis. Results: Between December 2019 and June 2023, 24 patients with a median age of 53 (range 28-69) received mini-TEDDi-R treatment. All patients had DLBCL, comprising 16 (66.7%) non-GCB, 6 (25%) GCB, and 2 (8.3%) transformed from FL. All patients experienced relapse in the CNS system after a median of 6 (range 1-17) prior therapies, and all (100%) patients received prior anthracycline treatment. A total of 21 patients (87.5%) had received multiple lines of therapy before mini-TEDDi-R. Among them, 19 patients (79.2%) had received HD-MTX based salvage therapy, 11 patients (45.8%) had received HD-Ara-c based salvage therapy, and 14 patients (58.3%) had been exposed to BTK inhibitors. Seven patients (29.2%) showed triple resistance to MTX, Ara-c, and BTK inhibitors. Six patients had previously undergone transplantation, and four patients had experienced failure of CD19 CART treatment. Thirteen patients (54.2%) had isolated CNS disease, while 11 patients (45.8%) had both CNS and peripheral disease. Thirteen patients (54.2%) underwent 1 cycle of mini-TEDDi-R, 8 patients (33.3%) completed 2 cycles, 2 patients (8.3%) finished 3 cycles, and 1 patient (4.2%) completed 4 cycles. The objective remission rate (ORR) was determined to be 70.8%, with a complete remission (CR) rate of 58.3%. Notably, patients (N=14) exposed to BTK inhibitors previously exhibited a similar CR rate compared to patients (N=10) who had not received prior BTK inhibitor treatment (50% vs. 70%, p = 0.348). Patients (N=19) who had undergone HD-MTX based salvage therapy achieved an ORR of 74% and a CR rate of 58%. No significant difference in response rate was observed between patients with peripheral and non-peripheral secondary CNS involvement. In patients who achieved complete remission, only one patient experienced a second CNS relapse. Four patients bridged to auto-HSCT, 2 patients bridged to CART treatment, and 4 patients underwent auto-HSCT combined with CART treatment for consolidation. The median overall survival and median PFS have not been reached within the 11.8-month follow-up period. Toxicity was evaluated over 39 cycles. Grade 3 and 4 neutropenia occurred in 51% and 16% of cycles, respectively, while febrile neutropenia was observed in 10% of cycles. The median duration of neutropenia was 6 days (range 4-10). Three cycles (8%) were complicated by infections graded as ≥G3, but no opportunistic infections (including Aspergillus) were observed. Grade 3 and 4 thrombocytopenia occurred in 26% and 14% of cycles, respectively. The median duration of neutropenia was 7 days (range 3-14). Conclusions: The mini-TEDDi-R regimen demonstrated a favorable remission rate in patients with DLBCL involving the CNS. The treatment was well-tolerated, and patients with tumors that were previously exposed to BTK inhibitors and HD-MTX treatment also showed positive responses to mini-TEDDi-R.

Factors affecting prognosis in patients treated with bevacizumab plus paclitaxel as first-line chemotherapy for HER2-negative metastatic breast cancer: an international pooled analysis of individual patient data from four prospective observational studies

BackgroundBevacizumab (BV) plus paclitaxel (PTX) is a treatment option in patients with HER2-negative metastatic breast cancer (mBC). We conducted an international pooled analysis with individual patient data to evaluate the effectiveness of BV + PTX as a first-line treatment for HER2-negative mBC patients under routine practice.MethodsA total of 2,474 mBC patients treated with BV + PTX from four prospective observational studies were analyzed. The primary endpoint was overall survival (OS). The other endpoints including identifying independent prognostic factors and validation of the modified Prognostic Factor Index (PFI) developed in the ATHENA trial.ResultsMedian follow-up time was 10.9 months (M). Median OS were 21.4 M (95% confidential interval 19.8–22.7 M). The seven independent prognostic factors (tumor subtype, age, ECOG performance status (PS), disease-free interval (DFI), liver metastases, number of metastatic organs, and prior anthracycline and/or taxane treatment) for OS found in this analysis included the five risk factors (RFs [DFI < 24 months, ECOG PS 2, liver metastases and/or > 3 metastasis organ sites, TNBC, prior anthracycline and/or taxane therapy]). High- (> 3 RFs [median OS 12.6 M]) and intermediate-risk groups (2 RFs [median OS 18.0 M]) had a significantly worse prognosis than the low-risk group (< 1 RF [median OS 27.4 M]), (p < 0.0001).ConclusionsThis international pooled analysis showed the effectiveness of first-line BV + PTX for HER2-negative mBC patients identifying seven independent prognostic factors as real-world evidence. The usefulness of the modified PFI developed in the ATHENA trial in predicting OS among patients receiving BV + PTX was also verified.

Primary efficacy and safety of letetresgene autoleucel (lete-cel; GSK3377794) pilot study in patients with advanced and metastatic myxoid/round cell liposarcoma (MRCLS).

11500 Background: Lete-cel is an autologous T-cell therapy targeting NY-ESO-1 tumors using a genetically modified, high-affinity T-cell receptor. MRCLS is a sarcoma with poor response to current immunotherapy approaches and limited treatment options. The cancer testis antigen NY-ESO-1 is expressed in 80‒90% of MRCLS tumors, making this a promising target. This report summaries the primary efficacy and safety results of a pilot study of lete-cel in patients (pts) with advanced or metastatic MRCLS. Methods: This is an open label, study of lete-cel in pts with advanced or metastatic MRCLS following reduced-dose (Cohort 1 [C1]; 30 mg/m2 fludarabine [flu] x 3d + 600 mg/m2 cyclophosphamide [cy] x 3d) or standard dose (Cohort 2 [C2]; 30 mg/m2 flu x 4d + 900 mg/m2 cy x 3d) lymphodepletion (LD). Key eligibility criteria were: age ≥18 y; HLA-A*02:01; A*02:05, or A*02:06; advanced or metastatic NY-ESO-1+ MRCLS (≥30% of cells 2+/3+ by IHC); prior anthracycline treatment, and measurable disease. The transduced T cell dose range was 1– 8 × 109. Response was assessed at weeks 4, 8, 12, 24, then every 3 months (mo) until disease progression, death, or withdrawal. Investigator-assessed (IA) ORR by RECIST v1.1 was the primary efficacy endpoint. Secondary endpoints included safety, independently assessed ORR by RECIST v1.1, time to response (TTR), duration of response (DOR), progression-free survival (PFS). Overall survival (OS) was an exploratory endpoint. Results: 23 pts enrolled from March 2017 to February 2020. The median age was 47.0 yrs (range 33 to 72). 20 pts were dosed with T cells, 10 in each cohort with a median transduced T cell dose of 4.6 x 109. 8 of 20 pts (40%) had 1 line of prior therapy, 6 pts (30%) had 2 lines, and 6 pts (30%) had ≥3 lines. The median follow-up was 5.6 (C1) and 12.9 (C2) mo. In C1 the IA ORR was 20%, with best response (BR) of partial response (PR) in 2 pts and BR of stable disease (SD) in 8 pts. The median TTR was 1.9 mo, median DOR was 5.3 mo (95% CI: 1.9-8.7), and median PFS was 5.4 mo (95% CI: 2.0-11.5). In C2 the IA ORR was 40%, with BR of PR in 4 pts and BR of SD in 5 pts. The median TTR was 1.9 mo, median DOR was 7.5 mo (95% CI: 6.0-NE), and median PFS was 8.7mo (95% CI: 0.9-NE). OS is not yet mature. All pts experienced at least 1 treatment-emergent adverse event (TEAE). 55% of pts experienced serious TEAEs. 90% of pts had Gr ≥3 TE neutropenia, with 83% probability of resolution of initial Gr ≥3 occurrence by Day 30. Cytokine release syndrome occurred in 80% of pts, of which 25% were Gr 3, with 1st onset within 5d of infusion and median duration 7.5d. No Graft-vs-host disease, immune effector cell–associated neurotoxicity syndrome, Guillain-Barré Syndrome were reported. Conclusions: Treatment with a single dose of lete-cel showed anti-tumor activity, including response and long median PFS with an acceptable safety profile in pts with advanced and metastatic MRCLS. Clinical trial information: NCT02992743.

Left atrial strain in cardiac surveillance of bone marrow transplant patients with prior anthracycline exposure

BackgroundBone marrow transplantation (BMT) has significantly improved survival rates in various hematological malignancies. However, this has led to an increased prevalence of long-term cardiotoxicity, particularly in those with prior anthracycline (AC) therapy. ObjectivesTo evaluate changes in left atrial (LA) volume and function, including LA strain, in BMT patients with prior AC exposure and evaluate its utility as a marker of diastolic dysfunction. MethodsThis was a cross-sectional analysis of 79 BMT patients with prior AC exposure who underwent a comprehensive surveillance transthoracic echocardiogram compared to age-matched healthy volunteers. Left ventricular (LV) and LA parameters were evaluated between the 2 groups. BMT patients were stratified using traditional measures of diastolic function and additionally utilizing LA strain. ResultsLV systolic dysfunction with reduced LVEF (13/79) or global longitudinal strain (29/79) was present in BMT patients. There were no differences in LA volumes between the two groups. LA reservoir strain (30.1 ± 11.2% vs 34.1 ± 9.6%, p < 0.001) and LA conduit strain (13.6 ± 8.4% vs 17.0 ± 10.5%, p < 0.001) were reduced in the BMT group compared to controls. LA reservoir strain had modest correlation with mitral annular e′ velocity (r = 0.468, p < 0.001). Using current diastolic function guidelines, 26/79 BMT patients had evidence of diastolic dysfunction. However, utilizing LA reservoir strain, an additional 35 patients were identified. ConclusionsLA strain can identify early diastolic dysfunction in BMT patients with prior AC treatment. With diastolic dysfunction known to precede systolic dysfunction post AC, changes in LA reservoir strain may identify more patients with cardiac dysfunction, prompting increased surveillance and treatment.

Abstract 12572: Low Incidence of Cardiovascular Events in Patients With Metastatic Sarcoma Using Upfront Dexrazoxane and High-Dose Doxorubicin

Background: Prognosis for soft tissue sarcoma (STS) remains poor with a progression free survival of 4.6 months. Doxorubicin is a central and effective treatment option, though cardiotoxicity frequently limits dosing. Dexrazoxane has been shown to protect the heart but questions of possible reduced tumor efficacy have limited dexrazoxane to be used only after administration of 300 mg/m2 of doxorubicin. We explored the use of up-front dexrazoxane to mitigate the cardiotoxic effects of doxorubicin in a single-arm non-inferiority trial patients with STS. Methods: Patients with metastatic or unresectable STS without prior anthracycline treatment were eligible for enrollment. The study was powered to demonstrate that dexrazoxane does not prevent a decrease of progression free survival (PFS), with a PFS more than 3.7 months considered non-inferior. Secondary aims included cardiac related mortality and the incidence of heart failure or cardiomyopathy. Patients were allowed to continue on doxorubicin beyond 600mg/m2 if they were deriving benefit and were not demonstrating evidence of cardiac dysfunction. Patients with concerns about cardio-toxicity were referred to a cardio-oncologist. Results: 62 patients were started on study treatment and had at least one year of follow-up. Patients received a median of five cycles (375 mg/m2, range 75-3075 mg/m2) of doxorubicin. The upfront use of dexrazoxane with doxorubicin demonstrated a PFS of 5.5 months (95% CI 4.2-8.4 months). No patients required cardiac hospitalization on protocol. Two patients developed new LV dysfunction with LV ejection fraction below 50% on core lab evaluation with recovery in one and persistent LVEF &lt; 50% in one. There were no deaths attributed to doxorubicin. Conclusion: Up-front dexrazoxane prevented severe cardiac systolic dysfunction in patients receiving high cumulative doses of doxorubicin without reducing progression free survival (5.5 months vs 4.6 months in historical controls).

Vinorelbine Plus Platinum in Patients with Metastatic Triple Negative Breast Cancer and Prior Anthracycline and Taxane Treatment.

Currently, there is no preferred standard chemotherapy regimen available for patients with metastatic triple negative breast cancer (mTNBC) and no cohort studies on the efficacy of vinorelbine plus platinum (NP) regimen in patients with mTNBC who failed to anthracyclines and/or taxanes have been reported. We present the single-center, retrospective experience of NP regimen in a total of 41 patients with mTNBC.All patients were treated with NP regimen, main combination used was vinorelbine-cisplatin in 34 patients (82.9%).The median follow-up was 36.8 months. Objective response rate was 34.1% (n = 14) in the whole study group. Three patients experienced complete response (7.3%), 11 patients acquired partial response (26.8%), stable disease was observed in 14 patients (34.1%), and 10 patients (24.4%) had progressive disease. Response evaluation was not applicable in 3 patients who received the treatment of NP regimen after surgical removal of the metastatic lesions. The median overall survival and progression-free survival were 18.9 months (95% confidence interval, 15.6–22.1 months) and 6.7 months (95% confidence interval, 2.9–10.5 months), respectively. The main adverse events were grade 3/4 neutropenia (n = 20, 48.8%) and grade 1/2 gastrointestinal toxicity (n = 20, 48.8%).NP regimen is active and tolerable in patients with mTNBC pretreated with anthracyclines and/or taxanes. Therefore, among other chemotherapy regimens, NP combination may provide a rational treatment option for this patient subset.

Phase II and Pharmacological Study of Oral Docetaxel Plus Cyclosporin A in Anthracycline Pre-Treated Metastatic Breast Cancer

Previously, we demonstrated that oral docetaxel plus the P-glycoprotein (Pgp; ABCB1) inhibitor cyclosporin A (CsA) is safe and results in adequate exposure to docetaxel. This phase II study evaluates the anti-tumor activity, safety and pharmacokinetics of oral docetaxel in combination with CsA in women with advanced breast cancer. Patients with measurable advanced breast cancer were given one flat dose of 100 mg oral docetaxel, preceded by one single dose of 15 mg/kg CsA, weekly for 6 weeks in a cycle of 8 weeks. Pharmacokinetic monitoring of docetaxel and CsA was performed in week 1 and 9. Thirty-three patients with a median age of 50 years were recruited. Thirty patients were evaluable for toxicity and twenty-six for response. All had received prior anthracycline treatment. The treatment was generally well tolerated with manageable toxicity although many patients needed a dose reduction, most commonly because of fatigue and uncomplicated neutropenia. The median treatment duration was 16 weeks (range 6 - 32). The overall response rate in evaluable patients was 42% (95% CI: 23 - 63) and the median overall survival was 12.2 months (8.4 - 23.1). The interpatient variability in the area under the curve of 100 mg orally administered docetaxel was moderate, respectively 49 and 30% in week 1 and 9. Weekly oral docetaxel, combined with the booster drug CsA, is an active and safe treatment in anthracycline pre-treated patients with advanced breast cancer.

Sunitinib in combination with trastuzumab for the treatment of advanced breast cancer: activity and safety results from a phase II study

BackgroundThis phase II study evaluated the efficacy and safety/tolerability of sunitinib plus trastuzumab in patients with HER2-positive advanced breast cancer (ABC).MethodsEligible patients received sunitinib 37.5 mg/day and trastuzumab administered either weekly (loading, 4 mg/kg; then weekly 2 mg/kg) or 3-weekly (loading, 8 mg/kg; then 3-weekly 6 mg/kg). Prior trastuzumab and/or lapatinib treatment were permitted. The primary endpoint was objective response rate (ORR).ResultsSixty patients were enrolled and evaluable for safety; 57 were evaluable for efficacy. The majority of patients (58%) had received no prior chemotherapy in the metastatic setting. The ORR was 37%; the clinical benefit rate (CBR; percent objective response plus stable disease ≥ 24 weeks) was 56%. Among patients who were treatment-naïve or had received only adjuvant therapy, the ORR was 44% and the CBR was 59%. Overall, median overall survival had not been reached and the 1-year survival rate was 91%. The majority of adverse events (AEs) were mild to moderate in severity. Forty percent of patients experienced AEs related to measured left ventricular ejection fraction (LVEF) declines, which occurred more frequently in patients who had received prior anthracycline treatment. Ten percent of patients exhibited symptoms related to LVEF declines. One patient died on study from cardiogenic shock. Antitumor response and several safety parameters appeared to correlate with sunitinib exposure.ConclusionsSunitinib plus trastuzumab demonstrated antitumor activity in patients with HER2-positive ABC, particularly those who were treatment-naïve or had only received prior adjuvant treatment. Sunitinib plus trastuzumab had acceptable safety and tolerability in patients with HER2-positive ABC who had not received prior anthracycline therapy.Trial registrationNCT00243503

Real-world analysis of eribulin in metastatic breast cancer (MBC): An assessment of time to treatment failure (TTF) in a community oncology setting.

174 Background: There have been important advances in the treatment of patients with MBC. However, certain patient subgroups such as whose who are triple negative remain a therapeutic challenge. Eribulin is the newest cytotoxic to gain regulatory approval for MBC in the Unites States. In this analysis, the safety and efficacy of eribulin in TNBC patients and those with prior anthracycline exposure were assessed in an early cohort treated in a U.S. community oncology setting. Methods: Ninety patients treated in eight community oncology clinics across the U.S. were identified. Patients were followed from the first cycle of eribulin until disease progression, discontinuation due to toxicity, or death. Data collection included baseline patient and disease characteristics, prior and subsequent anticancer therapy, use of supportive care drugs, number and type of dose limiting toxicity, delivered dose intensity, duration of eribulin therapy and time to treatment failure (TTF). Results: Eribulin was administered after a median of three prior lines of chemotherapy (range 0 to 15). The drug was delivered as a single agent in 79 of 90 patients (88%) at the clinically approved dosage of 1.4 mg/m2on days 1 and 8 of a 21 day cycle. Patients received a median of 4 cycles (1 to 16) for an overall mean duration of 2.9 months (0 to 14.2 months). Approximately 17 of 90 patients (18.9%) were identified as triple negative and 57 of 90 (63.3%) had received prior anthracycline treatment. The median TTF (inter quartile range) was 4 mon (2.3 to 5.6) in all patients. There were no significant differences in TTF by triple negative status (HR=0.1.22, p = 0.49) and prior exposure to anthracyclines (HR=0.78, p = 0.15). In all patients, the most common dose limiting toxicities were neutropenia (32%), anemia (31%), neuropathy (21%) and febrile neutropenia (8.9%). These events led to the premature discontinuation of eribulin in 8 of 90 patients (8.9%). Conclusions: TTF with eribulin was comparable regardless of triple negative status and prior exposure to anthracyclines. These findings are consistent with results from previous clinical studies and warrant further real-world analyses in a larger population.

S5-7: A Phase 2, Randomized, Open-Label, Study of Neratinib (HKI-272) vs Lapatinib Plus Capecitabine for 2nd/3rd-Line Treatment of HER2+ Locally Advanced or Metastatic Breast Cancer.

Abstract Background: Neratinib (N), an irreversible pan-tyrosine kinase inhibitor (TKI), with activity against HER1, -2 and -4, has shown antitumor activity in patients (pts) with HER2+ breast cancer (BC). Lapatinib (L), a reversible HER1 and -2 TKI is approved in combination with capecitabine (C) for treatment of pts with HER2+ advanced or metastatic BC who had prior therapy. Materials and Methods: This phase 2, randomized, open-label study evaluated safety and efficacy of N 240 mg/day vs L 1,250 mg/day plus C 2,000 mg/m2/day (14 days/21 day cycle) in pts with HER2+ locally advanced or metastatic BC. Eligible pts had: ≤2 prior trastuzumab regimens, prior taxane treatment, and no prior anthracycline treatment with cumulative dose &amp;gt;400 mg/m2 doxorubicin, &amp;gt;800 mg/m2 epirubicin, or &amp;gt;equivalent dose of other anthracycline. Primary endpoint was progression-free survival (PFS; investigator-assessed); secondary endpoints included safety, overall survival (OS), objective response rate (ORR), and clinical benefit rate (CBR;% pts with complete response, partial response, or stable disease ≥24 wks). Tumor assessments were every 6 wks for the first 48 wks, then every 12 wks until progressive disease (PD; RECIST 1.0) or initiation of new anticancer therapy. Results: Overall, 117 pts were randomized to N and 116 to L plus C (LC). Mean age (SD; range) was 53.9 y (10.3; 28–79); 60% were White, 34% Asian, and 6% other. Prior treatments included: trastuzumab (229 pts: 168 metastatic or locally advanced, 51 adjuvant, 10 neoadjuvant), taxanes (230 pts), and anthracycline (156 pts). Median treatment duration (range) was 126.5 days (1-636) for N and 201 days (13-622) for LC. Median relative dose intensity (actual/expected exposure) for N was 100%. As of data cutoff, 84% had discontinued treatment; 65% from PD (N 63%, LC 67%), 9% for adverse events (AEs; N 7%, LC 11%). In the ITT cohort, for N and LC, respectively, median PFS (95% CI) was 4.5 mo (3.1−5.7) and 6.8 mo (5.9−8.2; P = 0.091; hazard ratio = 1.3 [95% CI, 1.0−1.8]); median OS (95% CI) was 19.4 mo (19.4−22.2; 41 deaths) and 19.0 mo (16.9-NA; 35 deaths; P = 0.180); ORR (95% CI) was 29% (21-38) and 41% (32-50; P = 0.067); CBR (95% CI) was 44% (35-54) and 64% (54-73; P = 0.003). Most common drug-related treatment-emergent AEs (TEAEs; any grade) were diarrhea (N 84%, LC 67%), nausea (34%, 38%), palmar-plantar erythrodysesthesia (PPE; 5%, 63%), and rash (18%, 34%); for grade ≥3, diarrhea (28%, 10%) and PPE (0, 14%). Dose reductions/discontinuations from diarrhea occurred in 13/3 pts on N, and 15/7 pts on LC. Study deaths for N and LC, respectively, included: 36 pts (31%) and 32 pts (28%) from PD; 5 pts (4%) and 3 pts (3%) from AEs unrelated to study drug. Discussion: In this setting of pts less heavily pre-treated than in the pivotal LC trial, single agent N demonstrated high anti-tumor activity (ORR 29%), confirming results from prior N phase 2 trials. N alone did not appear to be as effective as LC. No unexpected TEAEs were observed; N was well tolerated in pts with HER2+ locally advanced or metastatic BC; while diarrhea was more frequent on N than LC, it was manageable with antidiarrheals and did not lead to more treatment discontinuations. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S5-7.

Pixantrone (PIX) Inhibition of Doxorubicinol (DOXOL) Formation in Human Myocardium: Implications for Cardiac Safety in Non-Hodgkin Lymphoma (NHL) Patients with Prior Anthracycline Treatment

Abstract 4966 BackgroundDoxorubicin (DOX) and related drugs are incompletely cleared from the heart, persist for months to years (Stewart et al Anticancer Res 1993), and slowly transform to longer-lived and more toxic secondary alcohol metabolites (eg, DOXOL) that are associated with an increased lifetime risk of congestive heart failure (Minotti et al J Pharmacol Exp Ther 2010). Anthracycline-related cardiotoxicity can be precipitated by enhanced stress or exposure to drugs that increase DOXOL formation. PIX is a novel aza-anthracenedione that is under development in patients with NHL that relapsed or was refractory after DOX-containing combination therapy. In preclinical models, PIX produced substantially less cardiotoxicity than DOX or MITOX even when animals were pretreated with DOX. Compared to anthracyclines and the anthracenedione analogue, mitoxantrone (MITOX), PIX lacks a hydroquinone moiety that binds iron and facilitates cardiotoxic free radical reactions. To further establish that it is safe in patients with NHL and prior DOX exposure, PIX should also have no effect on or diminish DOXOL formation from the cardiac residues of first-line DOX. AimsTo characterize the effects of PIX on DOXOL formation in a translational cardiac model of DOX administration followed by PIX administration. MITOX was used as the comparator. MethodsMyocardial samples that were routinely discarded during aorto-coronary bypass grafting were dissected into strips and loaded with 10 μM DOX in plasma. After 30 min the strips were subjected to 2h multiple washouts to simulate post-treatment clearance. The strips were then incubated for 1.5h in fresh anthracycline-free plasma w/wo 1 μM PIX or MITOX. After the experiments, DOX(OL), PIX, and MITOX were extracted from the soluble fractions of the strips and assayed by HPLC. Pharmacometabolic interactions of 10 μM or 50 μM DOX with increasing concentrations of PIX or MITOX were also studied in NADPH-supplemented isolated soluble fractions. ResultsAfter sequential DOX loading/clearance and PIX or MITOX administration, PIX:DOX ratios were significantly higher than MITOX:DOX ratios in soluble fractions of human myocardial strips. This correlated with inhibition of DOXOL formation by both PIX and MITOX, but PIX decreased DOXOL levels in a significant manner when compared to MITOX (Table). In isolated soluble fractions, both PIX and MITOX, in a concentration-dependent manner, inhibited the metabolism of 10 μM DOX to DOXOL; however, PIX caused stronger inhibition (Figure). Increasing DOX to 50 μM abated inhibition by MITOX but not by PIX. DiscussionPIX inhibited DOXOL formation in a translation model of human heart used to simulate sequential DOX and PIX administration. This finding was obtained under pharmacokinetically relevant conditions that probed DOX and PIX at their clinically documented plasma Cmax values of 10 μM or 1 μM, respectively. Studies with isolated soluble fractions suggest that PIX diminished DOXOL formation by noncompetitive inhibition of NADPH-dependent reductases. MITOX was less effective than PIX at diminishing DOXOL formation, which correlated with the lower MITOX:DOX ratios in treated human myocardial strips and with the competitive mode of action of MITOX. By inhibiting formation of toxic and long-lived DOXOL, PIX potentially is a cardiac tolerable therapeutic agent for patients with NHL that failed or relapsed after DOX treatment.TreatmentDOX (nmol/g)Anthracenedione (nmol/g)Anthracenedione:DOX (%)DOXOL (nmol/g)DOX1.8 ± 0.2−−0.005 ± 0.001DOX + MITOX1.5 ± 0.10.13 ± 0.0211.3 ± 1.80.004 ± 0.002DOX + PIX2.0 ± 0.20.35 ± 0.03*16.9 ± 1.1*0.002 ± 0.001†n= 5-9 (triplicate); * P<0.01 vs MITOX; †P<0.05 vs DOX alone [Display omitted] Inhibition of DOXOL formation by PIX and MITOX in isolated soluble fractions of human myocardium incubated with NADPH (0.25 mM) and DOX for 4h. Control DOXOL was 0.15–0.19 nmoles/mg of protein at 10 μM DOX and 0.34–0.84 nmoles/mg of protein at 50 μM DOX. Each inhibition curve is the mean and SE of three experiments. Disclosures:Salvatorelli:Cell Therapeutics, Inc: Research Funding. Gonzalez Paz:Cell Therapeutics, Inc: Research Funding. Singer:Cell Therapeutics, Inc: Employment. Menna:Cell Therapeutics, Inc: Research Funding. Minotti:Cell Therapeutics, Inc: Research Funding.

A literature-based meta-analysis taxane-based doublet versus single-agent taxane chemotherapy in patients with advanced breast cancer

Clinical trials have reported conflicting results as to whether taxane-based doublet improves outcome over single-agent taxane in patients with advanced breast cancer. We performed a meta-analysis comparing primary and secondary end points of taxane-based doublet with single-agent taxane chemotherapy in patients with advanced breast cancer and prior anthracycline treatment. The event-based relative risk ratio (RR) with 95% confidence intervals (95% CI) was derived, and a test of heterogeneity was applied. Four eligible trials (2,343 patients) were selected from 488 studies that initially were identified. A significant difference in favoring taxane-based doublet over single-agent taxane was observed in progression-free survival (PFS) (RR, 1.33; 95% CI, 1.02-1.75; P = 0.039) and partial response (PR) (RR, 1.43; 95% CI, 1.10-1.86; P = 0.008). The ORR was higher for patients receiving taxane-based doublet, although not statistically significant (RR, 1.17; 95% CI, 0.91-1.50; P = 0.220). Whereas there was no difference in 1-year survival rate (1-year SR) (RR, 1.05; 95% CI, 0.94-1.17; P = 0.422), clinical benefit (CB) (RR, 1.02; 95% CI, 0.95-1.09; P = 0.642), and complete response (CR) (RR, 0.75; 95% CI, 0.31-1.79; P = 0.512). Toxicities did not differ significantly except stomatitis and diarrhea. Taxane-based doublet appeared to improve PFS and PR compared with single-agent taxane in the treatment of patients with advanced breast cancer. Further prospective, randomized, controlled trials will be necessary.

A phase II study of gemcitabine plus paclitaxel in patients with metastatic breast cancer and prior anthracycline treatment

To investigate the efficacy and safety of gemcitabine-paclitaxel in Chinese patients with metastatic breast cancer following anthracycline failure in a multicenter, open-label, single-arm, phase II clinical trial. Chinese female patients with unresectable, locally recurrent or metastatic breast cancer who had relapsed after neo-adjuvant anthracycline-based chemotherapy were included. All patients had measurable disease and an Eastern Cooperative Oncology Group performance status of 0 or 1 at baseline. Gemcitabine (1250 mg/m(2) )-paclitaxel (175 mg/m(2) ) was administered on a 3-weekly schedule until disease progression, and patients were followed up for 12 months (post-enrollment). The primary end point was objective response rate; secondary end points included duration of response, progression-free survival and overall survival. Overall 60 patients were enrolled. Their mean age was 46.9 (SD ± 9.0) years and 90% of patients had metastatic disease. All patients had previously received chemotherapy. A total of 48 patients (80%) completed the 12-month follow up, and 40 patients (67%) completed at least six cycles of study therapy. The objective response rate (complete response + partial response) was 50% (95% CI: 36.6-63.4). Median duration of response was 5.6 months (95% CI: 4.4-7.6) and median progression-free survival was 7.6 months (95% CI: 5.8-8.8). Overall survival at 12 months was 87% (95% CI: 77.9-95.2). Laboratory toxicities were primarily hematologic, including Grade 3 and 4 neutropenia (n = 27 [45%]) and leukopenia (n = 18 [30%]). Eight patient deaths (13%) were not treatment-related. Gemcitabine-paclitaxel combination therapy is an active and well-tolerated chemotherapy regimen, with expected and manageable toxicity in Chinese patients with metastatic breast cancer.

A double-blind, randomized, prospective, phase II trial of capecitabine (Cap) plus enzastaurin (Enz) versus cap plus placebo in patients (pts) with advanced breast cancer (BrCa) and prior anthracycline and taxane treatment.

1054 Background: This international trial studied the efficacy and safety of Cap plus Enz in treating advanced BrCa. Methods: Eligible pts (advanced BrCa, prior anthracycline and taxanes, ≤2 prior chemotherapy regimens and performance status ≤2) were randomized to 1250 mg/m2 Cap (days 1 to 14) and a loading dose of 1125 mg Enz on day 1 of Cycle 1 preceding daily 500 mg Enz (Cap-E) or daily placebo (Cap-P) as continuous oral 21-day cycle treatment. Pts discontinued due to progression, death, or adverse event (AE). Response was assessed before alternate cycles. The primary endpoint, progression-free survival (PFS), was compared between arms using log-rank test. Planned enrollment of 60 pts/study arm provided 80% power to detect a 40% PFS improvement with Cap-E over Cap-P (1-sided type-I error=0.20). Results: Prespecified efficacy and safety conditions were not met in a planned interim analysis and the study was terminated. All data from study enrollment to termination were analyzed. 85 pts were randomized (Cap-E, n=42; Cap-P, n=43; median age, 54.2 years) and received ≥1 study drug dose. There were no statistically significant differences between Cap-E and Cap-P, respectively, in PFS (median [95% CI]=2.8 months [2.1, 4.6] versus 4.3 months [2.9, 6.2]; log-rank p=0.237), overall survival (median [95% CI]=9.9 months [7.0, 16.6] versus 14.9 months [9.9, 19.3); log-rank p=0.181), best overall response (11.9% versus 11.6%; Fisher's Exact p=1.00) or duration of response (median [95% CI]=4.3 months [2.2, 4.3] versus 3.5 months [2.8, N/A]; log-rank p=0.812). More Cap-E than Cap-P pts, respectively, experienced ≥1 drug-related (d-r) Grade 3/4 toxicity (42.9% versus 32.6%), d-r serious AE (16.7% versus 14.0%) and d-r hospitalization (14.3% versus 9.3%). Fewer Cap-E (9.5%) than Cap-P pts (11.6%) discontinued due to d-r AEs. There were 4 study d-r deaths (Cap-E, n=2; Cap-P, n=2) on therapy or within 30 days of study treatment discontinuation. Conclusions: When compared with Cap-P, Cap-E did not improve survival outcomes and increased d-r toxicity. These data do not support use of Cap-E in this patient population. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lilly Lilly Lilly Lilly, Roche Lilly

Anthracycline-rechallenge using pegylated liposomal doxorubicin (PLD) in previously treated patients with metastatic breast cancer (MBC): A meta-analysis using pooled individual data from four prospective trials

1047 Background: Few data are available on the efficacy of anthracycline rechallenge using PLD. Methods: Pooled individual data from 4 prospective trials (Keller, J Clin Oncol. 2004; O'Brien, Ann Oncol. 2004; Al-Batran, Br J Cancer. 2006; and Al-Batran, Oncology. 2006) were utilized to evaluate the activity of PLD in pts with MBC previously treated with conventional anthracyclines. Primary endpoint was clinical benefit rate (CBR), defined as objective response or stable disease, both lasting ≥ 6 months. CBR was assessed in the entire group (primary hypothesis CBR ≥ 30%) and in pre-defined subgroups of pts depending on the most important features of their prior anthracycline-based therapy. Results: The studies comprised a total 935 pts, of whom 274 pts had received PLD after prior exposure to conventional anthracyclines. At the time of PLD therapy, these (274) pts were heavily pre-treated for MBC (median lines of previous chemotherapy 4, range 1 to 9, and 93.4% of pts received PLD after ≥ 2 previous chemotherapies for MBC). Prior anthracycline treatment was adjuvant, anti-metastatic, or both in 14%, 46%, or 40% of pts, respectively. The overall CBR from PLD was 32.2% (95% CI, 26.7%-37.8%), with no difference between pts who were considered anthracycline resistant (based on the study records) and those who were not (31.9% vs. 31.6%, respectively; p = 1). There was also no difference in CBR from PLD between pts who received prior anthracyclines adjuvant only (33.3%), anti-metastatic only (34.4%) or both (29.4%; p = 0.71). There was a trend towards a higher CBR in pts who received PLD at &gt; 12 months vs ≤ 12 months since the end of their prior conventional anthracycline treatment (34.2% vs. 26.3%, respectively; p = 0.21). Higher CBR (up to 47%) and longer survival times were observed in pts without taxane pretreatment or with a low number of previous chemotherapies, most likely reflecting a less advanced disease in these pts. Conclusions: This meta-analysis demonstrates a clinical benefit from PLD in MBC pts previously treated with multiple chemotherapies, including anthracyclines. Interestingly, the CBR was independent of resistance to, setting of, or time since previous conventional anthracycline therapy. [Table: see text]

The Utility of Radionuclide Ventriculography (RNV) Prior to Anthracycline Chemotherapy in Patients with Acute Myeloid Leukemia: A Retrospective, Single Institution Study.

Background: Despite cardiotoxicity, anthracyclines remain one of the most important classes of cytotoxic agents in the management of hematological malignancy. For over two decades, monitoring of left ventricular ejection fraction (LVEF) has been recommended to identify patients at risk of developing overt cardiac failure. As anthracycline cardiotoxicity is closely correlated with cumulative dose, and current chemotherapy protocols limit exposure to these agents, we sought to investigate whether routine LVEF estimation by RNV remains necessary in patients undergoing treatment for acute myeloid leukemia (AML). We also sought to determine whether subgroups of patients could be identified who were at higher or lower risk of cardiotoxicity.Methods: Between 2000 and 2006, 104 patients underwent induction chemotherapy for AML at the Alfred Hospital. Retrospective review of prior cardiac history, cumulative anthracycline dose and results of RNV assessment was undertaken. RNV was performed according to established protocols in the best left anterior oblique projection to obtain maximal septal separation between left and right ventricles allowing a robust and reproducible measure of LVEF.Results: Median patient age was 59 years (range 17–74); 50% were female. 4 patients had prior exposure to anthracylines and one patient had a history of cardiac disease. Induction chemotherapy consisted of cytosine arabinoside (standard dose 93%; high dose 7%) combined with an anthracycline (idarubicin 94%, daunorubicin 5%, amsacrine 1%). Of the 104 patients who underwent induction chemotherapy, 25 (24%) had one and 47 (45%) had two courses of cytosine arabinoside based consolidation chemotherapy. All patients had LVEF measured by RNV prior to induction. 62% and 32% of patients had repeat assessment prior to their first and second consolidation chemotherapy cycles respectively. For all patients receiving idarubicin, the cumulative dose was < 60 mg/m2 in 43% and ≥60 mg/m2 in 57%. Five patients had chemotherapy management changed as a result of RNV monitoring: one did not receive an anthracycline due to baseline LVEF impairment and four patients had amsacrine in place of idarubicin after induction due to a reduction in LVEF. Six patients in total had a reduction in LVEF of greater than 20%, however none developed clinically significant cardiac decompensation. Two of these had risk factors for anthracycline induced cardiotoxicity: one prior anthracycline treatment with mediastinal radiotherapy and one a pre-existing reduction in LVEF. Cumulative idarubicin dose, cytosine arabinoside dose, age or gender did not predict for a fall in LVEF.Conclusion: Despite minimal overall anthracycline cardiotoxicity, clinically significant falls in LVEF occurred in 6% of patients and was largely unpredictable. However, even though RNV enabled this group of patients to be easily identified the optimal management of patients with asymptomatic falls in LVEF remains to be determined.

A Phase II Trial of Vinorelbine and Pegylated Liposomal Doxorubicin in Patients With Pretreated Metastatic Breast Cancer

The objective of the present study is to investigate the clinical efficacy and tolerance of vinorelbine and pegylated liposomal doxorubicin (PLD) in patients with metastatic breast cancer (MBC) with prior taxane and/or anthracycline treatment. A total of 25 patients who previously received taxane- and/or anthracycline-based chemotherapy as first- and/or second-line treatment of MBC were entered into the study and were treated with 20 mg/m2 vinorelbine on day 1 and 8 and 30 mg/m2 PLD on day 1 every 3 weeks. All were evaluated for efficacy, quality of life, and tolerance. Three complete and 6 partial responses were observed in 25 patients for an objective response rate of 36% (95% confidence interval: 17-55%). Eight patients (32%) had stable disease of not less than 3 months and 8 patients (32%) had disease progression. The median progression-free survival was 6.7 months (range, 2-18 months), and the median overall survival was 13.2 months (range, 3-31 months). Severe toxicities (grade 3 or above) were neutropenia (16%) and mucositis (8%). The health-related quality of life assessed before each cycle by specific questionnaire did not differ significantly over the treatment period. The combination of vinorelbine and PLD for anthracycline- and/or taxane-pretreated patients with MBC is an active and safe regimen that does not compromise the quality of life.

BAY 43–9006 as single oral agent in patients with metastatic breast cancer previously exposed to anthracycline and/or taxane

577 Background: BAY 43–9006 targets the ras/raf signaling pathway and inhibits VEGFR-2, VEGFR-3 and or PDGFR-β growth factors. A study was conducted to assess anti-tumor activity and the toxicity profile in patients (pts) with metastatic breast cancer (MBC). Methods: A two-stage phase II study was conducted with pts with MBC who had measurable disease and were candidates for 1st or 2nd line chemotherapy and had previously received an anthracycline and/or a taxane in the neoadjuvant, adjuvant, or metastatic setting. Pts started with a dose of 400 mg twice daily on days 1–28 of each 4 week cycle. Based on interval adverse events (AEs), a dose reduction was considered as 400 mg given one time daily. Primary endpoint was tumor response defined as a complete or partial response (PR) according to RESIST. The study required 40 pts, but was to be terminated if 0 or 1 responses occurred among 1st 20 eligible pts. Results: 23 pts enrolled with a median age of 54 (range 37–70) but 3 were declared ineligible. All 23 pts were included in all analyses except efficacy analysis as stated per protocol. Fifteen (65%) had visceral metastasis; 22 (96%) had prior anthracycline treatment (tx); 16 (70%) had prior taxane tx.; 10 (44%) had received prior chemotherapy for metastatic disease and 14 (61%) had a prior relapse free interval of 12 months (mos) or more. Pts received tx for a median of 2 cycles (range 1–8) with a median follow-up of 7.2 mos. Dose reductions were due to dermatitis/skin rash (3), hand/foot skin reaction (2), hypertension (1) and cramping hands/feet (1). No grade 4 AEs occurred and grade 3 AEs included acne (2), hand/foot skin reaction (1), neutropenia (1), cough (1), wound infection (1), and prolonged PTT (1). Among the 20 pts eligible for efficacy analysis one pt (5%; 95% CI 0.5–20.5%) achieved a PR with duration of 3.6 mos and one pt achieved stable disease for at least 6 mos. The 6-month overall survival rate was 81% and the progression-free survival rates were 53% at 2 mos, 24% at 4 mos and 6% at 6 mos. Median time to progression was 2 mos. Based on the lack of sufficient response, we did not proceed with the 2nd stage of this study. Conclusion: Treatment with oral BAY 43–9006, while well tolerated, does not have sufficient activity to warrant further testing as a single agent in this disease setting. [Table: see text]

Phase II study of ixabepilone in patients (pts) with taxane-resistant metastatic breast cancer (MBC): Final report

10505 Background: Ixabepilone is the first epothilone analog in a new class of antineoplastic agents, which optimizes the properties of the naturally occurring epothilone B. The epothilones promote tumor cell death by uniquely binding to tubulin and stabilizing microtubules. Methods: This international, multicenter, open-label Phase II trial was designed to assess the activity of ixabepilone in pts with highly resistant MBC who had progressed following taxane treatment. Eligible pts were aged ≥18 years with MBC (progressed on or within 4 months of taxane therapy [or within 6 months if adjuvant taxane only]). Pts must have received a taxane as their last regimen. Pts were excluded if they had received ≥3 prior chemotherapy regimens for MBC or had ≥Grade 2 neuropathy. Ixabepilone was administered intravenously as a 3-hour infusion at a dose of 40 mg/m2 every 3 weeks. Results: Of 49 pts (median age 54 years, range 30–81), 86% of pts had received at least two prior chemotherapy regimens. 98% had received prior anthracycline treatment. 73% of pts had progressed within 1 month of their last taxane dose. 84% had visceral metastases. Pts received a median of three cycles (range 1–5) and median cumulative dose of 120 mg/m2 (range 40–498 mg/m2). The tumor response rate (number of responders [complete and partial response]/number of response-evaluable pts) was 12% (95% CI = 4.7–26.5%). All the responders (n = 6) had partial responses; five of the six had not responded to prior taxane therapy. The responders received a median of 10.5 cycles (range 5–15) and had a median duration of response of 10.4 months (95% CI = 6.3–22.0 months). In 20 pts (41%) stable disease was reported as the best overall outcome. The majority of these pts (16 of 20, 80%) received ≥4 cycles of ixabepilone therapy. The median time to progression was 2.2 months (95% CI = 1.4–3.2 months); the median survival was 7.9 months (95% CI = 6.1–14.5 months). Conclusions: Ixabepilone (40 mg/m2 as a 3-hour infusion every 3 weeks) demonstrates promising antitumor activity, along with an acceptable safety profile in pts with clearly defined taxane-resistant MBC. [Table: see text]

Powerful Prognostic Stratification By [18F]Fluorodeoxyglucose Positron Emission Tomography in Patients With Metastatic Breast Cancer Treated With High-Dose Chemotherapy

This study examines the use of [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET) for the evaluation of the therapeutic response for patients treated with high-dose chemotherapy (HDC) with autologous stem cell transplantation for metastatic breast cancer (MBC) focusing on prognostic stratification. Forty-seven patients with MBC were treated with a maximum of three cycles of HDC. Therapeutic response was assessed with conventional imaging (CImg; including a computed tomography in all cases and ultrasound, mammography, and bone scanning as clinically indicated) and by FDG-PET study performed after the last cycle of HDC. Parameters analyzed for predicting survival were FDG-PET and CImg results, pattern of disease, prior treatment, and HDC regimen. Complete responses were observed in 16 patients (37%) with CImg and 34 patients (72%) with FDG-PET. The FDG-PET result was the most powerful and independent predictor of survival; patients with a negative post-treatment FDG-PET had a longer median survival than patients with a positive FDG-PET (24 months v 10 months; P < .001). By multivariate analysis the relative risk (RR) of death was higher in patients with FDG-PET-positive disease (RR, 5.3), prior anthracycline treatment (RR, 3.3), or with visceral metastasis (RR, 2.4). A single FDG-PET study performed after completion of HDC for MBC can powerfully stratify for survival. This may have implications for how we should assess outcome after conventional-dose therapy for MBC and warrants additional study.