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Phase II Evaluation of Liposomal Doxorubicin with Docetaxel in Patients with Metastatic Breast Cancer.

ABSTRACT: BACKGROUND: Taxanes are effective in treating metastatic breast cancer. Liposomal doxorubicin (LD) is as effective as doxorubicin but less toxic. PATIENTS AND METHODS: This phase II trial assessed the combination of LD and docetaxel (D). Between 12/2002 and 9/2005, 12 women received monthly LD (30 mg/m(2)) and weekly D (30 mg/m(2)). Cycles were continued until progression or toxicity. Primary outcome was time to progression. Secondary endpoints included response rate, time to treatment failure, duration of response, survival, and toxicity. RESULTS: Median age was 49 (31-60) years. 9 (75%) patients had estrogen receptor-positive or progesterone receptor-positive tumors. 5 (41.7%) women had her-2/neu-positive tumors. 4 women stopped participation due to toxicity, and 7 due to progression. 8 (67%) participants (95% confidence interval (CI) 51.6-94.5%) had a partial response, and 2 (16.7%) had stable disease. Median time to progression was 9.6 months (95% CI 4.7-12.2). Median time to treatment failure was 6.5 months (95% CI 4.4-10.5). Median survival was 22.1 months (95% CI 9.6-40.8). Median duration of partial response was 2.7 months (95% CI 2.4-10.5). 10 (83%) women experienced grade 3/4 toxicities: neutropenia 3 (25%), infection 3 (25%), stomatitis 5 (41.7%), nausea 2 (16.7%), vomiting 1 (8.3%), dyspnea 2 (16.7%), pericardial effusion 1 (8.3), and palmar-plantar erythrodysesthesia 1 (8.3%). CONCLUSIONS: LD and D resulted in an encouraging response and unacceptable toxicities.

SUBMITTER: Fasano J

PROVIDER: S-EPMC3357161 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Phase II Evaluation of Liposomal Doxorubicin with Docetaxel in Patients with Metastatic Breast Cancer.

Fasano Julie J Hershman Dawn D Novik Yelena Y Levinson Benjamin B Blozie Kim K Tiersten Amy D AD

Breast care (Basel, Switzerland) 20100202 1

BACKGROUND: Taxanes are effective in treating metastatic breast cancer. Liposomal doxorubicin (LD) is as effective as doxorubicin but less toxic. PATIENTS AND METHODS: This phase II trial assessed the combination of LD and docetaxel (D). Between 12/2002 and 9/2005, 12 women received monthly LD (30 mg/m(2)) and weekly D (30 mg/m(2)). Cycles were continued until progression or toxicity. Primary outcome was time to progression. Secondary endpoints included response rate, time to treatment failure, ...[more]

PMID: 22619636

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Project description:BackgroundThe aim of this study was to improve activity over single human epidermal growth factor receptor 2 (HER2)-blockade sequential neaodjuvant regimens for HER2-positive breast cancer, by exploiting the concomitant administration of trastuzumab, taxane and anthracycline, while restraining cardiac toxicity with use of liposomal doxorubicin, and by adding metformin, based on preliminary evidence of antitumor activity.Patients and methodsThis multi-center, single-arm, two-stage phase II trial, assessed the safety and the activity of a new treatment regimen for HER2-positive, early or locally advanced breast cancer. Patients received six 21-day cycles of non-pegylated liposomal doxorubicin, 50 mg/m2 intravenously (i.v.) on day 1, docetaxel, 30 mg/m2 i.v. on days 2 and 9, trastuzumab, 2 mg/kg/week i.v. on days 2, 9, and 16 (with 4 mg/kg loading dose), in association with metformin 1000 mg orally twice daily. The primary endpoint was the rate of pathological complete response (pCR) in the breast and axilla (ypT0/is ypN0). A subgroup of patients performed a 3-deoxy-3-18F-fluorothymidine positron emission tomography (FLT-PET) at baseline and after one cycle.ResultsAmong 47 evaluable patients, there were 18 pCR [38.3%, 95% confidence interval (CI) 24.5-53.6%]. A negative estrogen-receptor status, high Ki67, and histological grade 3 were related with pCR, although only grade reached statistical significance. FLT-PET maximum standardized uptake value after one cycle was inversely related to pCR in the breast (odds ratio 0.29, 95% CI 0.06-1.30, p = 0.11). Toxicity included grade 3-4 neutropenia in 70% and febrile neutropenia in 4% of patients, grade 1-2 nausea/vomiting in 60%/38%, and grade 3 in 4%/2%, respectively, grade 1-2 diarrhea in 72%, and grade 3 in 6%. There were two cases of reversible grade 2 left-ventricular ejection-fraction decrease, and one case of sharp troponin-T increase.ConclusionsThe concomitant administration of trastuzumab, liposomal doxorubicin, docetaxel, and metformin is safe and shows good activity, but does not appear to improve activity over conventional sequential regimens.

Project description:BackgroundAnthracyclines and taxanes are effective drugs in breast cancer (BC), but their toxicity profiles limit their use in combination. A dose-finding study was performed to determine maximum tolerated doses (MTDs) of nonpegylated liposomal doxorubicin (TLC-D99) and docetaxel (DTX) as a dose-dense schedule, to maintain dose intensity, and to limit toxicity, particularly cardiac.MethodsTwenty-four patients were enrolled, 12 with metastatic BC, 5 with locally advanced BC, and 7 with early BC. An intra- and interpatient approach was planned in two sequential steps. In the first step, TLC-D99 was administered at dose levels of 40, 45, and 50 mg/m(2) plus DTX at a fixed dose of 50 mg/m(2). In the second step, TLC-D99 was administered at the dose established in the first step plus DTX at dose levels of 55, 60, and 65 mg/m(2). Every treatment cycle was delivered on day 1 every 14 days. Pegylated granulocyte colony-stimulating factor was scheduled on day 2. Dose-limiting toxicities (DLTs) were defined as G4 hematological; G3 nonhematological; ≥10% or ≥20% left ventricular ejection fraction (LVEF) reduction if the final value was <50% or ≥50%, respectively; severe arrhythmia; and symptomatic heart failure. LVEF was evaluated by echocardiography every two cycles, and precursor brain natriuretic peptide (pBNP) and cardiac troponin I (cTnI) were monitored on days 1 and 2.ResultsFive DLTs occurred (20.8%). No cardiac event of congestive heart failure was reported; 2 events of grade 3 cardiac dysfunction (8.3%), including a ≥20% LVEF reduction in 1 patient and symptomatic arrhythmia in another; 2 incidences of G4 neutropenia (8.3%); and 1 occurrence of G3 asthenia (4.2%) were reported. MTDs were not reached. The recommended doses were established as TLC-D99 50 mg/m(2) and DTX 65 mg/m(2). Cumulatively, mild (G1-G2) cardiac dysfunction was observed in 58.4% of patients: G1 cardiac arrhythmia was noted in 50%, G1-G2 general cardiac toxicity occurred in 25%, and concomitant toxicity was present in 17%. cTnI never increased. pBNP was increased in 25% and was associated with limiting arrhythmia in 4% and cardiac dysfunction in 16%.ConclusionDose-dense TLC-D99 50 mg/m(2) and DTX 65 mg/m(2) can be safely administered in combination every 2 weeks for breast cancer, with the highest projected dose intensity for each drug at 25 and 32.5 mg/m(2) per week, respectively.

Project description:BACKGROUND:Olaratumab is a platelet-derived growth factor receptor-? (PDGFR?)-targeting monoclonal antibody blocking PDGFR? signaling. PDGFR? expression is associated with a more aggressive phenotype and poor ovarian cancer outcomes. This randomized, open label phase II study evaluated olaratumab plus liposomal doxorubicin compared with liposomal doxorubicin alone in advanced ovarian cancer patients. METHODS:Patients with platinum-refractory or platinum-resistant advanced ovarian cancer were randomized 1:1 to receive liposomal doxorubicin (40?mg/m2, intravenous infusion) administered every 4?weeks with or without olaratumab (20?mg/kg, IV infusion) every 2?weeks. Patients were stratified based on prior response to platinum therapy (refractory vs resistant). The primary efficacy endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate, duration of response, and safety. RESULTS:A total of 123 patients were treated (62 olaratumab+liposomal doxorubicin; 61 liposomal doxorubicin). Median PFS was 4.2?months for olaratumab+liposomal doxorubicin and 4.0?months for liposomal doxorubicin (stratified hazard ratio [HR]?=?1.043; 95% confidence interval [CI] 0.698-1.558; p?=?0.837). Median OS was 16.6?months and 16.2?months in the olaratumab+liposomal doxorubicin and liposomal doxorubicin arms, respectively (HR?=?1.098; 95% CI 0.71-1.71). In the platinum-refractory subgroup, median PFS was 5.5?months (95% CI 1.6-9.2) and 3.7?months (95% CI 1.9-9.2) in the olaratumab+liposomal doxorubicin (n?=?15) and liposomal doxorubicin arms (n?=?16), respectively (HR?=?0.85; 95% CI 0.38-1.91). Overall, 59.7% (olaratumab+liposomal doxorubicin) and 65.6% (liposomal doxorubicin) of patients reported grade???3 adverse events regardless of causality. The most common treatment-emergent adverse events (all grades) regardless of causality were fatigue related (61%), nausea (57%), and constipation (52%) with olaratumab+liposomal doxorubicin and nausea (64%), fatigue related (62%), and mucositis (46%) with liposomal doxorubicin. CONCLUSIONS:The addition of olaratumab to liposomal doxorubicin did not result in significant prolongation of PFS or OS in platinum-resistant or platinum-refractory ovarian cancer. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT00913835 ; registered June 2, 2009.

Dataset Information

Phase II Evaluation of Liposomal Doxorubicin with Docetaxel in Patients with Metastatic Breast Cancer.

Publications

Phase II Evaluation of Liposomal Doxorubicin with Docetaxel in Patients with Metastatic Breast Cancer.

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