Doxorubicin, paclitaxel and gemcitabine: a Phase I study of a new sequential treatment in stage III B - IV breast cancer

Based on the synergistic interactions of the sequence doxorubicin-paclitaxel-gemcitabine obtained in our preclinical study, a Phase I trial was conducted to evaluate the feasibility of this new sequence in breast cancer. Patients with stage IIIB-IV breast cancer received doxorubicin on day 1, paclitaxel on day 2 and gemcitabine on day 6 and 13 (steps IIa, III and V) in cohorts of 3 patients. From March 1999 to December 2000, 9 patients were treated. The most important toxicity was hematological. The maximum tolerated dose was reached at the second level because dose-limiting toxicity occurred in 3 patients. Non hematological toxicities were alopecia, diarrhea, asthenia, nausea, mucositis, paresthesia and myalgia. A Phase II trial is ongoing to further investigate the activity of this new sequential treatment with doxorubicin (50 mg/m2 day 1), paclitaxel (160 mg/m2 day 2) and gemcitabine (800 mg/m2 day 6) in advanced breast cancer.     

High Efficacy of Paclitaxel and Doxorubicin as First-Line Therapy in Advanced Breast Cancer: A Phase I-II Study

Abstract

The aim of this study was to define the maximum tolerated dose (MTD) of paclitaxel (TAX) in combination with doxorubicin (ADM). To evaluate the efficacy and tolerability of this combination, TAX was administered in escalating doses of 30 mg/m², starting from 120 mg/m², by 1 hour continuous infusion, per group of three patients; ADM was administered at a fixed dose of 50 mg/m², 24 hours before administering TAX (phase I). The combination was recycled every 3 weeks. In phase II, TAX was administered at the MTD defined in phase I.

Thirty-six women were enrolled. The MTD of TAX was 220 mg/m². Objective responses were observed in 28/34 (82%) assessable patients. The median progression-free survival was 11.8 months and overall survival 27.8 months. The main clinical toxicity was neutropenia (grade III-IV) of short duration (94%). Two patients developed cardiac toxicity.

The combination TAX+ADM is very effective in advanced breast cancer.     

Phase II Study of Paclitaxel and Dasatinib in Metastatic Breast Cancer

Background

Overexpression and activation of tyrosine kinase Src has been linked to breast carcinogenesis and bone metastases. We showed the feasibility of combining the SRC inhibitor dasatinib with weekly paclitaxel in patients with metastatic breast cancer (MBC) and herein report the subsequent phase II trial.

A Phase III Study of Balugrastim Versus Pegfilgrastim in Breast Cancer Patients Receiving Chemotherapy With Doxorubicin and Docetaxel

Objectives.

This study aimed to evaluate the efficacy and safety of once-per-cycle balugrastim versus pegfilgrastim for neutrophil support in breast cancer patients receiving myelosuppressive chemotherapy.

Methods.

Breast cancer patients (n = 256) were randomized to 40 or 50 mg of subcutaneous balugrastim or 6 mg of pegfilgrastim ≈24 hours after chemotherapy (60 mg/m² doxorubicin and 75 mg/m² docetaxel, every 21 days for up to 4 cycles). The primary efficacy parameter was the duration of severe neutropenia (DSN) in cycle 1. Secondary parameters included DSN (cycles 2–4), absolute neutrophil count (ANC) nadir, febrile neutropenia rates, and time to ANC recovery (cycles 1–4). Safety, pharmacokinetics, and immunogenicity were assessed.

Results.

Mean cycle 1 DSN was 1.0 day with 40 mg of balugrastim, 1.3 with 50 mg of balugrastim, and 1.2 with pegfilgrastim (upper limit of 95% confidence intervals for between-group DSN differences was <1.0 day for both balugrastim doses versus pegfilgrastim). Between-group efficacy parameters were comparable except for time to ANC recovery in cycle 1 (40 mg of balugrastim, 2.0 days; 50 mg of balugrastim, 2.1; pegfilgrastim, 2.6). Median terminal elimination half-life was ≈37 hours for 40 mg of balugrastim, ≈36 for 50 mg of balugrastim, and ≈45 for pegfilgrastim. Antibody response to balugrastim was low and transient, with no neutralizing effect.

Conclusion.

Once-per-cycle balugrastim is not inferior to pegfilgrastim in reducing cycle 1 DSN in breast cancer patients receiving chemotherapy; both drugs have comparable safety profiles.

Implications for Practice:

This paper provides efficacy and safety data for a new, once-per-cycle granulocyte colony-stimulating factor, balugrastim, for the prevention of chemotherapy-induced neutropenia in patients with breast cancer receiving myelosuppressive chemotherapy. In this phase III trial, balugrastim was shown to be not inferior to pegfilgrastim in the duration of severe neutropenia in cycle 1 of doxorubicin/docetaxel chemotherapy, and the safety profiles of the two agents were similar. Once-per-cycle balugrastim is a safe and effective alternative to pegfilgrastim for hematopoietic support in patients with breast cancer receiving myelosuppressive chemotherapy associated with a greater than 20% risk of developing febrile neutropenia.     

A Phase II Trial of Dose-Dense Neoadjuvant Gemcitabine,Epirubicin, and Albumin-Bound Paclitaxel With Pegfilgrastim in the Treatment of Patients With Locally Advanced Breast Cancer

BackgroundNeoadjuvant anthracycline/taxane combinations, with or without gemcitabine, produce pathologic complete responses (pCRs) in 15%-25% of patients. In this multicenter phase II study, we attempted to increase efficacy and decrease toxicity of a 3-drug gemcitabine-containing neoadjuvant regimen by administering dose-dense therapy with pegfilgrastim, and including albumin-bound paclitaxel as the taxane.Patients and MethodsA total of 123 patients with locally advanced breast cancer were enrolled. Patients were treated with 6 doses of neoadjuvant gemcitabine 2000 mg/m², epirubicin 50 mg/m², and albumin-bound paclitaxel 175 mg/m² intravenously administered at 14-day intervals. Following neoadjuvant chemotherapy, patients underwent either mastectomy or breast conservation surgery; pathologic response to treatment was assessed. Postoperatively, patients received 4 doses of gemcitabine 2000 mg/m² with albumin-bound paclitaxel 220 mg/m² at 14-day intervals. Pegfilgrastim 6 mg was administered subcutaneously on day 2 following each dose of chemotherapy.ResultsA total of 116 patients (95%) completed neoadjuvant chemotherapy and had subsequent surgical resection. Twenty-three patients (20%) had a pCR. The estimated 3-year progression-free survival (PFS) and overall survival rates were 48% and 86%, respectively. Neoadjuvant treatment was well tolerated; only 11% of the patients had grade 3/4 neutropenia, with 1 episode of neutropenic fever. Other grade 3/4 toxicities occurred in < 10% of the patients.ConclusionNeoadjuvant biweekly chemotherapy with gemcitabine/epirubicin/albumin-bound paclitaxel with pegfilgrastim is feasible and well tolerated. The pCR rate of 20% and the 3-year PFS rate of 48% are similar to results achieved with other commonly used neoadjuvant regimens.     

A Southwest Oncology Group Randomized Phase II Study of Doxorubicin and Paclitaxel as Frontline Chemotherapy for Women with Metastatic Breast Cancer

PURPOSE: To evaluate whether the high complete response (CR) rates for the combination of doxorubicin and paclitaxel in metastatic breast cancer observed in two European studies could be replicated in a multi-institutional cooperative group trial. PATIENTS AND METHODS: This was a phase II study with 91 patients randomized between either doxorubicin (60 mg/m(2)) followed immediately by paclitaxel (200 mg/m(2) over 3 h) (AT), or with doxorubicin (60 mg/m(2)) followed immediately by cyclophosphamide (600 mg/m(2)) (AC). Treatment was limited to six cycles of therapy for the doxorubicin and paclitaxel combination. Left ventricular ejection fraction was evaluated at on study and after four and six cycles of treatment on AT. RESULTS: Estimates of overall objective response were 31% (with 9% CR) and 39% (with 11% CR) for patients on the AT and AC regimens, respectively. Response was lower than anticipated on the standard AC arm. On average the reduction of LVEF was similar in the two groups, with no patients developing congestive heart failure during the six cycles of therapy, although one patient in the AT group died of delayed congestive heart failure. CONCLUSIONS: The results of this multi-institutional study in patients with metastatic breast cancer suggest that the combination of doxorubicin and paclitaxel is well tolerated with relatively low rates of cardiac toxicity if the total dose of doxorubicin is held to 相似文献   

Phase I/II Trial of Combined Pegylated Liposomal Doxorubicin and Cyclophosphamide in Metastatic Breast Cancer

Introduction

Doxorubicin in combination with cyclophosphamide is active in breast cancer; however, its use in metastatic cancer is limited owing to cardiotoxicity. Pegylated liposomal doxorubicin (PLD) was formulated to decrease the toxicity of conventional doxorubicin. We evaluated the safety and efficacy of PLD with metronomic oral cyclophosphamide.

Efficacy of Dose Dense Doxorubicin and Cyclophosphamide Followed by Paclitaxel versus Conventional Dose Doxorubicin,Cyclophosphamide Followed by Paclitaxel or Docetaxel in Patients with Node-Positive Breast Cancer

Background: Adding taxanes to adjuvant antracycline and cyclophosphamide (AC) in combination mayprovide significant improvement in node-positive and high risk node-negative breast cancer (BC) patients.However, the optimal dose and the role of dose-dense (DD) chemotherapy have yet to be determined. The aimof this study was to compare the efficacy of a DD paclitaxel (P)-AC combination with conventional weekly P-ACor docetaxel D-AC combinations in patients with node-positive breast cancer. Materials and Methods: Newlydiagnosed 280 node-positive BC patients diagnosed from 1998 to 2013 in three clinics were retrospectivelyanalyzed. Demographic and medical data were collected from the medical charts. Patients were categorizedto 3 groups according to treatment arms: arm A, ddAC-P; arm B, weekly P and AC combination; and arm C;T and AC combination. Adjuvant trastuzumab was added for HER2-positive patients. Kaplan-Meier survivalanalysis was carried out for disease free survival (DFS) and overall survival (OS). The log-rank test was usedto examine the statistical significance of the differences observed between the groups. Two-sided P values <0.05were considered statistically significant. Results: Of the total of 280 patients, 101 were in arm A, 114 in arm Band 65 in arm C.The median ages were 49, 50 and 46, respectively (p=0.11). Median follow-up was 39 (3-193)months. Stage, lymphovascular and perineural invasion, receptor patern, and menopausal status were similar inthe 3 treatment arms, but HER2 positivity was significantly lower in arm A, compared to arms B and C (25.7%,53.1%, 41.5% in arms A, B and C, respectively; p<0.001). Also grade 3 tumors were significantly less frequentin treatment arm A compared to arm B and C (27.3%, 56.8% and 49.2% , respectively, p=0.01). Afterunivariateand multivariate analysis were performed, 3-year DFS rates were 89%, 81%, and 75%, respectively (p=0.12) andthree year OS rates were 96.6%, 89%, and 75% (p=0.62). Conclusions: In this study, no significant differencewas found between adjuvant dose dense and conventional taxane treatment regimens.     

Phase I Study of Intravenous PSC-833 and Doxorubicin: Reversal of Multidrug Resistance

PSC-833 reverses multidrug resistance by P-glycoprotein at concentrations <1000 ng/ml. A phase I study of PSC-833 and doxorubicin was conducted to determine the maximum tolerated dose and to investigate pharmacokinetics. PSC-833 was intravenously infused as a 2-h loading dose (LD) and a subsequent 24-h continuous dose (CD). Doxorubicin was infused over 5 min, 1 h after the LD. The starting dose was 1 mg/kg for both LD and CD with 30 mg/m² doxorubicin; these dosages were increased to 2 and 10 mg/kg and 50 mg/m², respectively. Thirty-one patients were treated. Nausea/ vomiting was controllable with granisetron and dexamethasone. Neutropenia and ataxia were dose limiting. Steady-state concentrations of PSC-833 >1000 ng/ml were achieved at a 2 mg/kg LD and a 10 mg/kg CD. Ex-vivo bioassay revealed that activity in serum for reversing multidrug resistance was achieved in all patients; IC₅₀ of P-glycoprotein expressing 8226/Dox₆; in patients' serum was decreased from 5.9 to 1.3 μg/ml ( P <0.0001) by PSC-833 administration. Doxorubicin clearance was 24.3±13.7 (mean±SD) liter/h/m², which was lower than the 49.0±16.9 liter/h/m² without PSC-833 ( P <0.0001). The relationship between doxorubicin exposure and neutropenia did not differ between patients treated and not treated with PSC-833. The recommended phase II dose of PSC-833 was 2 and 10 mg/kg for LD and CD, respectively, which achieved a sufficient concentration in serum to reverse drug resistance, as confirmed by bioassay. The dose of doxorubicin should be reduced to 40 mg/m², not because of the pharmacodynamic interaction between PSC-833 and doxorubicin affecting hematopoiesis, but because of pharmacokinetic interaction.     

Efficacy and Toxicity of Gemcitabine and Pegylated Liposomal Doxorubicin in Recurrent Platinum - Resistant/Refractory Epithelial Ovarian Cancer

Background: Treatment of patients with platinum resistant/refractory ovarian cancer is a significant problem.In this study, we evaluated the efficacy and tolerability of the combination of gemcitabine and pegylated liposomaldoxorubicin (PLD) in patients with platinum resistant/refractory ovarian cancer. Patients and Methods: Weretrospectively evaluated the activity and toxicity of gemcitabine and PLD combination in 35 patients withrecurrent platinum resistant/refractory ovarian cancer who had been treated and followed up in 7 centers inTurkey between December 2005 and June 2008. The patients received gemcitabine 1.000 mg/m2 on day 1 and 8,and PLD 25 mg/m2 on day 1 every 28 days. Results: A total of 187 cycles (median, 6 cycles) were delivered. Anobjective response rate of 28,6 % (1 complete, 9 par tial response) was achieved. Additionally, 16 patients (45.7%) had disease stabilization. The median time-to-progression was 6 months (95 % confidence interval, 4-8) andthe median overall survival was 17 months (95 % confidence interval, 12-22). Grade 3-4 hematologic toxicitieswere as follows: leucopenia (14.3%), neutropenia (8.6%), and anemia (2.9%). One febrile neutropenic episode(2.9%) was observed. Non-hematologic toxicity was well tolerated and easily managed and no grade 3-4palmoplantar erytrodysestesia (PPE) was observed. Conclusion: The combination of gemcitabine and PLD isan effective and tolerable treatment option, with 74.3 % disease control rate for patients with platinum resistant/refractory ovarian cancer.     

Phase II Study of Gemcitabine and Bevacizumab As First-Line Treatment in Taxane-Pretreated,HER2-Negative,Locally Recurrent or Metastatic Breast Cancer

BackgroundIn first-line treatment of metastatic breast cancer, the best use of the available therapeutic agents is unclear. This study evaluated the efficacy and safety of combined therapy with bevacizumab and gemcitabine.PatientsWomen who were to undergo first-line treatment for locoregionally recurrent or metastatic breast cancer were eligible. Patients must have received a taxane-containing regimen in the neoadjuvant and/or adjuvant setting with a ≥ 12-month disease-free interval.MethodsThis was a single-arm, phase II trial. On day 1 of each 14-day cycle, patients received gemcitabine (2500 mg/m²) followed by bevacizumab (10 mg/kg). Patients were treated until complete response, progressive disease (PD), or intolerable toxicity. The primary endpoint was progression-free survival (PFS).ResultsFifty-two women were enrolled and treated. The median PFS was 4.8 months (95% confidence interval [CI], 3.4-7.6), the 1-year overall survival rate was 68.7% (95% CI, 54.1%-79.5%), and the response rate was 21.4% (95% CI, 10.3%-36.8%). The clinical benefit rate was 35.7%. The median PFS in the triple-negative (n = 19) and non–triple-negative (n = 33) subsets was 3.9 months (95% CI, 2.7-11.7) and 4.9 months (95% CI, 3.4-8.1), respectively. The most common (all grades) drug-related adverse events (AEs) were nausea (51.9%), fatigue (46.2%), decreased appetite (25.0%), and anemia (25.0%). The most common grade 3 or grade 4 drug-related AEs were neutropenia (13.5%), leukopenia (11.5%), and hypertension (7.7%).ConclusionAlthough the gemcitabine-bevacizumab doublet appears active, the median PFS was lower than expected. There were no unexpected safety signals at this dose and schedule of this combination.     

Platinol (CDDP) and Continuous Intravenous Infusion 5-Fluorouracil in Refractory Stage IV Breast Cancer: A Phase II Study

Twenty-four patients with refractory Stage IV breast cancer were teated with platinol (100 mg/m² i.v. Day 1) and 5-fluorouracil (1000 mg/m² as a continuous infusion over 24 h daily for 5 days). Objective responses occurred in 12 of 24patients (50%). The median duration of response was 4.9 months. Platinol and 5-fluorouracil in combination are active agents in patients with refractory breast cancer, and clinical trials are warranted in previously untreated patients.     

Phase II Trial of Neoadjuvant Weekly Nanoparticle Albumin-Bound Paclitaxel,Carboplatin, and Biweekly Bevacizumab Therapy in Women With Clinical Stage II or III HER2-Negative Breast Cancer

BackgroundWe hypothesized that adding bevacizumab to neoadjuvant chemotherapy (NCT) with nab-P and carboplatin would increase the rates of pCR in BC patients and that early changes in tumor vascularity imaged by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) would predict pCR.MethodsThirty-three women with clinical stage II or III HER2-negative BC received nab-P 100 mg/m2 and carboplatin area under the curve = 2 on days 1, 8, and 15 in combination with bevacizumab 10 mg/kg on days 1 and 15 administered every 28 days.ResultsSix patients (18%) achieved pCR, all pCRs occurred in triple-negative BC (TNBC) (pCR = 50% for TNBC). At the end of cycle 2, the changes in relative angiogenic volume were significantly different between responders and nonresponders (P = .001). The major toxicity of this NCT was myelosuppression.ConclusionNCT with weekly nab-P, carboplatin, and biweekly bevacizumab resulted in a pCR rate that was neither superior to the historical data with anthracycline- or taxane-containing NCT nor to carboplatin and taxane combinations in patients with HER2-negative BC. In patients with TNBC, the observed pCR rate was 50%. The early changes in the relative angiogenic volume imaged by DCE-MRI could predict pCR.