Phase II Study of Sequential Administration of Docetaxel Followed by Doxorubicin and Cyclophosphamide as First-Line Chemotherapy in Metastatic Breast Cancer

2001 ◽  
Vol 19 (14) ◽  
pp. 3367-3375 ◽  
Author(s):  
D. Khayat ◽  
P. Chollet ◽  
E. C. Antoine ◽  
S. Monfardini ◽  
G. Ambrosini ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Metastatic Breast ◽  
Severe Infection ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
First Line ◽  
Ventricular Ejection Fraction ◽  
Sequential Administration ◽  
Line Chemotherapy

PURPOSE: To evaluate the feasibility and efficacy of a sequential administration of four cycles of docetaxel (100 mg/m2 every 3 weeks) followed by four cycles of doxorubicin and cyclophosphamide (AC; 60/600 mg/m2 every 3 weeks), with subsequent consolidation with docetaxel or AC, as first-line chemotherapy in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Forty-eight patients received 443 cycles of chemotherapy (median, 11 cycles/patient; range, 1 to 13 cycles). A total of 267 cycles of docetaxel (60.3%) and 176 of AC (39.7%) were given. Consolidation therapy was given to 33 patients (29 with docetaxel). RESULTS: Grade 4 neutropenia was the most frequent toxicity (83% of patients). This was not cumulative and was rarely complicated by febrile neutropenia or severe infection. The nonhematologic safety profile was favorable: there were no grade 4 adverse events, and grade 3 episodes were infrequent. Docetaxel-specific toxicities were generally not severe. With a median cumulative doxorubicin dose of 397 mg/m2 (range, 150 to 543 mg/m2), two incidences of unrelated congestive heart failure after further treatment with anthracyclines and two of asymptomatic left ventricular ejection fraction decrease were observed. Among the 42 assessable patients, five (12%) had complete and 25 (60%) had partial responses, for an overall response rate of 71% (95% confidence interval, 55% to 84%). Median duration of response was 53 weeks (range, 12 to 72 weeks), and median time to progression was 46 weeks (range, 3 of 72 weeks). With a median follow-up of 40.4 months, median survival was 32 months (range, 2 to 55 months). CONCLUSION: This docetaxel-based sequential schedule is safe and effective in first-line therapy for MBC, without incurring cumulative toxicity, and provides a feasible chemotherapeutic option in this clinical setting.

Phase II Trial of Liposome-Encapsulated Doxorubicin, Cyclophosphamide, and Fluorouracil as First-Line Therapy in Patients With Metastatic Breast Cancer

1999 ◽  
Vol 17 (5) ◽  
pp. 1425-1425 ◽  
Author(s):  
Vicente Valero ◽  
Aman U. Buzdar ◽  
Richard L. Theriault ◽  
Nozar Azarnia ◽  
Gustavo A. Fonseca ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Phase Ii ◽  
Cardiac Toxicity ◽  
Metastatic Breast ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Survival Duration ◽  
First Line ◽  
Ventricular Ejection Fraction

PURPOSE: To determine the efficacy and safety profile, including the risk for cardiac toxicity, of liposome-encapsulated doxorubicin (TLC D-99), fluorouracil (5-FU), and cyclophosphamide as first-line chemotherapy in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Forty-one women were registered in this phase II study. All patients had measurable disease and no previous chemotherapy for MBC. Treatment consisted of TLC D-99 60 mg/m2 and cyclophosphamide 500 mg/m2 on day 1 and 5-FU 500 mg/m2 on days 1 and 8 every 3 weeks. Serial cardiac monitoring, including endomyocardial biopsies, was performed. RESULTS: The overall response rate was 73% (95% confidence interval, 57% to 86%). The median duration of response was 11.2 months, the median time to treatment failure was 8.1 months, and the median overall survival duration was 19.4 months. The median number of cycles per patient was 10. The median cumulative dose of TLC D-99 was 528 mg/m2. Ten patients required hospitalization for febrile neutropenia. Nausea/vomiting, stomatitis, and fatigue higher than grade 2 occurred in 12%, 15%, and 41% of patients, respectively. Twenty-one patients reached a cumulative doxorubicin dose greater than 500 mg/m2. Three patients (7%) were withdrawn from the study due to protocol-defined cardiac toxicity, two because of a decrease in left ventricular ejection fraction to ≤ 40%, and one because her endomyocardial biopsy result was grade 1.5. One patient had congestive heart failure that was probably nonanthracycline related. CONCLUSION: This chemotherapy regimen, including TLC D-99, was highly active against MBC and associated with low cardiac toxicity despite high cumulative doses of doxorubicin.

Subcutaneous Trastuzumab with Pertuzumab and Docetaxel in HER2-Positive Metastatic Breast Cancer: Final Analysis of MetaPHER, A Phase 3b Single-Arm Safety Study

2020 ◽  
Author(s):  
Sherko Kümmel ◽  
Carlo Alberto Tondini ◽  
Jacinta Abraham ◽  
Zbigniew Nowecki ◽  
Bartosz Itrych ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Adverse Events ◽  
Metastatic Breast ◽  
Left Ventricular ◽  
The Body ◽  
Left Ventricular Ejection ◽  
Fixed Dose ◽  
Her2 Positive ◽  
Ventricular Ejection Fraction

Abstract BACKGROUND Intravenous trastuzumab, pertuzumab, and docetaxel is first-line standard of care for patients with HER2-positive metastatic breast cancer. Subcutaneous trastuzumab plus intravenous pertuzumab and chemotherapy has shown similar safety and tolerability to intravenous trastuzumab in patients with HER2-positive early and metastatic breast cancer; however, in the metastatic setting, this has yet to be shown globally.METHODS In this open-label, single-arm, multicenter phase 3b study, eligible patients were ≥18 years old with histologically/cytologically confirmed previously untreated HER2-positive metastatic breast cancer. All patients received ≥1 dose of subcutaneous trastuzumab (fixed-dose 600 mg) plus intravenous pertuzumab (loading dose: 840 mg/kg; maintenance dose: 420 mg/kg) and docetaxel (≥6 cycles; initial dose 75 mg/m2) every 3 weeks. The primary objective was safety and tolerability; secondary objectives included efficacy.RESULTS At clinical cutoff, 276 patients had completed the study; median duration of follow-up was 27 months. The most common any-grade adverse events were diarrhea, alopecia, and asthenia. The most common grade ≥3 adverse events were neutropenia, febrile neutropenia, and hypertension. There were no cardiac deaths and mean left ventricular ejection fraction was stable over time. Median investigator-assessed progression-free survival was 18.7 months; objective response rate was 75.6%.CONCLUSIONS Efficacy/safety results of subcutaneous trastuzumab plus intravenous pertuzumab and docetaxel in metastatic breast cancer are consistent with historical evidence of intravenous trastuzumab. These findings further support the body of evidence indicating that subcutaneous administration does not affect the safety and efficacy profile of trastuzumab in HER2-positive breast cancer. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02402712 (date of registration: 30th March 2015)

Cardiac safety of pegylated liposomal doxorubicin (PLD) in combination with trastuzumab (T) in patients with metastatic breast cancer (MBC): Results from a multicenter phase II study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 1106-1106 ◽  
Author(s):  
E. Stickeler ◽  
D. O. Watermann ◽  
J. Woll ◽  
M. Foeldi ◽  
G. Gitsch
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Phase Ii ◽  
Metastatic Breast ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Cardiac Safety ◽  
Ventricular Ejection Fraction ◽  
Cardiac Side Effects

1106 Background: Combination therapy of doxorubicin and trastuzumab is highly effective for Her2 positive MBC but characterized by frequent cardiac toxicity (CT). PLD can significantly reduce CT compared to conventional doxorubicin. Patients and Methods: 15 patients were enrolled in a phase II trial to evaluate cardiac safety of T (4 mg/Kg loading dose day 2, followed by weekly 2 mg/Kg) in combination with PLD (40 mg/m2 IV bolus day 1, q 28 d). 75% of pts. presented with more than 1 metastatic site and 40% for second line treatment. PLD was administered for 6 or 9 cycles, respectively, T until disease progression. To assess CT, all pts were evaluated with electrocardiogram (ECG) and echocardiograms (E) for Left Ventricular Ejection Fraction (LVEF) at baseline, every cycle during PLD and T, and every three months during T therapy alone. CT was defined as appearance of signs/ symptoms of congestive heart failure and/or an absolute decrease in LVEF > 10 units (below 50%) or decrease in LVEF > 15 units (above 50%). Results: Four pts. received 6 cycles, 4 pts. received 9 cycles of PLD, 4 pts discontinued treatment due to PD, 3 pts. due to toxicity. After a median follow up time of 15.4 months, 6 pts. (42.9%) demonstrated a clinical benefit and median OS was 16.2 months. Non cardiac side effects were mild with only 3 CTC Grade 3 events of 247 treatment cycles (1.2%). Three pts. developed minor ECG changes without pathological significance and 5 pts. had minor changes in their E with slight diastolic (n=3) or systolic (n=2) dysfunction. During follow-up, 3 pts. were diagnosed with pathological E findings, including 1 slight decrease of LVEF, one diffuse hypokinesia and one strong decrease in LVEF.The median LVEF in the study cohort was 66.1% at baseline, 62.7% after 6 cycles of therapy, 64.4% at the first follow up and did not change significantly until the 5 th examination. Conclusions: This study supports the combination of PLD and H in pts. with HER2 overexpressing metastatic breast cancer as a safe and feasible therapy. Due to the promising clinical response rates in this prognostically unfavorable group, this combination should be evaluated in larger studies as a potential regimen for adjuvant treatment of breast cancer. No significant financial relationships to disclose.

T-ACT (WJOG7112G): A randomized phase II study of weekly paclitaxel ± trastuzumab in patients with HER2-positive advanced gastric or gastro-esophageal junction cancer refractory to trastuzumab combined with fluoropyrimidine and platinum.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. TPS218-TPS218 ◽  
Author(s):  
Taito Esaki ◽  
Akitaka Makiyama ◽  
Tomomi Kashiwada ◽  
Ayumu Hosokawa ◽  
Junji Kawada ◽  
...  
Keyword(s):  
Metastatic Breast ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Rank Test ◽  
First Line ◽  
Her2 Positive ◽  
Eligibility Criteria ◽  
Ventricular Ejection Fraction ◽  
Significance Level ◽  
Line Chemotherapy

TPS218 Background: Trastuzumab (Tmab) is a key drug for HER2 positive breast and gastric or gastro-esophageal junction (G/GEJ) cancer. While use of Tmab beyond progression (TBP) showed a benefit in HER2-positive metastatic breast cancer, clinical significance of TBP for HER2-positive G/GEJ cancer has not been clarified. Objective:This study compares the efficacy of paclitaxel (PTX) + Tmab with PTX alone in patients with unresectable or metastatic HER2-positive G/GEJ cancer who failed first-line chemotherapy with Tmab + fluoropyrimidine + platinum. Methods: Enrolled patients will be randomized to receive PTX (80 mg/m2, on day 1, 8 15, every 4 weeks) + Tmab (8 mg/kg loading dose and 6 mg/kg thereafter, on day 1, every 3 weeks) or PTX alone. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival, time to treatment failure, response rate, disease control rate, safety, and translational biomarker research. A total of 69 events are required to achieve 80% power for one-sided log rank test with 10% significance level, expecting the median PFS of the PTX and the PTX + Tmab arms will be 3 and 5 months. In consideration of patient with censoring and dropout, the planned sample size is totally 90 patients. Major eligibility criteria are: HER2-positive advanced G/GEJ adenocarcinoma; refractory to first-line chemotherapy with fluoropyrimidine, platinum, and Tmab (at least three doses); within 6 weeks after last Tmab administration; no prior therapy with taxane or anti-HER2 drugs except Tmab; ECOG PS 0-2; adequate organ function; left ventricular ejection fraction ≥ 50%. Tumor tissue, blood serum, and circulating tumor DNA are collected before the study treatment for biomarker analyses to explore the predictive marker of the TBP strategy. As of September 2016, 89 patients were randomized. Clinical trial information: 000009297.

Reduced Cardiotoxicity and Preserved Antitumor Efficacy of Liposome-Encapsulated Doxorubicin and Cyclophosphamide Compared With Conventional Doxorubicin and Cyclophosphamide in a Randomized, Multicenter Trial of Metastatic Breast Cancer

2001 ◽  
Vol 19 (5) ◽  
pp. 1444-1454 ◽  
Author(s):  
Gerald Batist ◽  
Gopal Ramakrishnan ◽  
Chandra Sekhar Rao ◽  
Aruna Chandrasekharan ◽  
John Gutheil ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Median Time ◽  
Metastatic Breast ◽  
Response Rates ◽  
Left Ventricular ◽  
Antitumor Efficacy ◽  
Left Ventricular Ejection ◽  
Time To Progression ◽  
First Line

PURPOSE: To determine whether Myocet (liposome-encapsulated doxorubicin; The Liposome Company, Elan Corporation, Princeton, NJ) in combination with cyclophosphamide significantly reduces doxorubicin cardiotoxicity while providing comparable antitumor efficacy in first-line treatment of metastatic breast cancer (MBC). PATIENTS AND METHODS: Two hundred ninety-seven patients with MBC and no prior chemotherapy for metastatic disease were randomized to receive either 60 mg/m2 of Myocet (M) or conventional doxorubicin (A), in combination with 600 mg/m2 of cyclophosphamide (C), every 3 weeks until disease progression or unacceptable toxicity. Cardiotoxicity was defined by reductions in left-ventricular ejection fraction, assessed by serial multigated radionuclide angiography scans, or congestive heart failure (CHF). Antitumor efficacy was assessed by objective tumor response rates (World Health Organization criteria), time to progression, and survival. RESULTS: Six percent of MC patients versus 21% (including five cases of CHF) of AC patients developed cardiotoxicity (P = .0002). Median cumulative doxorubicin dose at onset was more than 2,220 mg/m2 for MC versus 480 mg/m2 for AC (P = .0001, hazard ratio, 5.04). MC patients also experienced less grade 4 neutropenia. Antitumor efficacy of MC versus AC was comparable: objective response rates, 43% versus 43%; median time to progression, 5.1% versus 5.5 months; median time to treatment failure, 4.6 versus 4.4 months; and median survival, 19 versus 16 months. CONCLUSION: Myocet improves the therapeutic index of doxorubicin by significantly reducing cardiotoxicity and grade 4 neutropenia and provides comparable antitumor efficacy, when used in combination with cyclophosphamide as first-line therapy for MBC.

Multicenter Phase III Randomized Trial Comparing Docetaxel and Trastuzumab With Docetaxel, Carboplatin, and Trastuzumab As First-Line Chemotherapy for Patients With HER2-Gene-Amplified Metastatic Breast Cancer (BCIRG 007 Study): Two Highly Active Therapeutic Regimens

2011 ◽  
Vol 29 (2) ◽  
pp. 149-156 ◽  
Author(s):  
Vicente Valero ◽  
John Forbes ◽  
Mark D. Pegram ◽  
Tadeusz Pienkowski ◽  
Wolfgang Eiermann ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Randomized Trial ◽  
Metastatic Breast ◽  
Left Ventricular ◽  
Phase Iii ◽  
Left Ventricular Ejection ◽  
Time Curve ◽  
Ventricular Ejection Fraction ◽  
Significant Difference

Purpose Docetaxel-trastuzumab (TH) is effective therapy for HER2-amplified metastatic breast cancer (MBC). Preclinical findings of synergy between docetaxel, carboplatin, and trastuzumab (TCH) prompted a phase III randomized trial comparing TCH with TH in patients with HER2-amplified MBC. Patients and Methods Two hundred sixty-three patients were randomly assigned to receive eight 3-week cycles of TH (trastuzumab plus docetaxel 100 mg/m2) or TCH (trastuzumab plus carboplatin at area under the serum concentration-time curve 6 and docetaxel 75 mg/m2). Trastuzumab was given at 4 mg/kg loading dose followed by a 2 mg/kg dose once per week during chemotherapy, and then 6 mg/kg once every 3 weeks until progression. Results Patient characteristics were balanced between groups. There was no significant difference between TH and TCH in terms of the primary end point, time to progression (medians of 11.1 and 10.4 months, respectively; hazard ratio, 0.914; 95% CI, 0.694 to 1.203; P = .57), response rate (72% for both groups), or overall survival (medians of 37.1 and 37.4 months, respectively; P = .99). Rates of grades 3 or 4 adverse effects for TH and TCH, respectively, were neutropenic-related complications, 29% and 23%; thrombocytopenia, 2% and 15%; anemia, 5% and 11%; sensory neuropathy, 3% and 0.8%; fatigue, 5% and 12%; peripheral edema, 3.8% and 1.5%; and diarrhea, 2% and 10%. Two patients given TCH died of sepsis, and one patient given TH experienced sudden cardiac death. Absolute left ventricular ejection fraction decline > 15% was seen in 5.5% of patients on the TH arm and 6.7% of patients on the TCH arm. Conclusion Adding carboplatin did not enhance TH antitumor activity.TH (docetaxel, 100 mg/m2) and TCH (docetaxel, 75 mg/m2) demonstrated efficacy with acceptable toxicity in women with HER2-amplified MBC.

scholarly journals Subcutaneous trastuzumab with pertuzumab and docetaxel in HER2-positive metastatic breast cancer: Final analysis of MetaPHER, a phase IIIb single-arm safety study

2021 ◽  
Author(s):  
Sherko Kuemmel ◽  
Carlo A. Tondini ◽  
Jacinta Abraham ◽  
Zbigniew Nowecki ◽  
Bartosz Itrych ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Objective Response ◽  
Subcutaneous Administration ◽  
Metastatic Breast ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Fixed Dose ◽  
Her2 Positive ◽  
Ventricular Ejection Fraction

Abstract Purpose Intravenous trastuzumab, pertuzumab, and docetaxel are first-line standard of care for patients with HER2-positive metastatic breast cancer (mBC). MetaPHER is the first study assessing the safety and tolerability of subcutaneous trastuzumab plus intravenous pertuzumab and chemotherapy in a global patient population with HER2-positive mBC. Methods In this open-label, single-arm, multicenter, phase 3b study, eligible patients were ≥ 18 years old with histologically/cytologically confirmed previously untreated HER2-positive mBC. All received ≥ 1 subcutaneous trastuzumab 600 mg fixed dose plus intravenous pertuzumab (loading dose: 840 mg/kg; maintenance: 420 mg/kg) and docetaxel (≥ 6 cycles; initial dose 75 mg/m2) every 3 weeks. The primary objective was safety and tolerability; secondary objectives included efficacy. Results At clinical cutoff, 276 patients had completed the study; median duration of follow-up was 27 months. The most common any-grade adverse events were diarrhea, alopecia, and asthenia; the most common grade ≥ 3 events were neutropenia, febrile neutropenia, and hypertension. There were no cardiac deaths and mean left ventricular ejection fraction was stable over time. Median investigator-assessed progression-free survival was 18.7 months; objective response rate was 75.6%. Conclusions Safety and efficacy with subcutaneous trastuzumab plus intravenous pertuzumab and docetaxel in mBC are consistent with historical evidence of intravenous trastuzumab with this combination. Findings further support subcutaneous administration not affecting safety/efficacy profiles of trastuzumab in HER2-positive BC with increased flexibility in patient care. A fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection has recently been approved for the treatment of HER2-positive early/mBC, further addressing the increasing relevance of and need for patient-centric treatment strategies. Trial registration NCT02402712

scholarly journals Concurrent Trastuzumab and HER2/neu-Specific Vaccination in Patients With Metastatic Breast Cancer

2009 ◽  
Vol 27 (28) ◽  
pp. 4685-4692 ◽  
Author(s):  
Mary L. Disis ◽  
Danelle R. Wallace ◽  
Theodore A. Gooley ◽  
Yushe Dang ◽  
Meredith Slota ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Metastatic Breast Cancer ◽  
T Cell ◽  
Growth Factor ◽  
Combination Therapy ◽  
Metastatic Breast ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction

Purpose The primary objectives of this phase I/II study were to evaluate the safety and immunogenicity of combination therapy consisting of concurrent trastuzumab and human epidermal growth factor receptor 2 (HER2)/neu-specific vaccination in patients with HER2/neu-overexpressing metastatic breast cancer. Patients and Methods Twenty-two patients with stage IV HER2/neu-positive breast cancer receiving trastuzumab therapy were vaccinated with an HER2/neu T-helper peptide-based vaccine. Toxicity was graded according to National Cancer Institute criteria, and antigen specific T-cell immunity was assessed by interferon gamma enzyme-linked immunosorbent spot assay. Data on progression-free and overall survival were collected. Results Concurrent trastuzumab and HER2/neu vaccinations were well tolerated, with 15% of patients experiencing an asymptomatic decline in left ventricular ejection fraction below the normal range during combination therapy. Although many patients had pre-existing immunity specific for HER2/neu and other breast cancer antigens while treated with trastuzumab alone, that immunity could be significantly boosted and maintained with vaccination. Epitope spreading within HER2/neu and to additional tumor-related proteins was stimulated by immunization, and the magnitude of the T-cell response generated was significantly inversely correlated with serum transforming growth factor beta levels. At a median follow-up of 36 months from the first vaccine, the median overall survival in the study population has not been reached. Conclusion Combination therapy with trastuzumab and a HER2/neu vaccine is associated with minimal toxicity and results in prolonged, robust, antigen-specific immune responses in treated patients.

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