A phase I study of a HER2/neu bispecific antibody with granulocyte-colony-stimulating factor in patients with metastatic breast cancer that overexpresses HER2/neu

PURPOSE In vitro data suggest that prolonged exposure to paclitaxel enhances breast cancer cytotoxicity. Our objective in this phase I study was to determine the tolerability of paclitaxel administered by 72-hour continuous intravenous (i.v.) infusion (CIVI) in combination with high-dose cyclophosphamide and granulocyte colony-stimulating factor (G-CSF) in the ambulatory setting to metastatic breast cancer patients. PATIENTS AND METHODS Paclitaxel was administered over 72 hours by CIVI and cyclophosphamide was given daily by i.v. bolus on days 1, 2, and 3, followed by G-CSF every 21 days. The availability of ambulatory infusion pumps and paclitaxel-compatible tubing permitted outpatient administration. RESULTS Fifty-five patients with metastatic breast cancer who had been previously treated with a median of two prior chemotherapy regimens were entered onto the study. Dose-limiting toxicity of grade 4 neutropenia for longer than 5 days and grade 4 thrombocytopenia occurred in three of five patients treated with paclitaxel 160 mg/m2 CIVI and cyclophosphamide 3,300 mg/m2 followed by G-CSF. The maximum-tolerated dose (MTD) was paclitaxel 160 mg/m2 CIVI and cyclophosphamide 2,700 mg/m2 in divided doses with G-CSF. Nonhematologic toxicities were moderate and included diarrhea, mucositis, and arthalgias. Although hemorrhagic cystitis developed in six patients, recurrence was prevented with i.v. and oral mesna, which permitted continued outpatient delivery. One hundred seventy-four cycles were safely administered in the ambulatory setting using infusional pumps and tubing. Objective responses occurred in 23 (one complete and 22 partial) of 42 patients with bidimensionally measurable disease (55%; 95% confidence interval, 38% to 70%), with a response rate of 73% (11 of 15) seen at the highest dose levels. CONCLUSION Paclitaxel by 72-hour CIVI with daily cyclophosphamide followed by G-CSF can be administered safely in the ambulatory setting, has acceptable toxicity, and is an active regimen in the treatment of metastatic breast cancer.

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Phase I study of taxol plus doxorubicin plus granulocyte colony-stimulating factor (G-CSF) in patients with metastatic breast cancer

European Journal of Cancer ◽

10.1016/0959-8049(93)91260-r ◽

1993 ◽

Vol 29 ◽

pp. S117 ◽

Cited By ~ 1

Author(s):

JA O'Shaughnessy ◽

J Fisherman ◽

M McCabe ◽

M Noone ◽

KH Cowan

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Phase I ◽

Phase I Study ◽

Metastatic Breast ◽

Granulocyte Colony Stimulating Factor ◽

Colony Stimulating Factor ◽

Stimulating Factor ◽

Factor G

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Phase I/II study of 72-hour infusional paclitaxel and doxorubicin with granulocyte colony-stimulating factor in patients with metastatic breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.1996.14.3.774 ◽

1996 ◽

Vol 14 (3) ◽

pp. 774-782 ◽

Cited By ~ 49

Author(s):

J S Fisherman ◽

K H Cowan ◽

M Noone ◽

A Denicoff ◽

S Berg ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Phase I ◽

Overall Response Rate ◽

Response Rate ◽

Metastatic Breast ◽

Granulocyte Colony Stimulating Factor ◽

Colony Stimulating Factor ◽

Stimulating Factor ◽

Doxorubicin Administration

PURPOSE We conducted a phase I/II trial of concurrently administered 72-hour infusional paclitaxel and doxorubicin in combination with granulocyte colony-stimulating factor (G-CSF) in patients with previously untreated metastatic breast cancer and bidimensionally measurable disease. PATIENTS AND METHODS We defined the maximum-tolerated dose (MTD) of concurrent paclitaxel and doxorubicin administration and then studied potential pharmacokinetic interactions between the two drugs. Forty-two patients who had not received prior chemotherapy for metastatic breast cancer received 296 total cycles of paclitaxel and doxorubicin with G-CSF. RESULTS The MTD was determined to be paclitaxel 180 mg/m2 and doxorubicin 60 mg/m2 each by 72-hour infusion with G-CSF. Diarrhea was the dose-limiting toxicity (DLT) of this combination, with three of three patients developing abdominal computed tomographic (CT) scan evidence of typhlitis (cecal thickening) at the dose level above the MTD. All patients developed grade 4 neutropenia (absolute neutrophil count [ANC] < 500 microL), generally less than 5 days in duration. This combination was generally safely administered at dose levels at or below the MTD. The overall response rate was 72% (28 of 39 patients; 95% confidence interval [CI], 55% to 85%), with 8% complete responses (CRs) (three of 39; 95% CI, 2% to 21%) and a median response duration of 9 months. The median overall survival time for all patients is 23 months, with a median follow-up duration of 28 months. Pharmacokinetic studies showed that administration of paclitaxel and doxorubicin together by 72-hour infusion did not affect the steady-state concentrations of either drug. CONCLUSION Concurrent 72-hour infusional paclitaxel and doxorubicin can be administered safely, but is associated with significant toxicity. The overall response rate of this combination in untreated metastatic breast cancer patients is similar to that achieved with other doxorubicin-based combination regimens. The modest complete response rate achieved suggests that this schedule of paclitaxel and doxorubicin administration does not produce significant additive or synergistic cytotoxicity against breast cancer.

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Phase II Trial of Doxorubicin and Docetaxel Plus Granulocyte Colony-Stimulating Factor in Metastatic Breast Cancer: Eastern Cooperative Oncology Group Study E1196

Journal of Clinical Oncology ◽

10.1200/jco.2000.18.12.2369 ◽

2000 ◽

Vol 18 (12) ◽

pp. 2369-2377 ◽

Cited By ~ 60

Author(s):

Joseph A. Sparano ◽

Anne O’Neill ◽

Paul L. Schaefer ◽

Carla I. Falkson ◽

William C. Wood

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Phase Ii ◽

Phase Ii Trial ◽

Metastatic Breast ◽

Phase Iii ◽

Left Ventricular Ejection ◽

Granulocyte Colony Stimulating Factor ◽

Colony Stimulating Factor ◽

Stimulating Factor

PURPOSE: The purpose of this multi-institutional phase II trial was to evaluate the efficacy and toxicity of doxorubicin and docetaxel plus granulocyte colony-stimulating factor (G-CSF) in patients with metastatic breast cancer. The primary objective was to determine whether the combination produced a response rate of at least 50%. PATIENTS AND METHODS: Fifty-four patients with metastatic breast cancer received doxorubicin (60 mg/m2 by intravenous [IV] injection) followed 1 hour later by docetaxel (60 mg/m2 by IV infusion over 1 hour) every 3 weeks for up to eight cycles. All patients also received G-CSF. RESULTS: Objective response occurred in 29 (57%) of 51 eligible patients (95% confidence interval [CI], 42% to 70%), including three patients who had a complete response (6%; 95% CI, 1% to 16%). The median response duration was 7 months (95% CI, 6.0 to 15.0 months), median time to treatment failure was 7.6 months (95% CI, 6.2 to 9.9 months), and the median survival was 27.5 months (95% CI, 21.5 months to upper limit not reached). The median cumulative doxorubicin dose was 395 mg/m2 (range, 60 to 480 mg/m2). Fifteen patients (28%) were documented to have a decrease in the left ventricular ejection fraction below normal, and three patients (6%; 95% CI, 1% to 15%) developed congestive heart failure. CONCLUSION: Using criteria that we had defined a priori, the doxorubicin-docetaxel regimen as used in this study was sufficiently active and tolerable to justify a phase III comparison with doxorubicin-cyclophosphamide in early-stage breast cancer.

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Paclitaxel and recombinant human granulocyte colony-stimulating factor as initial chemotherapy for metastatic breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.1993.11.10.1943 ◽

1993 ◽

Vol 11 (10) ◽

pp. 1943-1951 ◽

Cited By ~ 147

Author(s):

B S Reichman ◽

A D Seidman ◽

J P Crown ◽

R Heelan ◽

T B Hakes ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Metastatic Disease ◽

Objective Response ◽

Metastatic Breast ◽

Neutropenic Fever ◽

Granulocyte Colony Stimulating Factor ◽

Colony Stimulating Factor ◽

Highly Active ◽

Stimulating Factor

PURPOSE A phase II study of Taxol (paclitaxel; Bristol-Myers Squibb Co, Princeton, NJ) as initial chemotherapy for metastatic breast cancer was conducted. Recombinant human granulocyte colony-stimulating factor (rhG-CSF) was used to ameliorate myelosuppression, the anticipated dose-limiting toxicity. PATIENTS AND METHODS Twenty-eight patients with bidimensionally measurable breast cancer who had not received prior chemotherapy for metastatic disease were treated. Taxol was administered at 250 mg/m2 as a continuous 24-hour intravenous (i.v.) infusion every 21 days. rhG-CSF was administered at 5 micrograms/kg/d subcutaneously on days 3 through 10. RESULTS Objective responses were observed in 16 of 26 assessable patients (62%; 95% confidence interval, 41% to 80%). There were three (12%) complete responses (CRs) and 13 (50%) partial responses (PRs). Ten of 16 patients (63%) who had received prior adjuvant chemotherapy responded, which included one CR and four PRs among eight patients who had received prior doxorubicin-containing therapy. Responses were observed in all sites of metastatic disease. The median time to first objective response was 5 weeks (range, 1 to 14). Administration of rhG-CSF was associated with a short duration of neutropenia (median, 2 days with absolute neutrophil count < 500 cells/microL). Eight of 26 patients (31%) who received more than one course received subsequent therapy without dose reduction. One hundred seventy-eight cycles of treatment were administered, with a median of six cycles per patient (range, one to 19). Eight courses (4.5%) were associated with admissions for neutropenic fever. Twenty-two patients (79%) did not require admission for neutropenic fever. Treatment was well tolerated. Adverse effects included generalized alopecia in all patients. Myalgias, arthralgias, and peripheral neuropathy were mild. No hypersensitivity reactions and no cardiac toxicity were observed. CONCLUSION Taxol is highly active as initial chemotherapy for metastatic breast cancer. Administration of rhG-CSF reduced the incidence, depth, and duration of neutropenia, compared with published prior experience. Further studies of Taxol in breast cancer, including combinations with other active agents, are clearly warranted.

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Phase I study of mitozantrone, methotrexate and mitomycin with granulocyte colony-stimulating factor (filgrastim) in patients with advanced breast cancer

British Journal of Cancer ◽

10.1038/bjc.1994.433 ◽

1994 ◽

Vol 70 (5) ◽

pp. 980-983 ◽

Cited By ~ 1

Author(s):

MER O'Brien ◽

M Nicolson ◽

A Montes ◽

A Tidy ◽

S Ashley ◽

...

Keyword(s):

Breast Cancer ◽

Phase I ◽

Advanced Breast Cancer ◽

Phase I Study ◽

Advanced Breast ◽

Granulocyte Colony Stimulating Factor ◽

Colony Stimulating Factor ◽

Stimulating Factor

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Phase I study of mitozantrone, methotrexate and mitomycin with granulocyte colony-stimulating factor in patients with advanced breast cancer

The Breast ◽

10.1016/0960-9776(93)90068-q ◽

1993 ◽

Vol 2 (3) ◽

pp. 185

Author(s):

M.E.R. O'Brien ◽

M. Nicolson ◽

A. Montes ◽

A. Tidy ◽

S. Ashley ◽

...

Keyword(s):

Breast Cancer ◽

Phase I ◽

Advanced Breast Cancer ◽

Phase I Study ◽

Advanced Breast ◽

Granulocyte Colony Stimulating Factor ◽

Colony Stimulating Factor ◽

Stimulating Factor

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Dose-intensive vinorelbine with concurrent granulocyte colony-stimulating factor support in paclitaxel-refractory metastatic breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.1997.15.4.1395 ◽

1997 ◽

Vol 15 (4) ◽

pp. 1395-1400 ◽

Cited By ~ 111

Author(s):

R B Livingston ◽

G K Ellis ◽

J R Gralow ◽

M A Williams ◽

R White ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Growth Factor ◽

Response Rate ◽

Single Agent ◽

Metastatic Breast ◽

Granulocyte Colony Stimulating Factor ◽

Colony Stimulating Factor ◽

Grade 3 ◽

Stimulating Factor

PURPOSE We evaluated weekly single-agent intravenous (IV) vinorelbine as salvage therapy for metastatic breast cancer. After the first five patients, all received elective growth factor support with granulocyte colony-stimulating factor (G-CSF; filgrastim) in an attempt to maximize delivered dose-intensity (DDI). Objective tumor response, DDI, and toxicity were assessed, as well as time to progression (TTP) and survival. PATIENTS AND METHODS This single-center nonrandomized trial enrolled 40 patients. Anthracycline exposure and subsequent progression were common to all patients, and 38 of 40 were paclitaxel-refractory. Vinorelbine was given initially at 30 mg/m2/wk, then at 35 mg/m2/wk in a phase I/II design, which involved first intermittent (6 days of 7) and then continuous (daily) administration of G-CSF at 5 micrograms/kg. RESULTS The maximum-tolerated starting dose was 35 mg/m2/wk with continuous G-CSF support. The mean DDI was 27.7 mg/m2/wk for all patients. There were two complete responses (CRs) and eight partial responses (PRs) in 40 assessable patients for an overall response rate of 25% (95% confidence interval [CI], 13% to 41%). The median TTP was 13 weeks and median survival time 33 weeks. The dose-limiting toxicity was neutropenia, with dose delay or reduction required in 14 of 27 patients entered at 35 mg/m2. Febrile neutropenia that required hospitalization was unusual (three of 40 patients, 8%). There were no treatment-related deaths. Grade 3/4 thrombocytopenia occurred in nine patients (23%) and 26 patients (65%) required RBC transfusions for anemia. Seven patients (18%) had reversible grade 3/4 nonhematologic complications, primarily related to neurotoxicity. Grade > or = 3 mucositis was absent. CONCLUSION Concurrent administration of weekly vinoralbine and daily G-CSF is feasible and permits an increase in DDI for vinorelbine of 43% to 76% over that reported in series without growth factor support. The response rate, TTP, and survival data are encouraging for therapy given to heavily pretreated patients with metastatic breast cancer. Vinorelbine is not cross-resistant with paclitaxel and should be considered for further trials in the dose-intensified mode made possible by G-CSF, alone or combined with other agents.

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