Adjuvant docetaxel and cyclophosphamide plus trastuzumab in patients with HER2-amplified early stage breast cancer: a single-group, open-label, phase 2 study.

BACKGROUND: Previous results suggest that docetaxel plus cyclophosphamide improves disease-free survival (DFS) and overall survival compared with doxorubicin plus cyclophosphamide in early stage breast cancer. We assessed the addition of 1 year of trastuzumab to a non-anthracycline regimen, docetaxel plus cyclophosphamide, in patients with HER2-amplified early stage breast cancer and examined whether this regimen was equally effective in patients with TOP2A-amplified and TOP2A-non-amplified disease. METHODS: This was an open-label, single-group, phase 2 study. Eligible patients were aged 18-75 years; had Eastern Cooperative Oncology Group performance status of 1 or less; HER2-amplified early stage breast cancer; operable, histologically confirmed, invasive carcinoma of the breast; adequate tumour specimen available for FISH analysis of TOP2A status; and adequate haematological, renal, hepatic, and cardiac function. Patients received four 21-day cycles of intravenous docetaxel 75 mg/m(2), plus intravenous cyclophosphamide 600 mg/m(2), plus intravenous trastuzumab 4 mg/kg (loading dose) on day 1 and 2 mg/kg on days 1, 8, and 15 during chemotherapy, followed by trastuzumab 6 mg/kg every three weeks for the remainder of 1 year. The primary endpoint was 2-year DFS in TOP2A-amplified and TOP2A-non-amplified patients; the primary analysis was done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00493649. FINDINGS: 493 patients were enrolled between June 15, 2007, and Aug 5, 2009. After a median follow-up of 36·1 months (IQR 35·5-36·7), 2-year DFS was 97·8% (95% CI 94·2-99·2) and 2-year overall survival was 99·5% (95% CI 96·2-99·9) for the 190 patients with TOP2A-amplified disease; 2-year DFS was 97·9% (95% CI 94·9-99·1) and 2-year overall survival was 98·8% (95% CI 96·2-99·6) for the 248 patients with TOP2A-non-amplified disease; 55 patients were not assessable for TOP2A status. In the 486 patients who received at least one dose of study drug, the most common adverse events of any grade were fatigue (284 patients, 58·4%), neutropenia (250, 51·4%), and nausea (217, 44·7%). The most common grade 3-4 toxic effects were neutropenia (229, 47·1%), febrile neutropenia (30, 6·2%), fatigue (21, 4·3%), and diarrhoea (16, 3·3%). Cardiac dysfunction occurred in 29 (6·0%) patients (12 [2·5%] grade 1, 15 [3·1%] grade 2, and two [0·4%] grade 3). 23 patients had at least one study-related serious adverse event. 16 patients stopped trastuzumab because of cardiac dysfunction. INTERPRETATION: A short, four-cycle regimen of docetaxel and cyclophosphamide combined with trastuzumab could be an option for adjuvant treatment of women with lower risk HER2-amplified early breast cancer, irrespective of TOP2A status. FUNDING: Sanofi.

Long-Term Follow-Up of the Anthracyclines in Early Breast Cancer Trials (USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 [NRG Oncology]).

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The primary joint efficacy analysis of the Anthracyclines in Early Breast Cancer (ABC) trials reported in 2017 failed to demonstrate nonanthracycline adjuvant therapy was noninferior to anthracycline-based regimens in high-risk, early breast cancer. Full analyses of the studies had proceeded when the prespecified futility boundary was crossed at a planned futility analysis for the ability to demonstrate noninferiority of a nonanthracycline regimen with continued follow-up. These results were presented with 3.3 years of median follow-up. This manuscript reports results of the final analyses of the study efficacy end points conducted with 6.9 years of median follow-up. Long-term analysis of invasive disease-free survival (IDFS), the primary end point of the ABC trials, remains consistent with the original results, as noninferiority of the nonanthracycline regimens could not be declared on the basis of the original criteria. The secondary end point of recurrence-free interval, which excluded deaths not due to breast cancer as events, favored anthracycline-based regimens, and tests for heterogeneity were significant for hormone receptor status (P = .02) favoring anthracycline regimens for the hormone receptor-negative cohorts. There was no difference in overall survival, and review of the type of IDFS events in the groups suggested reductions in cancer recurrences achieved with anthracycline regimens were offset by late leukemias and deaths unrelated to breast cancer.

Phase II randomized trial of weekly and every-3-week ixabepilone in metastatic breast cancer patients.

This multicenter, open-label, randomized phase II trial compared the efficacy and tolerability of weekly ixabepilone versus the standard 3 weekly dosing regimen. Patients with human epidermal growth factor receptor 2-negative, metastatic breast cancer (MBC) were randomly assigned to receive either ixabepilone 16 mg/m(2) as a 1-h intravenous (IV) infusion weekly on days 1, 8, and 15 of a 28-day cycle (1 week off therapy; n = 85), or 40 mg/m(2) as a 3-h IV infusion on day 1 of a 21-day cycle (n = 91), until disease progression or unacceptable toxicity. Randomization was stratified by (i) measurable versus nonmeasurable (evaluable) disease, (ii) ≤two versus >two prior chemotherapy regimens for MBC, and (iii) hormone receptor (HR)-positive versus HR-negative breast cancer. The primary endpoint was rate of progression-free survival (PFS) at 6 months. Of 176 randomized patients, 171 were treated. The 6-month PFS rate was significantly higher in patients treated with ixabepilone every 3 weeks (42.7, 95 % confidence interval [CI] 31.5-53.5) compared with those who received ixabepilone weekly (28.6, 95 % CI 18.9-38.9; log-rank P = 0.03). Every-3-week dosing significantly prolonged median PFS versus weekly dosing (5.3 vs. 2.9 months; log-rank P = 0.05). The every-3-week regimen was associated with higher rates of grade 3/4 toxicities, particularly neutropenia (38.2 vs. 6.1 %) and a higher rate of patient withdrawal due to adverse events. These results suggest that every-3-week ixabepilone is more effective than weekly treatment in MBC, albeit with more toxicity.

Results of a phase 2 study of bortezomib in patients with relapsed or refractory indolent lymphoma.

This study evaluated the efficacy and safety of single-agent bortezomib in indolent B-cell lymphoma that had relapsed from or was refractory to rituximab. Sixty patients enrolled: 59 were treated with bortezomib 1.3 mg/m(2) on days 1, 4, 8, and 11 for up to eight 21-day cycles; responders could receive 4 additional cycles; maintenance was optional. Fifty-three evaluable patients completed more than 2 cycles. The median age was 70 years, 53% female, Ann Arbor stage III-IIIE (28%) and IV (65%); 43 patients (72%) had more than 2 prior regimens; and 6 patients went on to maintenance. Overall responses are as follows: 1 complete response (1.9%), 3 unconfirmed complete response (5.7%), 3 partial response (5.7%), 34 stable disease (64.2%), and 12 progressive disease (22.6%). Median time to response = 2.2 months (range, 1.2-5.3 months); duration of response = 7.9 months (2.8-21.3 months); 1-year survival was 73% and 2-year survival was 58%; median survival = 27.7 months (range, 1.4-30.9 months); median progression-free survival = 5.1 months (range, 0.2-27.7 months), median time to progression = 5.1 months (range, 0.2-27.7 months), and median event-free survival = 1.8 months (range, 0.2-27.7 months). Treatment-related grade 3 or 4 adverse events included: thrombocytopenia (20%), fatigue (10%), neutropenia (8.5%), and neuropathy and diarrhea (6.8% each). This study demonstrates that bortezomib has modest activity against marginal zone and follicular lymphoma; it has the potential for combination with other agents in low-grade lymphomas. Maintenance therapy should be explored further.

Dose-dense doxorubicin and cyclophosphamide followed by dose-dense albumin-bound paclitaxel plus bevacizumab is safe as adjuvant therapy in patients with early stage breast cancer.

UNLABELLED: Every-2-week (dose-dense) adjuvant doxorubicin (A) plus cyclophosphamide (C) followed by cremophor-formulated paclitaxel (cf-P) was efficacious in metastatic breast cancer (BC). Albumin-bound paclitaxel (ab-P) was safe and more effective than cf-P, and the addition of bevacizumab to cf-P improved efficacy. This study compared the safety of dose-dense ab-P vs cf-P plus bevacizumab following dose-dense adjuvant AC for early-stage BC. PATIENTS AND METHODS: Women with operable, histologically confirmed BC were randomized to 4 cycles of dose-dense A 60 mg/m(2) plus C 600 mg/m(2) IV with SC pegfilgrastim, followed by 4 cycles of either dose-dense IV ab-P 260 mg/m(2) or cf-P 175 mg/m(2). Bevacizumab was given during and following chemotherapy. 97 and 96% of patients completed 4 cycles of AC therapy, while 84 and 85% of patients completed 4 cycles of taxane therapy in the ab-P and cf-P arms, respectively (N = 197). Baseline patient characteristics were similar. The most common grade ≥3 taxane-related adverse events (AEs) were fatigue and neutropenia. Dose reductions were similar between the treatment arms. During AC therapy, the majority of dose reductions were due to febrile neutropenia; during taxane therapy, the majority of cases were due to neuropathy. No taxane-related dose interruption occurred in the ab-P arm, while 3 occurred in the cf-P arm due to hypersensitivity reactions. The mean cumulative paclitaxel dose was 950.5 and 660.8 mg/m(2) in the ab-P and cf-P arms, respectively. A 44% higher paclitaxel dose was delivered in the ab-P compared with the cf-P arm (P < 0.0001), while achieving a similar safety profile. ab-P plus bevacizumab following AC therapy without prophylactic premedications was tolerable in early-stage BC patients.

Phase I study of pemetrexed and pegylated liposomal doxorubicin in patients with refractory breast, ovarian, primary peritoneal, or fallopian tube cancer.

PURPOSE: Pemetrexed and pegylated liposomal doxorubicin (PLD) are clinically active as single agents and preclinically synergistic. This phase I, open-label trial evaluated the maximum tolerated dose (MTD) and safety of pemetrexed followed by PLD in patients with breast or gynecologic cancers. PATIENTS: Using 3 + 3 dose escalation, cohorts of 3-9 patients received escalating doses of pemetrexed 400-500 mg/m(2) on days 1 and 15 and PLD 30-45 mg/m(2) on day 1 of a 28-day cycle. All patients received folic acid and vitamin B(12) until 21 days after last pemetrexed dose. Patients continued until dose-limiting toxicity (DLT) or progression (PD). RESULTS: From 11/05 to 2/08, 29 patients entered treatment; median age: 60.6 years (range, 47.5-80.1); ECOG PS 0/1: 27.6%/72.4%; primary disease site: ovarian (55.2%), breast (34.5%), peritoneum (10.3%); prior therapies: chemotherapy (100.0%), surgery (72.4%), hormones/biologics (35%), and radiation (20.7%). Pemetrexed/PLD dose levels: L1 = 400/30 (n = 4), L2 = 400/35 (n = 6), L3 = 500/35 (n = 9), L4 = 500/40 (n = 7), and L5 = 500/45 (n = 3). Treatment-related grade 3-4 toxicities: hematologic-neutropenia (86.2%), leukopenia (58.6%), thrombocytopenia (48.3%), anemia (41.4%); nonhematologic-mucosal inflammation (24.1%), febrile neutropenia (24.1%), hand-foot syndrome (13.8%), hypokalaemia (10.3%). Reasons for discontinuation: PD (48.3%), toxicity (27.6%), patient request (13.8%), and investigator request (10.3%). EFFICACY: 5 ovarian patients (20.8%) achieved partial response; median time to progression (TTP) was 6.1 months (range, 1.2-12.5). CONCLUSION: Pemetrexed plus PLD was reasonably tolerated in this heavily-pretreated population. MTD: pemetrexed 500 mg/m(2) and PLD 40 mg/m(2) may be carried forward to phase II studies in specific patient populations. TTP in platinum-refractory ovarian patients was greater than expected.

The addition of hormone therapy to tamoxifen does not prevent hot flashes in women at high risk for developing breast cancer.

Tamoxifen significantly reduces the risk of developing breast cancer in women at increased-risk. The usefulness of tamoxifen has been limited by its side effect profile, especially its propensity to worsen vasomotor symptoms. Hormone therapy (HT) has long been utilized to reduce vasomotor symptoms in peri- and post-menopausal women. The aim of this study was to compare the incidence of hot flashes, weight gain and other side effects associated with taking tamoxifen alone versus tamoxifen in combination with HT in high-risk women. One hundred eighty high-risk women were enrolled into one of two parallel study cohorts to receive tamoxifen alone (93 women) or tamoxifen with HT (87 women). Women were monitored at baseline, 3 months and then yearly for assessments of menopausal symptoms and toxicities associated with tamoxifen alone versus tamoxifen plus HT. We also assessed for differences in menopausal symptoms and toxicities by type of HT (estrogen vs. estrogen and progestin combination). Hot flash scores increased at 3 months and at 1 year compared with baseline in women on tamoxifen alone as well as for women on HT. Women on tamoxifen with estrogen only replacement had the greatest increase in hot flash scores, although this was not significantly different than the increase seen with tamoxifen alone. About 47% of participants on tamoxifen gained weight and there was a strong trend towards less weight gain in women on the combination of tamoxifen and HT, most pronounced for those on tamoxifen with estrogen alone replacement therapy. The addition of HT to tamoxifen therapy does not ameliorate tamoxifen-induced vasomotor symptoms. Tamoxifen associated weight gain, however, may be lessened by the addition of HT.

Randomized phase-II evaluation of letrozole plus dasatinib in hormone receptor positive metastatic breast cancer patients.

The non-receptor tyrosine kinase Src activation plays a role in the malignant progression of breast cancer, including development of endocrine therapy resistance and survival of bone metastases. This study investigated whether adding Src kinase inhibitor dasatinib to aromatase inhibitor (AI) therapy improved outcomes in estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer (MBC). Postmenopausal patients with ER-positive, HER2-negative MBC (0-1 prior chemotherapies and no prior AI for MBC) were eligible for this non-comparative, parallel group, phase-II study. Patients were randomized to letrozole (2.5 mg/day PO) alone or with dasatinib (100 mg/day PO). Patients with disease progression on letrozole alone could crossover to dasatinib plus continued letrozole. The primary endpoint was clinical-benefit-rate (CBR; complete response + partial response + stable disease ≥6 months). A total of 120 patients were randomized. The CBR of 71% (95% CI 58-83%) was observed with letrozole + dasatinib versus the projected CBR of the combination of 56%. The CBR of 66% (95% CI 52-77%) with letrozole alone also exceeded the projected CBR of 39% with letrozole alone. The CBR was 23% in the crossover arm of letrozole plus dasatinib in patients progressing on letrozole alone. Median progression-free survival with the combination was 20.1 months and 9.9 months with letrozole alone. Letrozole plus dasatinib was well tolerated, although 26% of patients required dasatinib dose reductions. In this non-comparative phase-II trial, the CBR of 71% and the median PFS of 20.1 months with letrozole + dasatinib are encouraging and suggest that dasatinib may inhibit the emergence of acquired resistance to AI therapy.

Phase II trial of gemcitabine/carboplatin (plus trastuzumab in HER2-positive disease) in patients with metastatic breast cancer.

BACKGROUND: Gemcitabine and carboplatin have significant preclinical synergy, and both provide synergistic antitumor activity in metastatic breast cancer (MBC) when used in combination with trastuzumab. The gemcitabine/ cisplatin combination is highly active in MBC with response rates (RRs) of approximately 50% in anthracycline- and taxane-pretreated patients and up to 80% in untreated subjects. This phase II trial studied the efficacy and safety of gemcitabine/carboplatin with or without trastuzumab in patients with MBC. PATIENTS AND METHODS: Patients were stratified into 3 groups: group 1, HER2-positive; group 2, HER2-negative and taxane- naive/remote (no taxanes within past 2 years); and group 3, HER2-negative and previous taxane therapy. Included were women aged > or = 18 years, Eastern Cooperative Oncology Group performance status of 0-2, with Response Evaluation Criteria in Solid Tumors-defined measurable MBC; HER2-negative or HER2 (3+) by immunohistochemistry or fluorescence in situ hybridization positive. All cycles were repeated every 14 days. On day 1, gemcitabine 1500 mg/m2 over 30 minutes was administered followed by carboplatin area under the curve of 2.5. Group 1 also received trastuzumab 8 mg/kg on day 1 of each cycle followed by 4 mg/kg for every 2 weeks thereafter. RESULTS: One hundred fifty patients were registered (50, 51, and 49 in groups 1, 2, and 3, respectively). The overall RRs were 64%, 27%, and 32%, respectively, with median time to progression of 7.2, 5.5, and 4.4 months, respectively. Overall, grade 3/4 toxicities included neutropenia (45%), leukopenia (17%), and thrombocytopenia (7%). Alopecia was infrequent: grade 1 (34%) and grade 2 (3%), and there was no significant cardiac toxicity. CONCLUSION: Gemcitabine/carboplatin/trastuzumab is highly active in patients with HER2-positive MBC. Gemcitabine/carboplatin is active in patients with HER2-negative MBC independent of previous taxane therapy. Gemcitabine/carboplatin with or without trastuzumab administered every 2 weeks is associated with a low frequency of serious toxicity.

Results of a phase II trial of cetuximab plus capecitabine/irinotecan as first-line therapy for patients with advanced and/or metastatic colorectal cancer.

BACKGROUND: XELIRI (capecitabine/irinotecan) is effective and well tolerated in metastatic colorectal cancer (mCRC). Cetuximab is active in mCRC alone or with chemotherapy. This study evaluated cetuximab plus XELIRI in first-line treatment of mCRC. PATIENTS AND METHODS: Subjects had histologically confirmed unresectable colorectal adenocarcinoma (with T4 lesions) after preoperative chemoradiation and/or metastases. Treatment was capecitabine 1700 mg/m2 (850 mg/m2 orally twice a day on days 1-14 for 3 weeks), irinotecan 200 mg/m2 intravenously (I.V.) on day 1 every 3 weeks, and weekly cetuximab (initially 400 mg/m2 I.V. [120 minutes], subsequently 250 mg/m2 [30 minutes]). RESULTS: Baseline characteristics (N = 70): 43 men (61%); median age, 61.5 years; Eastern Cooperative Oncology Group performance status 0/1 = 66%/34%; 94% adenocarcinoma. Previous therapy: surgery (91%), chemotherapy (14%), or radiation therapy (7%). Responses (patients completing > or = 2 cycles): complete response (5.7%), partial response (37.7%), stable disease (43.4%), and progressive disease (PD; 13.2%); 16 patients discontinued early (n = 4 allergic reaction, n = 2 withdrew consent, n = 2 death, and n = 8 other adverse events [AEs]). The overall per-protocol response rate was 43.4% (34% intent to treat [ITT]; disease control rate, 86.8%; 69% ITT). The median time to progression was 8.1 months (range, < 1-27.0 months), and the median time to response was 1.6 months (range, 1.1-8.4 months). The median survival was 20.5 months, and 45.7% of patients remain alive. Of the 38 deaths, 84% were because of PD. No death was treatment related. The most frequent grade 3/4 treatment-related AEs included diarrhea, neutropenia, and nausea/vomiting; 32% of patients required dose reductions. All patients are off the study primarily because of PD (34.3%) or AEs (40.0%). CONCLUSION: In summary, XELIRI plus cetuximab is a promising regimen that merits further study for first-line mCRC.

Five-year results of a phase II trial of preoperative 5-fluorouracil, epirubicin, cyclophosphamide followed by docetaxel with capecitabine (wTX) (with trastuzumab in HER2-positive patients) for patients with stage II or III breast cancer.

We aimed to increase pathologic complete response (pCR) in patients with invasive breast cancer by adding preoperative capecitabine to docetaxel following 5-fluorouracil, epirubicin, cyclophosphamide (FEC) (with trastuzumab for patients with HER2-positive disease) and to evaluate 5-year disease-free survival (DFS) associated with this preoperative regimen. Chemotherapy included four cycles of FEC100 (5-fluorouracil 500 mg/m2 , epirubicin 100 mg/m2 , cyclophosphamide 500 mg/m2 IV on Day 1 every 21 days) followed by 4 21-day cycles of docetaxel (35 mg/m2  days 1 and 8) concurrently with capecitabine (825 mg/m2 orally twice daily for 14 days followed by 7 days off) (wTX). For HER2-positive patients, treatment was modified by decreasing epirubicin to 75 mg/m2 and adding trastuzumab (H) in standard doses (FEC75-H →wTX-H). The study objective was to achieve a pCR rate in the breast and axillary lymph nodes of 37% in patients with HER2-negative breast cancer and of 67% in patients with HER2-positive breast cancer treated with preoperative trastuzumab. A total of 186 patients were enrolled on study. In an intent-to-treat analysis, the pCR rate was 31% (37/118, 95% CI: 24-40%) in the HER2-negative patients, 24% (15/62, 95% CI: 14-37%) in ER-positive/HER2-negative patients, 39% (22/56, 95% CI: 27-53%) in the ER-negative/HER2-negative patients, and 46% (29/63, 95% CI: 34-48%) in the HER2-positive patients. The pCR rate in the 40 trastuzumab-treated patients was 53% (21/40, 95% CI: 38-67%). Grade 3 and 4 adverse events included neutropenia, leukopenia, diarrhea, and hand-foot skin reactions. One trastuzumab-treated patient developed grade 3 cardiotoxicity, and 4 others experienced grade 1-2 decrements in left ventricular function; all five patients' cardiac function returned to their baseline upon completion of trastuzumab. At 5 years, disease-free survival was 70% in the HER2-negative population (78% in ER-positive/HER2-negative and 62% in the ER-negative/HER2-negative patients) and 80% in the HER2-positive patients (87% in the trastuzumab-treated HER2-positive patients). At 5 years, overall survival was 80% in the HER2-negative population (88% in ER-positive/HER2-negative and 71% in the ER-negative/HER2-negative patients) and 86% in the HER2-positive patients (94.5% in the trastuzumab-treated HER2-positive patients). FEC100 (FEC75 with trastuzumab) followed by weekly docetaxel plus capecitabine, with or without trastuzumab is a safe, effective preoperative cytotoxic regimen. However, the addition of capecitabine to docetaxel following FEC, with or without trastuzumab, did not increase pCR rates nor 5-year DFS over the rates that have been reported with standard preoperative doxorubicin/cyclophosphamide (AC) followed by paclitaxel, with or without trastuzumab. Therefore, the use of capecitabine as part of preoperative chemotherapy is not recommended.

Phase II trial of capecitabine and weekly paclitaxel in patients with metastatic breast cancer previously treated with every-3-week taxane therapy.

PURPOSE: We conducted a multicenter phase II trial to determine the efficacy/safety of capecitabine and weekly paclitaxel, a combination with preclinical evidence of synergy, in patients with metastatic breast cancer (MBC) previously treated with a taxane. PATIENTS AND METHODS: Eligibility criteria included measurable MBC, history of every-3-week taxane therapy (adjuvant or for MBC), and no previous taxane on a weekly basis, capecitabine, or infusional 5-fluorouracil. Patients received capecitabine 825 mg/m2 per dose orally twice daily (1650 mg/m2 per day) on days 1-14 and weekly paclitaxel 80 mg/m2 intravenously on days 1 and 8, followed by a 1-week rest period (every-3-week cycle) until progression or intolerable toxicity. Fifty-four women were treated, most with previous every-3-week taxane exposure as adjuvant therapy (n=43) rather than for MBC (n=11). The median number of delivered cycles was 7, with dose modifications in 30 patients. The intent-to-treat objective response rate (primary study endpoint) was 59% (95% confidence interval, 46%-72%), including 7 complete and 25 partial responses. RESULTS: Three patients had stable disease for>or=6 months, for a clinical benefit rate of 65% (95% confidence interval, 51%-76%). Median objective response duration, time to progression, and overall survival were 8.1 months, 8.4 months, and 21.6 months, respectively. Grade 3/4 treatment-related adverse events consisted of neutropenia (13%), anemia (2%), hand-foot skin reaction (20%), fatigue (7%), diarrhea (4%), nausea/vomiting (4%), and pain (2%). No patients developed grade 3/4 neuropathy. CONCLUSION: Capecitabine and weekly paclitaxel were highly active with acceptable tolerability in patients with MBC previously treated with a taxane, consistent with our recently published experience in taxane-naive women with MBC.

Anthracyclines in Early Breast Cancer: The ABC Trials-USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology).

Purpose Docetaxel and cyclophosphamide (TC) was superior to doxorubicin and cyclophosphamide (AC) in a trial in early breast cancer. However, activity of TC relative to AC regimens with a taxane (TaxAC) is unknown. Methods In a series of three adjuvant trials, women were randomly assigned to TC for six cycles (TC6) or to a standard TaxAC regimen. US Oncology Research (USOR) 06-090 compared TC6 with docetaxel, doxorubicin, and cyclophosphamide (TAC6). National Surgical Adjuvant Breast and Bowel Project (NSABP) B-46-I/USOR 07132 compared TC6, TAC6, or TC6 plus bevacizumab. NSABP B-49 compared TC6 with several standard AC and taxane combination regimens. Before any analysis of individual trials, a joint efficacy analysis of TC versus the TaxAC regimens was planned, with invasive disease-free survival (IDFS) as the primary end point. Patients who received TC6 plus bevacizumab on NSABP B-46-I/USOR 07132 were not included. A hazard ratio (HR) from a stratified Cox model that exceeded 1.18 for TC6 versus TaxAC was predefined as inferiority for TC6. The prespecified interim monitoring plan was to report for futility if the HR was > 1.18 when 334 IDFS events were observed (50% of 668 events required for definitive analysis). Results A total of 2,125 patients were randomly assigned to receive TC6 regimens and 2,117 patients were randomly assigned to receive TaxAC regimens. The median follow-up time was 3.3 years. There were 334 IDFS events, and the HR for TC6 versus TaxAC was 1.202 (95% CI, 0.97 to 1.49), which triggered early reporting for futility. The 4-year IDFS was 88.2% for TC6 and was 90.7% for TaxAC ( P = .04). Tests for treatment interaction by protocol, hormone receptor status, and nodal status were negative. Conclusion The TaxAC regimens improved IDFS in patients with high-risk human epidermal growth factor receptor 2-negative breast cancer compared with the TC6 regimen.

Phase I and pharmacokinetic study of the dolastatin-15 analogue tasidotin (ILX651) administered intravenously on days 1, 3, and 5 every 3 weeks in patients with advanced solid tumors.

PURPOSE: To determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics of tasidotin (ILX651), a dolastatin-15 analogue, when administered on days 1, 3, and 5 every 3 weeks in patients with advanced solid tumors. PATIENTS AND METHODS: Thirty-two patients were treated with 92 courses of tasidotin through seven dose levels determined by a modified Fibonacci scheme ranging from 3.9 to 45.7 mg/m(2). Pharmacokinetic samples were collected during the first course. RESULTS: Neutropenia was the principal DLT at the 45.7 mg/m(2)/d dose level. In addition, one patient also experienced grade 3 neutropenia complicated with grade 3 esophageal candidiasis and grade 3 dehydration. Only 1 of 11 patients treated at the MTD, 34.4 mg/m(2), experienced dose-limiting neutropenia. Other common, drug-related toxicities included mild to moderate fatigue, anemia, nausea, anorexia, emesis, alopecia, and diarrhea. The best observed antitumor response consisted of stable disease and was noted in 10 patients (31%); the median duration on study for those patients with stable disease was 99.5 days compared with 37.5 days for those patients with progressive disease. Tasidotin plasma concentrations declined biphasically with an effective half-life of < or =55 minutes, and approximately 11% was excreted unchanged in the urine. CONCLUSION: The recommended dose for phase II studies and the MTD when tasidotin is administered on days 1, 3, and 5 every 3 weeks is 34.4 mg/m(2). The favorable toxicity profile of tasidotin compared with other antitubulin agents, including other dolastatin analogues, and its novel mechanism of action support further disease-directed evaluation of this agent.

Phase II, Multicenter, Single-Arm, Feasibility Study of Eribulin Combined With Capecitabine for Adjuvant Treatment in Estrogen Receptor-Positive, Early-Stage Breast Cancer.

BACKGROUND: The present phase II, open-label, multicenter study explored the feasibility, safety, and tolerability of eribulin, a novel non-taxane microtubule inhibitor, plus capecitabine as adjuvant therapy. PATIENTS AND METHODS: Postmenopausal women with early-stage, human epidermal growth factor receptor 2 (HER2)-negative, estrogen-receptor (ER)-positive breast cancer received four 21-day cycles of treatment with eribulin mesylate (1.4 mg/m(2) intravenously on days 1 and 8 of each cycle) combined with capecitabine (900 mg/m(2) orally twice daily on days 1-14 of each cycle [standard schedule] or 1500 mg orally twice daily using a 7-days on/7-days off schedule [weekly schedule]). Feasibility was determined by the relative dose intensity (RDI) of the combination using prespecified criteria for 80% of patients achieving an RDI of ≥ 85%, with a lower 95% confidence boundary > 70%. RESULTS: The mean RDI was 90.6%, and the feasibility rate was 81.3% among women (n = 67, mean age, 61.3 years) receiving the standard schedule and 95.6% and 100% among women (n = 10, mean age 62.3 years) receiving the weekly schedule. Dose reductions, missed doses, and withdrawals due to adverse events (most commonly hand-foot syndrome) ascribed to capecitabine led to a higher RDI (93.5% vs. 87.8%) and feasibility rate (82.8% vs. 71.9%) for eribulin than for capecitabine using the standard dosing schedule. The most common adverse events were alopecia and fatigue. CONCLUSION: Eribulin plus capecitabine with standard or weekly dosing schedules is feasible in patients with early-stage, HER2-negative, ER-positive breast cancer. Full-dose eribulin (1.4 mg/m(2) on days 1 and 8) with capecitabine (1500 mg orally twice daily, 7 days on/7 days off) is recommended as a regimen for further evaluation.

Incidence and Predictive Factors for Recovery of Ovarian Function in Amenorrheic Women in Their 40s Treated With Letrozole.

PURPOSE: This prospective study assessed the impact of 2 years of aromatase inhibitor (AI) therapy on the incidence of ovarian function recovery (OFR) in women age 40 to 49 with estrogen receptor-positive breast cancer who were premenopausal at diagnosis and who underwent chemotherapy-induced amenorrhea during adjuvant treatment. PATIENTS AND METHODS: Women age 40 to 49 with estrogen receptor-positive breast cancer who had ceased menstruating with adjuvant cyclophosphamide-based chemotherapy, had postmenopausal serum estradiol (E2), and had received tamoxifen for ≥ 1 year were treated with letrozole (2.5 mg) daily for ≥ 2 years. Serum follicle-stimulating hormone (FSH) and E2 were measured at baseline and over 2 years. A general linear model was used to assess serial FSH by OFR. Logistic regression was used to assess baseline predictors and OFR. RESULTS: The study enrolled 177 women (145 women age 45 to 49 years and 32 women age 40 to 44 years). Of 173 evaluable patients, 67 (39%; 95% CI, 31% to 46%) regained ovarian function; 11 of these patients (6%; 95% CI, 3% to 10%) resumed menses, and 56 of these patients (32%; 95% CI, 25% to 39%) developed premenopausal E2 without menses. Among AI-naïve patients, serial FSH significantly increased over time (P < .001), did not vary significantly by OFR status (P = .55), but showed mild evidence of a decrease after month 12 for those who resumed menses (P = .0989). Age less than 45 years and inhibin B were significant multivariable baseline predictors of OFR. CONCLUSION: These results emphasize the challenge in determining definitive menopause in women with chemotherapy-induced amenorrhea. The risk of OFR during treatment with AIs in amenorrheic women in their 40s is high, and AI therapy should be avoided in these patients.

Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results.

PURPOSE: Docetaxel and capecitabine, a tumor-activated oral fluoropyrimidine, show high single-agent efficacy in metastatic breast cancer (MBC) and synergy in preclinical studies. This international phase III trial compared efficacy and tolerability of capecitabine/docetaxel therapy with single-agent docetaxel in anthracycline-pretreated patients with MBC. PATIENTS AND METHODS: Patients were randomized to 21-day cycles of oral capecitabine 1,250 mg/m(2) twice daily on days 1 to 14 plus docetaxel 75 mg/m(2) on day 1 (n = 255) or to docetaxel 100 mg/m(2) on day 1 (n = 256). RESULTS: Capecitabine/docetaxel resulted in significantly superior efficacy in time to disease progression (TTP) (hazard ratio, 0.652; 95% confidence interval [CI], 0.545 to 0.780; P =.0001; median, 6.1 v 4.2 months), overall survival (hazard ratio, 0.775; 95% CI, 0.634 to 0.947; P =.0126; median, 14.5 v 11.5 months), and objective tumor response rate (42% v 30%, P =.006) compared with docetaxel. Gastrointestinal side effects and hand-foot syndrome were more common with combination therapy, whereas myalgia, arthralgia, and neutropenic fever/sepsis were more common with single-agent docetaxel. More grade 3 adverse events occurred with combination therapy (71% v 49%, respectively), whereas grade 4 events were slightly more common with docetaxel (31% v 25% with combination). CONCLUSION: The significantly superior TTP and survival achieved with the addition of capecitabine to docetaxel 75 mg/m(2), with the manageable toxicity profile, indicate that this combination provides clear benefits over single-agent docetaxel 100 mg/m(2). Docetaxel/capecitabine therapy is an important treatment option for women with anthracycline-pretreated MBC.

Feasibility of quantifying the effects of epoetin alfa therapy on cognitive function in women with breast cancer undergoing adjuvant or neoadjuvant chemotherapy.

Impaired cognition, fatigue, and diminished quality of life (QOL) are commonly associated with breast cancer chemotherapy. This randomized, double-blind, placebo-controlled pilot trial assessed the feasibility of quantifying the effects of epoetin alfa on cognitive function and mood, and evaluated its effects on fatigue and QOL in patients with breast cancer treated with anthracycline-based adjuvant or neoadjuvant chemotherapy. Patients were randomized to receive epoetin alfa 40,000 U subcutaneously once weekly or placebo at the beginning of 4 cycles of chemotherapy administered over 12 weeks. Cognitive function was assessed by Executive Interview (EXIT25) and Clock Drawing Tasks; mood by Profile of Mood States; anemia-related symptoms, including fatigue, by the Functional Assessment of Cancer Therapy-Anemia (FACT-An) subscale; and QOL by Linear Analog Scale Assessment. Ninety-four patients were evaluable for efficacy and safety. Mean change in EXIT25 scores from baseline to cycle 4 in the epoetin alfa group was 1.3 +/- 3.3; the mean change was 0.3 +/- 2.4 in the placebo group (a negative change indicates improved executive function). There was no difference between groups in mean change in EXIT25 score from baseline to 6-month follow-up assessment. Mean hemoglobin levels were higher in the epoetin alfa group compared with the placebo group after 4 cycles of chemotherapy. Epoetin alfa recipients had less of a decrease in FACT-An subscale scores from baseline to cycle 4 and improvement in FACT-An subscale scores at 6-month follow-up assessment compared with placebo. Epoetin alfa therapy was well tolerated. These data suggest that epoetin alfa may have attenuated the cognitive impairment and fatigue that occurred during adjuvant breast cancer chemotherapy.

Results of a phase II open-label study of capecitabine in combination with irinotecan as first-line treatment for metastatic colorectal cancer.

BACKGROUND: Between July 2001 and September 2002, 49 eligible patients were enrolled in an open-label phase II study to assess the efficacy and safety of first-line treatment with capecitabine/irinotecan in metastatic colorectal cancer. PATIENTS AND METHODS: Patients received capecitabine (1000 mg/m2 twice daily) on days 1-14 and irinotecan (240 mg/m2) on day 1 of a 21-day cycle. Patients enrolled had a median age of 64.5 years, and 6% of patients had an Eastern Cooperative Oncology Group performance status of 2. Fifty-seven percent of patients were male. RESULTS: Forty-two patients were evaluable for response. There was 1 complete response (2%), 18 partial responses (43%), 20 cases of stable disease (48%), and 3 cases of disease progression (7%), for an overall response rate of 45% (95% CI, 30%-60%). The median duration of response was 5.7 months (range, 2.5-II.3 months). Median survival was 13.4 months (range, 1.2-28.8 months) and median progression-free survival was 6.2 months (range, 1.2-17.5 months). At 1 year, the estimated survival rate was 54% and the estimated progression-free survival rate was II%. The median number of cycles received was 6 (range, 1-18 cycles), and most patients (80%) required a dose modification because of diarrhea, nausea, and/or neutropenia. Grade 1/2 hand-foot syndrome occurred in 8 patients (16%). Grade 3/4 toxicities experienced by > or = 5% of patients included diarrhea (20%), neutropenia (12%), dehydration (10%), nausea (10%), anemia (6%), fatigue (6%), pain (6%), and vomiting (6%). CONCLUSIONS: First-line capecitabine/ irinotecan is an active combination for the treatment of metastatic colorectal cancer and feasible for use in the community-based setting. Despite significant toxicity with the regimen, the treatment was manageable with dose reduction or delay and should be investigated in phase III trials.

Patients with Slowly Proliferative Early Breast Cancer Have Low Five-Year Recurrence Rates in a Phase III Adjuvant Trial of Capecitabine.

PURPOSE: We conducted a randomized phase III study to determine whether patients with early breast cancer would benefit from the addition of capecitabine (X) to a standard regimen of doxorubicin (A) plus cyclophosphamide (C) followed by docetaxel (T). EXPERIMENTAL DESIGN: Treatment comprised eight cycles of AC→T (T dose: 100 mg/m(2) on day 1) or AC→XT (X dose: 825 mg/m(2) twice daily, days 1-14; T dose: 75 mg/m(2) on day 1). The primary endpoint was 5-year disease-free survival (DFS). RESULTS: Of 2,611 women, 1,304 were randomly assigned to receive AC→T and 1,307 to receive AC→XT. After a median follow-up of 5 years, the study failed to meet its primary endpoint [HR, 0.84; 95% confidence interval (CI), 0.67-1.05; P = 0.125]. A significant improvement in overall survival, a secondary endpoint, was seen with AC→XT versus AC→T (HR, 0.68; 95% CI, 0.51-0.92; P = 0.011). There were no unexpected adverse events. Of patients with estrogen receptor (ER)-positive/HER2-negative disease, 70% of whom were node-positive, 26% and 59% had tumors with a centrally assessed Ki-67 score of <10% or <20%, respectively, and only 17 (2%) and 53 (6%) DFS events, respectively, occurred in these groups at 7 years. CONCLUSIONS: The very low event rate in patients with ER-positive, low Ki-67 cancers, regardless of nodal status, strongly suggests that these patients should not be enrolled in adjuvant trials that assess 5-year DFS rates and that central Ki-67 analyses can identify these patients.