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Phase II interventional study (N0337) of capecitabine in combination with vinorelbine and trastuzumab for first- or second-line treatment of HER2-positive metastatic breast cancer: a north central cancer treatment group trial.

ABSTRACT: We conducted a multiinstitutional phase II study of capecitabine in combination with vinorelbine and trastuzumab in patients eligible to receive first- or second-line treatment for human epidermal growth factor receptor type 2 (HER2)-positive (HER2(+)) metastatic breast cancer (MBC).The study was designed to test that the true confirmed response rate (CRR) was at most 45% vs. a true CRR of at least 65%. Between March 2005 and June 2008, eligible patients received capecitabine 825 mg/m² orally on days 1 to 14, vinorelbine 25 mg/m² intravenously on days 1 and 8 every 3 weeks, and trastuzumab 8 mg/kg intravenously on day 1 week 1 and 6 mg/kg every 3 weeks. The main outcome measure was CRR.Of 47 women accrued, 45 were evaluable. This design required at least 25 confirmed responses in the 45 evaluable patients for the treatment to be considered promising. Thirty women (67%) achieved a confirmed response; 25 women (56%) had a confirmed partial response (PR); 5 women (11%) had confirmed complete responses (CRs). Median progression-free survival (PFS) was 11.3 months (95% confidence interval [CI], 8.4-16.7 months). Median overall survival was 28.5 months (95% CI, 24.8-36.4 months).This triplet combination demonstrated promising activity in patients with HER2(+) MBC.

SUBMITTER: Tan WW

PROVIDER: S-EPMC5655999 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Phase II interventional study (N0337) of capecitabine in combination with vinorelbine and trastuzumab for first- or second-line treatment of HER2-positive metastatic breast cancer: a north central cancer treatment group trial.

Tan Winston W WW Allred Jacob B JB Salim Muhammad M Flynn Patrick P Fishkin Paul A S PA Stella Philip J PJ Wiesenfeld Martin M Bernath Albert M AM Fitch Tom R TR Perez Edith A EA

Clinical breast cancer 20120401 2

<h4>Background</h4>We conducted a multiinstitutional phase II study of capecitabine in combination with vinorelbine and trastuzumab in patients eligible to receive first- or second-line treatment for human epidermal growth factor receptor type 2 (HER2)-positive (HER2(+)) metastatic breast cancer (MBC).<h4>Patients and methods</h4>The study was designed to test that the true confirmed response rate (CRR) was at most 45% vs. a true CRR of at least 65%. Between March 2005 and June 2008, eligible pa ...[more]

PMID: 22444716

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Project description:The ToGA study showed that trastuzumab plus chemotherapy prolonged median survival in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer. Among chemotherapy options, oxaliplatin might be as effective as cisplatin but has shown to be more tolerable. To further improve treatment options for patients with advanced gastric cancer, we initiated a study to evaluate the efficacy and safety of trastuzumab plus oxaliplatin/capecitabine in patients with HER2-positive advanced gastric cancer.CGOG1001 was an open-label, multicenter, prospective phase II study. Patients with chemotherapy-naive HER2-positive advanced gastric cancer were eligible. Trastuzumab was administered at a loading dose of 8 mg/kg followed by 6 mg/kg infusion every 3 weeks (q3w). Oxaliplatin was administrated as a 130 mg/m(2) infusion, q3w, for up to 6 cycles. Capecitabine 1000 mg/m(2) was given orally twice daily on days 1-14 followed by a 7-day rest interval. Trastuzumab and capecitabine were continued until disease progression or intolerable toxicity. The primary endpoint was objective response rate. Simon two-stage design (H0 = 40%, H1 = 60%, ? = 0.05, ? = 0.2) by Response Evaluation Criteria In Solid Tumors 1.0 was applied.Fifty-one patients were enrolled. Confirmed response was recorded in 46 patients. One patient achieved complete response and 33 patients achieved partial response (response rate 34/51 [66.7%] in the intent-to-treat population). Median follow-up time was 28.6 months, with a median progression-free survival of 9.2 months (95% confidence interval [CI]: 6.5-11.6) and a median overall survival (OS) of 19.5 months (95% CI: 15.5-26.0). Patients with a HER2/CEP17 ratio of greater than five achieved improved OS (20.9 vs 19.5 months, p = 0.001). The most common adverse events of grade 3 or above were thrombocytopenia (21.6%), neutropenia (13.7%), anemia (5.9 %) and leucopenia (3.9%).The addition of trastuzumab to oxaliplatin/capecitabine was well tolerated and the results demonstrated encouraging efficacy.ClinicalTrials.gov NCT01364493.

Project description:To assess pathologic complete response (pCR), clinical response, feasibility, safety, and potential predictors of response to preoperative trastuzumab plus vinorelbine in patients with operable, human epidermal growth factor receptor 2 (HER2)-positive breast cancer. EXPERIMENTAL DESIGN: 48 patients received preoperative trastuzumab and vinorelbine weekly for 12 weeks. Single and multigene biomarker studies were done in an attempt to identify predictors of response. RESULTS: 8 of 40 (20%) patients achieved pCR (95% confidence interval, 9-36%). Of 9 additional patients recruited for protocol-defined toxicity analysis, 8 were evaluable; 42 of 48 (88%) patients had clinical response (16 patients, clinical complete response; 26 patients, clinical partial response). T(1) tumors more frequently exhibited clinical complete response (P = 0.05) and showed a trend to exhibit pCR (P = 0.07). 5 (13%) patients experienced grade 1 cardiac dysfunction during preoperative treatment. Neither HER2 nor estrogen receptor status changed significantly after exposure to trastuzumab and vinorelbine. RNA profiling identified three top-level clusters by unsupervised analysis. Tumors with extremes of response [pCR (n = 3) versus nonresponse (n = 3)] fell into separate groups by hierarchical clustering. No predictive genes were identified in pCR tumors. Nonresponding tumors were more likely to be T(4) stage (P = 0.02) and express basal markers (P < 0.00001), growth factors, and growth factor receptors. Insulin-like growth factor-I receptor membrane expression was associated with a lower response rate (50% vs 97%; P = 0.001). CONCLUSIONS: Preoperative trastuzumab plus vinorelbine is active and well tolerated in patients with HER2-positive, operable, stage II/III breast cancer. HER2-overexpressing tumors with a basal-like phenotype, or with expression of insulin-like growth factor-I receptor and other proteins involved in growth factor pathways, are more likely to be resistant to this regimen.

Project description:Pertuzumab, trastuzumab, and docetaxel is standard of care for first-line treatment of HER2-positive metastatic breast cancer (MBC). However, alternative chemotherapy partners are required to align with patient/physician preferences and to increase treatment flexibility. We report VELVET Cohort 1 results in which the efficacy and safety of pertuzumab and trastuzumab, administered sequentially in separate infusions, followed by vinorelbine, were evaluated. Cohort 2, where pertuzumab and trastuzumab were administered in a single infusion, followed by vinorelbine, recruited after Cohort 1 was fully enrolled, will be reported later.In this multicenter, two-cohort, open-label, phase II study, patients with HER2-positive locally advanced or MBC who had not received chemotherapy or biological therapy for their advanced disease received 3-weekly pertuzumab (840 mg loading, 420 mg maintenance doses) and trastuzumab (8 mg/kg loading, 6 mg/kg maintenance doses), followed by vinorelbine (25 mg/m2 initial dose, 30-35 mg/m2 maintenance doses) on days 1 and 8 or 2 and 9 of each 3-weekly cycle. Study treatment was given until investigator-assessed disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed objective response rate (ORR) in patients with measurable disease at baseline per RECIST v1.1. Secondary endpoints included progression-free survival (PFS) and safety.Cohort 1 enrolled 106 patients. Investigator-assessed ORR was 74.2% (95% CI 63.8-82.9) in intent-to-treat patients with measurable disease (89/106 [84.0%]). Median PFS was 14.3 months (95% CI 11.2-17.5) in the intent-to-treat population. Treatment was reasonably well tolerated, with no unexpected toxicities. Diarrhea (61/106 patients [57.5%]) and neutropenia (54/106 [50.9%]) were the most common adverse events (AEs); neutropenia (33/106 [31.1%]) and leukopenia (14/106 [13.2%]) were the most common grade ?3 AEs. Serious AEs were reported in 32/106 (30.2%) patients. AEs led to study drug discontinuation in 36/106 patients (34.0%). Eighteen of 106 patients (17.0%) had AEs suggestive of congestive heart failure; however, there were no confirmed cases.The vinorelbine, pertuzumab, and trastuzumab combination is active and reasonably well tolerated. This regimen offers an alternative for patients who cannot receive docetaxel for first-line treatment of HER2-positive locally advanced or MBC.ClinicalTrials.gov: NCT01565083 , registered on 26 March 2012.

Dataset Information

Phase II interventional study (N0337) of capecitabine in combination with vinorelbine and trastuzumab for first- or second-line treatment of HER2-positive metastatic breast cancer: a north central cancer treatment group trial.

Publications

Phase II interventional study (N0337) of capecitabine in combination with vinorelbine and trastuzumab for first- or second-line treatment of HER2-positive metastatic breast cancer: a north central cancer treatment group trial.

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