Phase II Feasibility and Pharmacokinetic Study of Concurrent Administration of Trastuzumab and High-Dose Chemotherapy in Advanced HER2+ Breast Cancer

Abstract

Purpose: To evaluate the safety of concurrent treatment with trastuzumab and high-dose chemotherapy (HDC), using cyclophosphamide, cisplatin, and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), with autologous hematopoietic progenitor cells support, in patients with HER2؉ advanced breast cancer.Experimental Design: Patients with HER2-overexpressing high-risk primary breast cancer (HRPBC; defined as >4 involved nodes or inflammatory disease), or metastatic breast cancer (MBC) were eligible. Treatment consisted of a loading dose of trastuzumab at 4 mg/kg (day ؊5), HDC (days ؊5 to ؊2), autologous hematopoietic progenitor cells infusion on day 0, and weekly maintenance trastuzumab (2 mg/kg) from day ؉1 (minimum of 9 doses). Cardiac monitoring included serial left ventricular ejection fraction measurements before treatment and on days ؉20 and ؉65.Results: Thirty-three patients were prospectively enrolled (13 HRPBC, 20 MBC). Toxicity seemed similar to that expected with this HDC regimen alone. Neutrophils and platelets engrafted promptly. There were no cases of grade 4 or 5 toxicity. One patient experienced symptomatic grade 3 acute cardiac failure on day ؊4, responsive to treatment.Trastuzumab did not alter the pharmacokinetics of HDC. Eleven of twelve MBC patients with measurable disease (nine of them refractory to previous chemotherapy) experienced an objective response (9 complete and 2 partial responses). At median follow-up of 34 (13-58) months, all HRPBC patients remain alive and free of disease; the MBC group has event-free survival and overall survival rates of 45 and 70%, respectively.Conclusions: Incorporation of trastuzumab into HDC (cyclophosphamide, cisplatin, and BCNU) is feasible, with no apparent increased toxicity or pharmacokinetic interactions.

Combinatorial synergy induced by adenoviral-mediated mda-7 and Herceptin in Her-2+ breast cancer cells

“…Although this agent is only active in a minority (30%) of Her-2 þ tumors, treatments that enhance the activity of Herceptin should improve therapeutic outcome for a greater number of Her-2 þ patients. [5][6][7][8][9][10] In this study, we have used the novel approach of combining a gene drug (Ad-mda7) with the biological agent, Herceptin, and evaluated its antitumor effects against breast cancer cells. Preliminary results of this study have been reported.…”

“…7 The mda-7 gene was linked to an internal cytomegalovirus immediate early (CMV-IE) promoter and followed by Simian virus 40 polyadenylation (p(A)). Ad-Luc and AdCMVp(A) (Luciferase and empty vector, respectively) were used as control viruses.…”

“…2,3 Trastuzumab has been studied in Phase II and Phase III studies of women with Her-2-positive (Her-2 þ ) metastatic breast cancer (MBC), yielding significant benefits when used alone and in combination with various chemotherapeutic agents. [4][5][6][7] In these studies, Herceptin has shown additive antitumor activity, and statistically significant survival benefit, and is now being integrated into the adjuvant and neoadjuvant setting. [5][6][7][8][9][10] Trastuzumab plus taxanes is the only combination indicated for the treatment of patients with MBC whose tumors overexpress Her-2 and as a single agent in women with Her-2-overexpressing MBCs resistant to chemotherapy.…”

“…[4][5][6][7] In these studies, Herceptin has shown additive antitumor activity, and statistically significant survival benefit, and is now being integrated into the adjuvant and neoadjuvant setting. [5][6][7][8][9][10] Trastuzumab plus taxanes is the only combination indicated for the treatment of patients with MBC whose tumors overexpress Her-2 and as a single agent in women with Her-2-overexpressing MBCs resistant to chemotherapy. Although a subset of patients treated has shown cardiotoxicity, Herceptin is a generally well-tolerated drug and side effects that are commonly seen with chemotherapy are rarely observed.…”

“…Although a subset of patients treated has shown cardiotoxicity, Herceptin is a generally well-tolerated drug and side effects that are commonly seen with chemotherapy are rarely observed. [5][6][7][8][9][10][11][12][13][14] However, Herceptin shows activity in only 30% of Her-2 þ breast cancers -the reason why only a minority of tumors respond is not known.…”