Navelbine

[Rich66]

(w/Traz, w/AI, liver friendly, w/Cap, w/everolimus i.e. mTOR inhib)


Gan To Kagaku Ryoho. 2009 Dec;36(13):2631-5.
[A case of recurrent breast cancer responding to vinorelbine/trastuzumab combination therapy]

[Article in Japanese]
Fujisawa M, Uomori T, Takehara K, Mitsugi Y, Yoshino K, Okumura M, Machida M, Kitabatake T, Ishibiki Y, Kojima K, Ogura K, Matsumoto T.
Dept. of General Surgery, Juntendo University Nerima Hospital.
A 60-year-old woman with Stage II, ER-positive, PgR-positive, HER2 (2+) cancer in the right breast underwent right mastectomy with right axillary dissection after chemotherapy with EC followed by docetaxel (DOC) alone. Exemestane was used for postoperative adjuvant treatment. She underwent a right chest wall tumor resection for local recurrence. Hormone therapy was continued with toremifene in place of exemestane. In December 2007, two years after the second surgery, CEA was elevated and PET showed a local recurrence in the right chest wall and metastases to the right axillary nodes and liver. The tumor was ER-positive, PgR-negative and HER2 (3+) at recurrence, and vinorelbine/trastuzumab combination was initiated as first-line chemotherapy for the recurrent lesion and liver metastasis. All lesions in the right chest wall, right axillary nodes and liver disappeared from PET and CT images after five courses of the regimen, resulting in clinical CR. Vinorelbine combined with trastuzumab appears to be a useful therapy for HER2-positive recurrent breast cancer.

PMID: 20009469 [PubMed - in process]



Breast. 2010 Jan 28. [Epub ahead of print]
Preoperative therapy with trastuzumab and oral vinorelbine (+/- endocrine therapy) in patients with HER2-positive breast cancer.

Iorfida M, Bagnardi V, Balduzzi A, Dellapasqua S, Cardillo A, Luini A, Intra M, Minchella I, Veronesi P, Viale G, Goldhirsch A, Colleoni M.
Unit of Research in Medical Senology, European Institute of Oncology, Via Ripamonti 435, 20141, Milan, Italy; Department of Medicine, European Institute of Oncology Milan, via Ripamonti 435, Milan 20141, Italy.
BACKGROUND: Combined trastuzumab and intravenous vinorelbine yielded high clinical activity as preoperative treatment in patients (pts) with HER 2/neu positive breast cancer. PATIENTS AND METHODS: We tested a preoperative combination of trastuzumab with oral vinorelbine (oV) in pts with locally advanced (T2-T4 N0-3 M0) HER2-positive breast cancer. Trastuzumab was administered i.v q 3 wks and oV was administered at the dose of 55 mg/sqm on days 1 and 3 q 3 wks, for 8 courses. Pts with ER >/= 10% tumors received endocrine therapy with letrozole 2.5 mg/day, plus monthly triptorelin if premenopausal. RESULTS: Forty-five pts entered the study. The overall response rate (CR + PR) was 76% (95% CI: 60%-87%). pCR was observed in 4 pts (10%). Among ER-positive tumors 21/25 pts obtained a clinical response (84%) and two pts obtained a pCR (8%). CONCLUSIONS: The combination of trastuzumab and oral vinorelbine demonstrated encouraging activity in patients with HER 2 positive ER-positive tumors. Alternative strategies should be investigated in patients with endocrine non responsive disease. Copyright © 2010. Published by Elsevier Ltd.

PMID: 20117001 [PubMed - as supplied by publisher]




Eur J Cancer. 2009 Nov 25. [Epub ahead of print]
Mild to moderate liver dysfunction does not require dose reduction of oral or intravenous vinorelbine: Results of a pharmacokinetic study.

Kitzen JJ, Puozzo C, de Jonge MJ, Brandely M, Verweij J.
Dept. of Medical Oncology, Erasmus University Medical Center, Groene Hilledijk 301, 3075 EA Rotterdam, Netherlands.
We studied the pharmacokinetic profile of weekly oral and intravenous vinorelbine in cancer patients with various degrees of hepatic function, and assessed an intra-patient comparison of the pharmacokinetics of i.v. versus oral vinorelbine. In this open-label study, patients were randomised to receive an initial dose of vinorelbine at day 1 by either i.v. or the oral route followed by a second dose on day 8 via the alternative route. A total of 16 patients were included, 12 patients received the planned two administrations. Toxicities were similar for all cohorts and were mainly of haematological and gastrointestinal origin. Pharmacokinetic analysis of both routes did not reveal any differences between cohort I and II. Based on these findings in patients with mild to moderate liver dysfunction no dose modifications of vinorelbine have to be taken into consideration.

PMID: 19944596 [PubMed - as supplied by publisher]



Cancer Chemother Pharmacol. 2010 Mar;65(4):755-63. Epub 2009 Aug 9.
Phase II study of oral vinorelbine in combination with capecitabine as second line chemotherapy in metastatic breast cancer patients previously treated with anthracyclines and taxanes.

Jones A, O'Brien M, Sommer H, Nowara E, Welt A, Pienkowski T, Rolski J, Pham ML, Perraud K, Trillet-Lenoir V.
Royal Free Hospital, Londres NW3 2QG, UK. alison.jones@royalfree.nhs.uk
PURPOSE: Effective treatment options for patients with metastatic breast cancer (MBC) resistant/refractory to anthracyclines and/or taxanes are limited. Intravenous and oral combination of vinorelbine (VRL) and capecitabine were shown to be feasible and effective in first-line MBC. In order to evaluate the activity of the combination of an all oral regimen in a more advanced setting, we investigated a regimen combining oral VRL and capecitabine in a phase II study as second-line chemotherapy of MBC patients previously treated with anthracyclines and taxanes. PATIENTS AND METHODS: Forty patients (median age 52 years) with MBC received the combination of oral VRL 60 mg/m(2) on days 1, 8 and 15 plus capecitabine 1,000 mg/m(2) bid given from day 1 to day 14 in an open-label, international, multicentre, phase II study. Cycles were repeated every 3 weeks. The primary endpoint was response rate (RR) evaluated by an independent panel review. Secondary objectives included safety, duration of response, progression-free survival, overall survival and quality of life. RESULTS: All the patients had received prior chemotherapy with anthracyclines and taxanes, 75% were refractory/resistant to anthracycline and/or taxane, 72.5% presented with visceral involvement and the last prior chemotherapy for 87.5% of the patients was for advanced disease setting. The median number of administered cycles per patient was 4 (range 1-31). Eight responses were documented and validated by an independent panel review, yielding RRs of 20% [95% CI: 9-35.6] in the intent-to-treat (treated) population and 23.5% [95% CI: 10.7-41.2] in the 34 evaluable patients. Median progression-free survival and median overall survival were 3.4 months [95% CI: 2.3-5.5] and 11.3 months [95% CI: 8.1-16.4], respectively. The principal toxicities were anaemia, neutropenia (rarely complicated; only one patient experienced febrile neutropenia), fatigue and gastrointestinal toxicities with very few grade 3-4 non-haematological toxicities. CONCLUSIONS: In second-line treatment of MBC patients previously treated with anthracyclines and taxanes, oral VRL plus capecitabine is a safe regimen with an efficacy comparable to the other available combination regimens used in this heavily and resistant/refractory (75% of patients) pre-treated patients' population. Moreover, this well-tolerated combination offers the advantages of an all oral regimen.

PMID: 19669644 [PubMed - in process]

1: Anticancer Res. 2009 Feb;29(2):667-70.

A phase II trial of oral vinorelbine and capecitabine in anthracycline pretreated patients with metastatic breast cancer.

Finek J, Holubec L Jr, Svoboda T, Sefrhansova L, Pavlikova I, Votavova M, Sediva M, Filip S, Kozevnikova R, Kormunda S.
University Hospital Pilsen, Czech Republic. finek@fnplzen.cz
BACKGROUND: Optimal chemotherapy (CT) for advanced breast treatment should be effective, well tolerated and convenient. In this study the efficacy and safety of the fully oral combination of oral vinorelbine (Navelbine Oral) plus capecitabine (Xeloda) in metastatic breast cancer (MBC) patients pretreated with anthracycline, was evaluated. PATIENTS AND METHODS: In this phase II multicenter study, this combination CT was given as a first- or second-line therapy for MBC. The treatment schedule was: oral vinorelbine 60 mg/m2 day 1 and day 8 plus capecitabine 1,000 mg/m2 twice daily from day 1 to day 14, every 21 days. RESULTS: One hundred and fifteen patients were included in this trial. The median age was 58 years (range: 40-75). All the patients had received prior anthracycline-based chemotherapy. The combination was well tolerated, with, in particular, only 0.8% of patients presenting with febrile neutropenia. In the intention-to-treat (ITT) population, an objective response was achieved in 65 patients (56.5%). A complete response was achieved in 22 patients (19.1%); partial response in 43 patients (37.4%); stable disease in 36 patients (31.3%), and progressive disease was observed in 14 patients (12.2%). After a median follow-up of 10.0 months, the median progression-free survival (PFS) was 10.5 months and the median survival was 17.5 months. CONCLUSION: Oral vinorelbine-capecitabine shows very promising activity and low toxicity in MBC treatment, with high compliance of the patients.

PMID: 19331218 [PubMed - indexed for MEDLINE

Combination of the mTOR inhibitor everolimus (RAD 001) with Navelbine® (vinorelbine) and Herceptin® (trastuzumab)
SABC'08‏
Everolimus Promising in Heavily Pre-treated Metastatic Breast CancerResearchers from Europe have reported that the combination of the mTOR inhibitor everolimus (RAD 001) with Navelbine® (vinorelbine) and Herceptin® (trastuzumab) among heavily pre-treated, Herceptin-resistant metastatic breast cancer patients produced disease stabilization for at least six months in half of all patients. These results were recently presented at the 2008 annual San Antonio Breast Cancer Symposium.
Everolimus is an oral targeted therapy that works by inhibiting a protein known as the mammalian target of rapamycin (mTOR). The mTOR protein plays an important role in regulating cancer cell division and blood vessel growth. Activation of the mTOR pathway drives endocrine resistance in patients with breast cancer. RAD001, a derivative of rapamycinin, is an oral inhibitor of mTOR, a protein that acts as a central regulator of tumor cell division, cell metabolism, and blood vessel growth. RAD001 is being evaluated in the treatment of several types of cancer, including cancers of the breast, kidney, lung, stomach, and liver. Everolimus is not yet approved by the U.S. Food and Drug Administration but is continuing through clinical trials.
This Phase I trial evaluated the combination of everolimus, Navelbine, and Herceptin in 37 patients with metastatic, HER2-positive breast cancer who had received a median of five prior therapies. Patients had not received prior therapy with Navelbine and all were considered Herceptin-resistant. The primary objective was to establish the dose-limiting toxicity of everolimus, with secondary objectives including efficacy, drug interactions, and safety. Evaluable patients included those treated with 5 mg/day, 20 mg/week, or 30 mg/week on a 21-day cycle of everolimus in addition to Herceptin (4 mg/kg loading dose on day 1, followed by 2 mg/kg weekly) and Navelbine (25 mg/m² on days 1, 8 of each cycle). Clinical benefit, defined as complete response/partial response/disease stabilization for at least six months, was achieved in 50% of all patients. Rates of complete responses, partial responses, and disease stabilization were 3%, 15%, and 62%, respectively. Dose-limiting toxicities were stomatitis and neutropenia, which were most common in the 5 mg/day arm.
These researchers concluded that everolimus may provide a feasible new treatment option among Herceptin-resistant metastatic breast cancer patients who have received extensive prior therapies. Although still in early trials, clinical benefit achieved with the combination of everolimus, Navelbine, and Herceptin among this patient population is encouraging. The researchers established that 30 mg/week is a feasible dose for everolimus, while 5 mg/day is still under investigation.
Comments: These data are consistent with three studies presented at the 2008 annual meeting of the American Society of Clinical Oncology suggesting significant activity of everolimus in patients with HER2 positive breast cancer.

Reference: Fasolo A, Gianni L, Rorive A, et al. Multicenter phase I clinical trial of daily and weekly RAD001 (everolimus) in combination with vinorelbine and trastuzumab in patients with HER-2-overexpressing metastatic breast cancer with prior resistance to trastuzumab. 2008 annual San Antonio Breast Cancer Symposium. Abstract 406.