Vinorelbine In Patients Research Articles

A phase II trial of temozolomide and vinorelbine for patients with recurrent brain metastases

2050 Background: Temozolomide has shown modest efficacy in the treatment of recurrent brain metastases. We designed a regimen combining temozolomide with vinorelbine, a lipophilic agent that crosses the blood-brain barrier, trying to improve efficacy. Methods: This is a phase II trial with 28-day cycles using temozolomide (150 mg/m2, days 1–7 and 15–21) and vinorelbine on days 1 and 8. We previously reported a phase I trial that established an MTD of 30 mg/m2 of vinorelbine in this combination, but the dose was decreased to 25 mg/m2 in this phase II trial. The phase II component was planned as a two-stage clinical trial. Since two or more responses were observed after the 20 initial patients, 15 more assessable patients were required. This design had a 91% probability to detect a true response rate of 20% or more. The primary endpoint was objective radiographic response. Secondary endpoints include OS, PFS and toxicity. Patients = 18 years old with KPS = 60, adequate organ function and progressive or recurrent brain metastases were eligible. Results: Thirty-six patients (13 men, 23 women) with a median age of 56 years (range, 38–76) and median KPS of 80 were enrolled. The primary tumor sites were lung (n=19), breast (n=11), colon (n=2), bladder (n=1), endometrium (n=1), head/neck (n=1) and kidney (n=1). Prior therapies included whole-brain radiation therapy (81%), chemotherapy (97%), radiosurgery (42%) and brain metastasis resection (47%). Objective radiographic response was 7% (1 CR and 1 minor response); 4 patients had SD and 23 PD. Three patients withdrew consent and did not undergo follow-up scans, 2 patients did not receive the planned treatment and 2 patients recently began treatment and have not been assessed. The median follow-up was 12.3 weeks and 72% of patients have died. Median PFS and OS were 8.3 weeks and 5 months, respectively. Grade 3/4 toxicities were mainly hematological and 3 patients were removed from the study due to myelosuppression. Conclusions: In this heavily pretreated population of patients with brain metastases, adding vinorelbine to temozolomide does not seem to improve response rates as compared to temozolomide alone. Single-agent temozolomide also has a more favorable toxicity profile. [Table: see text]

A Prospective, Open Label, Randomized Phase II Trial of Weekly Docetaxel Versus Weekly Vinorelbine as First Line Chemotherapy in Patients With Androgen Independent Prostate Cancer

In previous phase I to III studies docetaxel and vinorelbine have shown promising activity in androgen independent prostate cancer. In the present trial we assessed the efficacy and tolerability of single agent low dose docetaxel vs vinorelbine in patients with advanced androgen independent prostate cancer. A total of 40 chemotherapy naive patients with histologically proven androgen independent prostate cancer, adequate androgen ablation, and clinical and/or biochemical progression were randomly assigned to receive either 25 mg/m(2) docetaxel (arm A) or 25 mg/m(2) vinorelbine (arm B) weekly. Treatment was continued until clinical and/or biochemical progression. In cases of progression patients switched to the alternative treatment arm. The primary end point was time to disease progression. Secondary end points included prostate specific antigen response rates in sequential treatment, analgesic response and toxicity. The current analysis showed a doubled risk of progression in treatment arm B. The median time to first disease progression was 14.5 months for arm A vs 4.4 months for arm B. The proportion of patients with a greater than 50% prostate specific antigen decrease on first line therapy was significantly higher in arm A (62.5%) compared to arm B (11.1%) (p = 0.0033). After progression to docetaxel second line vinorelbine yielded a greater than 50% prostate specific antigen response rate of 28.6% vs 62.5% for second line docetaxel. Clinically significant toxicity occurred more often in arm B with neutropenia grade 4 seen in 22% and grade 3 in 28% of patients (p = 0.0005) during the first treatment phase. While weekly application of both cytotoxic agents was well tolerated, this study demonstrates the superiority of docetaxel vs vinorelbine as monotherapy in the treatment of androgen independent prostate cancer.

A Phase II Study of Single-Agent Oral Vinorelbine in Patients with Pretreated Advanced Non–Small-Cell Lung Cancer

Intravenous vinorelbine has demonstrated its efficacy and tolerability in advanced non-small-cell lung cancer (NSCLC). An oral formulation of vinorelbine has been developed, and a number of phase II studies have shown its activity in chemotherapy-naive NSCLC, even in elderly patients, but no study has been performed to test activity and toxicity of oral vinorelbine in pretreated patients. The aims of our study were to investigate the activity and toxicity of oral vinorelbine in patients with NSCLC as salvage treatment. Twenty pretreated patients with locally advanced (n = 6) and metastatic (n = 14) NSCLC entered the study. The schedule was oral vinorelbine 60 mg/m(2) once a week until progression or development of unacceptable toxicity. Median age was 70 years (range, 49-84 years). Seventeen patients were evaluable for response and all for toxicity. A median of 9 cycles were administered (range, 2-21 cycles). No objective responses were reported, 5 patients experienced stable disease, and 12 patients had progressive disease. Median time to progression was 2 months (range, 1-6 months), and median survival was 4 months (range, 1-13 months). Treatment was well tolerated, with grade 4 neutropenia in 1 patient (heavily pretreated); grade 2 diarrhea in 2 patients; asthenia in 2 patients; and abdominal pain in 1 patient. Oral vinorelbine 60 mg/m(2) once a week is a very safe schedule in heavily pretreated locally advanced and metastatic NSCLC; however, at this dose, the drug is inactive. Other phase II studies with oral vinorelbine 80 mg/m(2) weekly are warranted.

Will Single-Time Tumor Profiling and a “Guilt by Association” Approach Allow Us to Outsmart HER2-Positive Breast Cancer?

Amplification of the HER2/Neu ( ERBB2 ) gene, the second member of the epidermal growth factor receptor (ErbB) tyrosine kinase family, occurs in ∼25% of invasive breast cancers and is associated with poor patient outcome ([1][1]). Trastuzumab (Herceptin), a humanized monoclonal IgG1 that binds to

Predictors of Resistance to Preoperative Trastuzumab and Vinorelbine for HER2-Positive Early Breast Cancer

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. Forty-eight 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. Eight 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). Five (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% versus 97%; P = 0.001). 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.

Multicenter phase II study of combination chemotherapy with capecitabine and intravenous vinorelbine in patients with pretreated metastatic breast cancer

AbstractBackground: Capecitabine and i.v. vinorelbine are both active in metastatic breast cancer with non‐overlapping toxicities. This study examined the efficacy and safety of the combination of these agents in patients with pretreated metastatic breast cancer.Methods: Patients previously treated for breast cancer, maximum of one prior metastatic regimen, received capecitabine 1000 mg/m2 b.d. for days 1–14 and vinorelbine 25 mg/m2 i.v. days 1 and 8 every 21 days. All patients had measurable disease and adequate baseline organ function. The primary endpoint was response and secondary endpoints time to progression, duration of response, survival and safety.Results: Twenty‐two patients (median age 56 years) received a median of six cycles. All patients had received anthracyclines and 64% taxanes. Objective responses were seen in 7/21 (33%, 95% confidence interval [CI] 18–57%), with two complete responses; stable disease was seen in 5/21 (24%, 95% CI 8–42%). Median duration of response was 6.9 months (95% CI 4.7–13.1), time to progression was 5.8 months (95% CI 2.8–6.8) and survival was 13.5 months (95% CI 6.9–19.9). The median dose intensity of vinorelbine was 75% of the intended dose and of capecitabine 85% of intended dose. The main toxicity was myelosuppression including 16 episodes of G3–4 neutropenia in 11 patients (50%). Other toxicities were generally mild to moderate.Conclusion: The combination of capecitabine and i.v. vinorelbine is active and well tolerated in patients with pretreated metastatic breast cancer. The recent availability of oral vinorelbine provides an opportunity to explore a fully oral combination.

Spanish Breast Cancer Research Group (GEICAM)

This section provides current contact details and a summary of recent or ongoing clinical trials being coordinated by Spanish Breast Cancer Research Group (GEICAM). Clinical trials include: FAC versus CMF as adjuvant chemotherapy for operable breast cancer: a study by the GEICAM group. GEICAM/8701Phase III study of concomitant versus sequential chemohormonotherapy (EC plus tamoxifen) as adjuvant chemotherapy for node-positive postmenopausal women. GEICAM/9401High-dose DICEP chemotherapy versus observation in metastatic breast cancer patients with monotopic disease responding to induction chemotherapy with paclitaxel plus epirubicin. Phase III GEICAM trial. GEICAM/9601Vinorelbine infusion over 96 hours in heavily pre-treated patients with metastatic breast cancer: a cooperative study by the GEICAM group. GEICAM/9702Phase II trial of gemcitabine in combination with vinorelbine in patients with metastatic breast cancer resistant to anthracyclines. GEICAM/9704A phase II trial for evaluation of sequential doxorubicin and docetaxel as first-line treatment in metastatic breast cancer. GEICAM/9801A multicenter phase III randomized trial comparing docetaxel with doxorubicin and cyclophosphamide (TAC) versus 5-fluorouracil with doxorubicin and cyclophosphamide (FAC) as adjuvant treatment of operable breast cancer patients with negative axillary lymph nodes. TARGET 0 / GEICAM/9805A multicenter phase III randomized trial to compare the sequential and the concomitant administration of doxorubicin and docetaxel, as first-line chemotherapy treatment for metastatic breast disease. GEICAM/9903Docetaxel plus gemcitabine administered every other week as first-line treatment for metastatic breast cancer. GEICAM/9904Weekly docetaxel as neo-adjuvant treatment in stage II and III breast cancer. GEICAM/9905A multicenter phase III randomized trial comparing 5-fluorouracil with epirubicin and cyclophosphamide (FEC) versus 5-fluorouracil with epirubicin and cyclophosphamide (FEC) followed by weekly paclitaxel as adjuvant treatment of operable breast cancer patients with positive axillary lymph nodes. GEICAM/9906An open, multicenter randomized phase IV trial for the administration of pamidronate to breast cancer patients with bone metastatic disease. GEICAM/2000-01A randomized phase III treatment to compare the administration of vinorelbine versus vinorelbine plus gemcitabine in patients with metastatic breast cancer previously treated with anthracyclines and taxanes. GEICAM/2000-04Maintenance phase III/IV study for the administration of Caelyx versus no treatment, after induction chemotherapy for metastatic breast cancer disease. GEICAM/2001-01A multicenter, cross-over, randomized trial with exemestane versus anastrozole as first-line hormonal treatment of postmenopausal women with metastatic breast cancer disease and positive hormone receptors. GEICAM/2001-03A multicenter, open-label randomized phase III trial for the administration of zoledronate to patients with advanced breast cancer disease and non-symptomatic bone metastasis. GEICAM/2001-05A multicenter phase II trial to evaluate the administration of gemcitabine with doxorubicin and paclitaxel (GAT) as neo-adjuvant treatment of stage III disease breast cancer patients. GEICAM/2002–01A phase II trial to evaluate the administration of doxorubicin with cyclophosphamide (AC) followed by weekly docetaxel (T) as neo-adjuvant treatment of stage II disease breast cancer patients. GEICAM/2002–03A multicenter, open-label, randomized phase III trial comparing six courses of FAC (fluorouracil, doxorubicin, cyclophosphamide) with four courses of FAC followed by 8-weekly administrations of Taxol in the adjuvant treatment of node-negative patients with operable breast cancer. GEICAM/2003–02A multicenter, open-label, randomized phase III trial comparing epirubicin plus cyclophosphamide (EC) followed by docetaxel (T) with epirubicin plus docetaxel (ET) followed by capecitabine (X) in the adjuvant treatment of node-positive patients with operable breast cancer. GEICAM/2003–10Open-label, no randomized, phases I–II of the treatment with Myocet/Taxotere/Herceptin as primary antineoplasic treatment in newly diagnosed breast cancer patients with HER2neu overexpression. GEICAM/2003–03Phase IV.II clinical trial with the combination of pegylated liposomal doxorubicin, cyclophosphamide and trastuzumab in patients with metastatic breast cancer with overexpression HER2neu. GEICAM/2004–05Randomized clinical trial to compare the benefit of adding trastuzumab to the combination of capecitabine plus vinorelbine as second-line treatment for patients with locally advanced non-operable breast cancer or metastatic breast cancer with overexpression of HER2, who have progressed to a previous line of treatment for metastatic disease that included trastuzumab in combination with taxanes. GEICAM/2004–06Phase IV.II clinical trial, multicenter, for administration of capecitabine concomitant to radiotherapy in patients with locally advanced breast cancer and HER2neu negatives. GEICAM/2005–01Phase IV.III, multicenter, open, randomized treatment study to evaluate the efficacy of maintenance therapy with capecitabine after standard chemotherapy with anthracyclines in patients with metastatic breast cancer. GEICAM/2005–04

A phase I trial of docetaxel and vinorelbine in patients with advanced non-small cell lung cancer

Advanced non-small cell lung cancer (NSCLC) remains a difficult cancer to treat, and evolution of platinum-free regimens in a first-line setting is ongoing. This was a dose-finding study on the docetaxel and vinorelbine combination. Docetaxel was given at 60 mg/m(2) on day 1 only, and vinorelbine was given on days 1 and 15 starting at 20 mg/m(2), then escalated to 30 and 40 mg/m(2) in two dose cohorts. Each cycle lasted 28 days. The maximum tolerated dose was 60 mg/m(2) docetaxel and 30 mg/m(2) vinorelbine. Twenty-one patients were enrolled and showed an overall response rate of 9.5%, with stable disease documented in 33% of patients. The dosage schedule of this combination resulted in acceptable toxicities. The median time to progression was 5.86 months (95% CI 2.50-9.22), and median survival was 10.96 months (95% CI 1.42-20.51) with a 1-year survival rate of 50%. This combination may be important for patients with NSCLC.

A Phase II Trial of Vinorelbine in Patients with Advanced Gastroesophageal Adenocarcinoma

Platinum-based combination chemotherapy regimens increasingly are accepted as a first-line treatment option for patients with advanced gastroesophageal adenocarcinoma. While active, such regimens also have been associated with toxicity. Vinorelbine is both well tolerated and active in patients with advanced breast, lung cancer, and squamous cell carcinoma of the esophagus, but has not previously been evaluated as a single agent in gastroesophageal adenocarcinoma. We, therefore, performed a Phase II study to assess the activity of vinorelbine in this disease. Twenty-nine patients with previously treated or untreated metastatic gastroesophageal adenocarcinoma were treated with weekly vinorelbine, administered at a dose of 25 mg/m2, and were followed for evidence of radiologic response, toxicity, and survival. Patients received a median of 8 weeks of therapy. While mild myelosuppression was common, only 17 percent of the treated patients developed Grade 3 or Grade 4 neutropenia. Other toxicities included Grade 1–2 constipation in 31 percent, and Grade 1–2 neuropathy in 13 percent of patients. The overall radiologic response rate was 7 percent, the median progression-free survival time was 1.9 months and the median overall survival time was 7.8 months. We conclude that vinorelbine has minimal toxicity but only minor antitumor activity in patients with advanced gastroesophageal adenocarcinoma.

The combination of cisplatin and vinorelbine with concurrent thoracic radiation therapy for locally advanced stage IIIA or IIIB non-small-cell lung cancer

The aims of this study were to assess the efficacy and toxicity of concurrent chemoradiotherapy with divided schedule of cisplatin and vinorelbine in patients with locally advanced non-small-cell lung cancer (NSCLC). Patients with previously untreated, unresectable, and stage IIIA or IIIB NSCLC were eligible if they had a performance status of 0 or 1, were 75 years or younger, and had adequate organ function. Twenty-six patients (24 men and 2 women; median age, 66 years; age range, 42-75 years) were enrolled. Both cisplatin (40 mg/m(2)) and vinorelbine (20 mg/m(2)) were given on days 1 and 8 every 3 weeks. Beginning on day 2 of chemotherapy, thoracic radiotherapy was given for approximately 6 weeks (2 Gy per fraction; total dose, 60 Gy). Five of the 26 patients achieved a complete response, and 16 achieved a partial response for an overall response rate of 80.8% (95% confidence interval, 60.6-93.4%). The median survival time was 23 months (range, 4-43 months). Overall survival rates at 1 and 2 years were 80 and 56%, respectively. Hematologic toxicities included grade 3-4 neutropenia in 84.6% of patients, grade 3-4 thrombocytopenia in 3.8%, and grade 3-4 anemia in 61.5%. Two patients (7.7%) had grade 3 radiation esophagitis that resolved completely without dilation. Grade 3-4 radiation pneumonitis occurred in two patients (7.7%) and was treated with corticosteroids. Both patients had a good partial resolution of symptoms and radiographic abnormalities. There were no treatment-related deaths. The actual delivered dose intensities for both cisplatin and vinorelbine were 79.5%. Radiotherapy was completed in 96% of patients. Concurrent chemoradiotherapy with cisplatin and vinorelbine administered on a divided schedule is effective and well tolerated in patients with locally advanced NSCLC.

The Utility of Gemcitabine and Vinorelbine in Patients with Blastic NK Lymphoma (CD4+/CD56+ Hematodermic Neoplasm).

Background: Blastic NK lymphoma, provisionally renamed CD4+/CD56+ hematodermic neoplasm in the latest WHO-EORTC classification of cutaneous lymphomas, is a rare, recently described malignancy. The derivation of these neoplasms is not completely understood, but it is felt to arise from either an NK or plasmacytoid dendritic cell precursor. Nonetheless, treatments for this aggressive malignancy have generally been in the form of intensive combination chemotherapy adapted from high-grade lymphoma or acute leukemia regimens. Despite initial responses to treatment, patients frequently relapse, with overall survival measured in months. Moreover, the high toxicity of these approaches limits their use in certain patients. Gemcitabine and vinorelbine are two chemotherapy agents with relatively mild side effect profiles and activity against cutaneous and T cell lymphomas. Here we describe two patients with blastic NK lymphoma who, because of advanced age and multiple comorbidities, received treatment with a combination of gemcitabine and vinorelbine (GN). For both patients, complete responses (CRs) were obtained. Patients and Methods: The first patient was a 73 year-old man with hypertension, recent hemorrhagic stroke with residual hemiparesis, and stable angina who presented with multiple cutaneous nodules along his face, trunk, and extremities. CT and PET scans were negative. Laboratories revealed pancytopenia, and bone marrow biopsy was negative although flow cytometry on the bone marrow aspirate showed increased CD56+ cells. The second patient was a 71 year-old male with poorly controlled diabetes and hypercholesterolemia; he also presented with extensive cutaneous nodules. CT and PET scans showed diffuse hypermetabolic lymphadenopathy; bone marrow was replaced by lymphoma. Skin biopsies from both patients showed large lymphoid cells expressing CD4, CD56, and HLA-DR; neither tumor expressed CD3, CD45RO, or TdT. Cytogenetics were normal for both patients. Results: Both patients received treatment with gemcitabine 800 mg/m2 and vinorelbine 15 mg/m2 given every two weeks with growth factor support. Both patients experienced significant improvement in their cutaneous lesions after the first cycle of treatment and subsequently obtained a CR by the fifth course. Once in CR, both patients had their chemotherapy schedules reduced to every four weeks to minimize side effects. The first patient had GN discontinued after 13 cycles and remained in CR for 10 months off therapy. He subsequently recurred in the skin, lymph nodes, and bone marrow. He was retreated with GN for an additional 14 cycles to date; he remains in CR nine months later on monthly therapy. The second patient developed recurrent disease in the skin at five months and was switched to alternate therapy. Conclusion: Blastic NK lymphoma (CD4+/CD56+ hematodermic neoplasm) is an aggressive lymphoma characterized by a poor prognosis and brief responses to intensive combination chemotherapy. Here we report two elderly patients with multiple comorbidities who responded to a mild chemotherapy regimen of GN given every two to four weeks. This regimen was well-tolerated and both patients attained a CR. The high activity in both patients and durability of response in one suggests GN should be considered for elderly patients with blastic NK lymphoma. Moreover, this report raises the possibility of incorporating these agents into other regimens for this rare disease.

Combination chemotherapy with gemcitabine and vinorelbine in the treatment of relapsed or refractory diffuse large B‐cell lymphoma: a phase‐II trial by the Hellenic Cooperative Oncology Group

To investigate the efficacy and toxicity of the combination of gemcitabine and vinorelbine in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBL), 22 patients with relapsed or refractory DLBL were treated with gemcitabine 1000 mg/m2 and vinorelbine 30 mg/m2 on days 1 and 8 every 3 wk for a maximum of six cycles. Fourteen patients were considered chemosensitive while eight patients were considered chemoresistant to the last treatment regimen. All 22 patients were assessed for response to treatment. Three patients (14%) achieved complete remission and eight patients (36%) had partial remission of their disease, with an overall response rate of 50%. With a median follow up of 44 months, the median time to progression (TTP) for all patients was 8.1 months while the median overall survival (OS) was 12.9 months. Toxicity was minimal and all patients were treated on an outpatient basis. The combination of gemcitabine and vinorelbine is an effective and well-tolerated regimen for patients with relapsed of refractory DLBL.

P-481 Cisplatin+gemcytabine versus cisplatin+vinorelbine in patients with stage IV nonsmall cell lung cancer (NSCLC): Results of single center experience

P-481 Cisplatin+gemcytabine versus cisplatin+vinorelbine in patients with stage IV nonsmall cell lung cancer (NSCLC): Results of single center experience

P-963 A phase II study evaluating the clinical efficacy of TG4010(MVA-MUC1-IL2) in association with cisplatin and vinorelbine in patients with non small cell lung cancer

P-963 A phase II study evaluating the clinical efficacy of TG4010(MVA-MUC1-IL2) in association with cisplatin and vinorelbine in patients with non small cell lung cancer

Phase II trial of oral vinorelbine for treatment of metastatic breast cancer in women 65 years and older: N003A

740 Background: Intravenous vinorelbine is a semi synthetic vinca alkaloid with known antitumor activity in breast cancer. The aim of this NCCTG phase II trial was to assess the efficacy and safety of oral vinorelbine in patients 65 years and older with metastatic breast cancer, as first or second line chemotherapy. Methods: Women 65 years and older with stage IV breast cancer, who had received at most one prior chemotherapy regimen for metastatic disease were enrolled in this one stage phase II study from January 2002 to February 2003. Prior adjuvant therapy was permitted. Oral vinorelbine gel capsules were administered at 60 mg/ m2 for 4 doses on days 1, 8, 15 and 22 of a 28 day cycle. Dose was increased to 70 mg/ m2 if at most one episode of grade 3 and no grade 4 myelosuppression occurred. Results: Twenty five eligible patients were enrolled. Characteristics: median age 73 (65–84); PS: 0 (40%), 1 (48%), 2 (12%); ER positive: 68%; prior adjuvant therapy: hormonal (36%), chemotherapy (36%), both (16%). Prior first line therapy: chemotherapy (32%); hormonal therapy (44%). Eleven (44%) had 3 or more metastatic sites, 18 (72%) had dominant visceral metastases. Twenty five patients were evaluable for response, all are off study treatment. Median cycles administered: 4 (1–20). For cycle 2, 11 patients were able to initiate the higher dose, 5 required 25% dose reduction. The overall response rate was 4% (90% CI: 0.1–20.4%); one patient achieved a partial response for 17.4 months. One patient (4%) maintained stable disease for more than 6 months while on treatment and progressed at 11.5 months. Median time to progression was 4.8 months (95% CI: 2.0–5.5 months) and the Kaplan-Meier estimated one-year survival was 48% (95% CI: 30–74.5%). Toxicity data were available for 24 patients. Grade 3 toxicities included neutropenia (13%), fatigue (13%), dizziness (8%) and leucopenia (8%). Others included grade 2 neuro-motor toxicity (13%) and neuro-sensory toxicity (8%). Conclusion: Oral vinorelbine was well tolerated but provided minimal anti-tumor activity at this dose in this population with metastatic breast cancer. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Sanofi Aventis, Bristol-Myers Squibb, Eli Lilly, Genentech, Pfizer

Late Phase II Clinical Study of Vinorelbine Monotherapy in Advanced or Recurrent Breast Cancer Previously Treated with Anthracyclines and Taxanes

At present, it is one of the most important issues for the treatment of breast cancer to develop the standard therapy for patients previously treated with anthracyclines and taxanes. With the objective of determining the usefulness of vinorelbine monotherapy in patients with advanced or recurrent breast cancer after standard therapy, we evaluated the efficacy and safety of vinorelbine in patients previously treated with anthracyclines and taxanes. Vinorelbine was administered at a dose level of 25 mg/m(2) intravenously on days 1 and 8 of a 3 week cycle. Patients were given three or more cycles in the absence of tumor progression. A maximum of nine cycles were administered. The response rate in 50 evaluable patients was 20.0% (10 out of 50; 95% confidence interval, 10.0-33.7%). Responders plus those who had minor response (MR) or no change (NC) accounted for 58.0% [10 partial responses (PRs) + one MR + 18 NCs out of 50]. The Kaplan-Meier estimate (50% point) of time to progression (TTP) was 115.0 days. The response rate in the visceral organs was 17.3% (nine PRs out of 52). The major toxicity was myelosuppression, which was reversible and did not require discontinuation of treatment. The results of this study show that vinorelbine monotherapy is useful in patients with advanced or recurrent breast cancer previously exposed to both anthracyclines and taxanes.

A phase I/II study of pemetrexed and vinorelbine in patients with non-small cell lung cancer

Pemetrexed and vinorelbine are active antineoplastic agents in non-small cell lung cancer (NSCLC). Phase I objectives include maximum tolerated dose (MTD) and recommended phase II dose determination, and pharmacokinetics of the pemetrexed-vinorelbine doublet in locally advanced or metastatic solid tumor patients (pts). Phase II objectives include tumor response evaluation, efficacy, and toxicity for first-line treatment of advanced NSCLC. Phase I pts received pemetrexed (day 1, 300-700 mg/m2) and vinorelbine (days 1 and 8, 15-30 mg/m2) every 21 days. Pharmacokinetics determined at cycle 1. Beginning with dose-level 3, folic acid and Vitamin B12 supplementation were given. Thirty-one phase I pts were enrolled. MTD was pemetrexed 700 mg/m2 and vinorelbine 30 mg/m2; and recommended phase II dose was pemetrexed 500 mg/m2 and vinorelbine 30 mg/m2. When administered in combination, pemetrexed and vinorelbine pharmacokinetics were consistent with single-agent administration. Thirty-seven (36 chemonaive) phase II NSCLC pts received pemetrexed-vinorelbine. Evaluable tumor response was 40%, with intent-to-treat 38%. One drug-related death occurred from febrile neutropenia with Staphylococcal infection. Grade 3/4 hematologic toxicities were neutropenia (65%) and febrile neutropenia (11%), while prevalent grade 3/4 non-hematologic toxicity was fatigue (27%). The pemetrexed-vinorelbine combination is well tolerated and shows activity as first-line treatment in advanced NSCLC patients.

A phase II trial of docetaxel and vinorelbine in patients with hormone-refractory prostate cancer

Recent studies of docetaxel have demonstrated improved survival over mitoxantrone and prednisone in patients with hormone-refractory prostate cancer (HRPC), supporting the study of novel docetaxel-containing regimens as primary therapy or following initial docetaxel-based therapy. To evaluate the combination of docetaxel and vinorelbine in the treatment of patients with HRPC, 40 patients with proven adenocarcinoma of the prostate with progressive metastatic disease despite androgen ablation were enrolled onto this phase II trial. Patients were treated with docetaxel 60 mg/m2 on day 1 and vinorelbine 15 mg/m2 on days 1 and 8 of a 21-day cycle. All patients received dexamethasone 8 mg twice daily for 4 days starting 1 day prior to the docetaxel infusion. After the first three patients were enrolled, filgrastim was added on days 2-6 and 9-13. Of the 40 patients enrolled, 19 had no prior chemotherapy and 21 had received at least one prior chemotherapy regimen. Of the 19 patients without prior chemotherapy and the 21 with prior chemotherapy, 7 (37%) and 6 (29%) , respectively, demonstrated a decrease in prostate specific antigen by > 50% maintained for at least 4 weeks. Out of eight patients with measurable disease, one achieved a partial response and four demonstrated stable disease. There was one patient with deep vein thrombosis, and febrile neutropenia was noted in only three patients after the protocol was modified to include filgrastim support. The combination of docetaxel and vinorelbine with filgrastim was well tolerated and active against HRPC in patients with or without prior chemotherapy.

Phase I study of the multidrug resistance inhibitor zosuquidar administered in combination with vinorelbine in patients with advanced solid tumours

Zosuquidar (LY335979) is an oral P-glycoprotein modulator. This phase I study was designed to determine the maximum tolerated dose (MTD) of zosuquidar in combination with vinorelbine. The effects of zosuquidar on vinorelbine pharmacokinetics were also examined. Patients with advanced solid tumours were treated with escalating doses of zosuquidar administered every 8-12 h on days 7-9 and 14-16 during cycle 1 then days 0-2, 7-9, and 14-16 from cycle 2 onwards, with vinorelbine 22.5-30 mg/m2 IV on days 1, 8 and 15 every 28 days. Of 21 patients registered, 19 were treated at four dose levels (zosuquidar 100-300 mg/m2). Two patients had prolonged and febrile neutropenia at the second dose level resulting in a reduction of the dose of vinorelbine in subsequent dose levels. There was another patient with dose-limiting febrile neutropenia at dose level four which resulted in the expansion of the dose level three. Eight patients had stable disease and no objective responses were seen. Vinorelbine pharmacokinetic studies showed reduced clearance when given with zosuquidar. The MTD was zosuquidar 300 mg/m2 orally every 12 h for 3 days weekly for 3 weeks with vinorelbine 22.5 mg/m2 IV weekly for 3 weeks every 28 days. Zosuquidar may inhibit vinorelbine clearance to a modest degree.

Tirapazamine with Cisplatin and Vinorelbine in Patients with Advanced Non–Small-Cell Lung Cancer: A Phase I/II Study

This phase I/II study was conducted to evaluate the safety and efficacy of tirapazamine in combination with cisplatin and vinorelbine for patients with advanced-stage IIIB/IV chemonaive non–small-cell lung cancer. Seventy patients with a Karnofsky performance status of ≥ 60% were included. In the phase I part of the study, 21 patients were treated on day 1 with tirapazamine (escalating doses of 260, 330, or 390 mg/m2), cisplatin (75 or 100 mg/m2), and vinorelbine (25 or 30 mg/m2) for a maximum of 6 cycles every 4 weeks. Vinorelbine was repeated every week. In the phase II part of the study, 49 patients were treated on day 1 with tirapazamine 390 mg/m2, cisplatin 100 mg/m2, and vinorelbine 30 mg/m2. The maximum tolerated dose was not reached. Muscle cramps, vomiting, nausea, tinnitus, neutropenia, and diarrhea were the most frequently reported adverse events in the phase I part of the study. Most of these events were grade 1 or 2. In the phase II part of the study, response rate was 47%, and median survival was 50 weeks. The most frequently reported adverse event was neutropenia. Asthenia, fever, anemia, vomiting, weight decrease, nausea, and muscle cramps were also noted. For patients treated at the maximum dose, dose reductions occurred 14% of tirapazamine cycles and in 4% of cisplatin cycles. The median number of cycles was 3. This regimen has a manageable toxicity profile. Response rate and median survival suggest that this combination might be more active than the cisplatin/vinorelbine combination. This triplet is currently being evaluated in a phase III study.