Vinorelbine in androgen-independent metastatic prostatic carcinoma—a phase II study

Morant, Rudolf; Schmitz, Shu Fang Hsu; Bernhard, J.; Thürlimann, Beat; Borner, Markus; Wernli, Martin; Egli, F; Forrer, P; Streit, A; Jacky, E; Hanselmann, Silvia; Bauer, Jean; Hering, F.; Schmid, Hans‐Peter

doi:10.1016/s0959-8049(02)00145-4

Cited by 26 publications

(15 citation statements)

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“…Similarly, the QL measures did not suggest an overall improvement during capecitabine treatment. This is an indication of limited palliation as described in our previous trial of vinorelbine (Morant et al, 2002b), which showed a comparable rate of clinical benefit (23%).…”

Section: Discussionsupporting

confidence: 56%

“…Starting in 1991, the Swiss Group for Clinical Cancer Research (SAKK) conducted four consecutive phase II trials within the framework of a master protocol to evaluate carboplatin (Jungi et al, 1998), idarubicin (Schmid et al, 1997), gemcitabine (Morant et al, 2000) and vinorelbine (Morant et al, 2002b), in patients with HRPC. The goal of these studies was to find promising new drugs for further testing in phase III trials.…”

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confidence: 99%

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Capecitabine in hormone-resistant metastatic prostatic carcinoma – a phase II trial

Morant¹,

Bernhard

Dietrich

et al. 2004

Br J Cancer

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The objective of the trial is to evaluate the efficacy of capecitabine in patients with metastatic hormone-resistant prostate carcinoma (HRPC), in terms of prostate-specific antigen (PSA) response and clinical benefit (decrease of pain or analgesic score) and its safety profile. In all, 25 patients with HRPC were enrolled on a phase II trial of capecitabine (Xeloda s ) at a dose of 1250 mg m À2 orally twice daily on days 1 -14 every 21 days. The inclusion criteria were PSA serum levels 43 Â upper limit of normal, a WHO performance status 0 -2, age o85 years and adequate bone marrow, liver and renal function. In patients with grade 2 or higher haematological toxicity on day 1 of the treatment cycle, therapy was first delayed, and then continued at a lower dose. Trial end points were PSA response and clinical benefit defined by quality of life (QL) data and analgesic consumption. The median age of patients was 70 years (range 54 -85 years). A median of three cycles of capecitabine was administered (range 1 -8). PSA response was observed in three patients (12%, 95% CI 3 -31%), with times to tumour progression of 18, 21 and 35 weeks, respectively. In these patients, the response durations were 12, 17 and 32 weeks, respectively. Minor PSA regression was also seen in two further patients. The median time to tumour progression of all patients was 12 weeks (95% CI 9 -15 weeks). Haematological toxicity was minor, with leukopenia grade 3 observed in one patient. There were three deaths during trial treatment, respectively, due to sepsis following mucositis and leukopenia, presumed sepsis with mucositis induced by chemotherapy and concomitant radiotherapy and cerebral dysfunction progressing to coma. Hand -foot syndrome grades 2 and 3 were observed in four patients each. Clinical benefit was observed in five patients (20%, CI 7 -41%). Based on toxicity data, we recommend a lower starting dose of 1000 mg m À2 orally twice daily. While capecitabine has some activity in HRPC, as suggested by observed PSA responses, we conclude that it is not worthwhile to investigate capecitabine monotherapy in a phase III trial. Combinations of capecitabine with other agents, such as vinorelbine or docetaxel, may prove to be more effective.

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Section: Discussionsupporting

confidence: 56%

mentioning

confidence: 99%

Capecitabine in hormone-resistant metastatic prostatic carcinoma – a phase II trial

Morant¹,

Bernhard

Dietrich

et al. 2004

Br J Cancer

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“…Compared with different vinca alkaloids, VNR shows markedly improved clinical efficacy and reduced toxicity (13). This drug is now widely used and licensed for the treatment of non-small cell lung cancer, breast cancer and ovarian cancer (14) and shows promise in relapsed or refractory Hodgkin's disease (15) and prostatic carcinoma (16). Like other antimicrotubule agents, VNR is known to be a promoter of apoptosis in cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Effect of Vinorelbine on cell growth and apoptosis induction in human osteosarcoma in vitro

et al. 2006

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Abstract. Vinorelbine (VNR) is a semi-synthetic vinca alkaloid known to exert its antitumour activity by interfering with the polymerisation of tubulin. It has shown a broad spectrum of activity in some advanced carcinomas of lung, breast and ovary. This report demonstrates for the first time the antiproliferative effect of VNR and its molecular mechanism in human osteosarcoma in vitro. TP53 wild-type HOS cells and TP53 mutated MG-63 cells were chosen for this study. In each cell line, VNR caused a significant dose-and time-dependent growth inhibition and induced apoptotic death independent of TP53 status. Phosphorylation and/or alteration of Bcl-2 were not induced by VNR, thereby indicating a new pathway utilised by the drug to induce apoptosis in this tumour in vitro. VNR produced a down-regulation of cyclin D1 and an upregulation of p53 expression in TP53 wild-type HOS cells, whereas no alteration in cyclin D1 expression was evident in the TP53 negative MG-63 cells. These data suggest a new potential use for Vinorelbine as a therapeutic agent against human osteosarcoma. IntroductionOsteosarcoma (OS) is the most frequent malignant bone tumour with a peak incidence in the second and third decade of life (1). As a result of the introduction of neoadjuvant chemotherapy, an improvement in the long-term survival rate from 10% to nearly 70% has been achieved (2). At present, osteosarcoma patients receive full neoadjuvant multi-agent chemotherapy immediately after diagnosis. Initial tumour size and detectable metastases at diagnosis are prognostic factors and serve together with the response to chemotherapy as a basis for the risk adapted postoperative therapy factor (3,4). Despite the improved survival rate, drug resistance is still one of the major problems in the treatment of this cancer (5). Alterations in the TP53 gene are frequent in human osteosarcoma cells and have been associated with resistance to chemotherapy as well as with poor prognosis in this malignancy (6,7). Pompetti et al (8) correlated TP53 mutations with a lack of therapy-induced apoptosis, while studies by Goto et al (9) demonstrated an association between loss of heterozygosity at TP53 locus and chemoresistance in human osteosarcoma.Different studies indicate that cells lacking a p53 function may present a higher sensitivity to anticancer drugs that induce DNA damage and to the cytotoxic effects of antimicrotubule agents (10-12). Vinorelbine (VNR) is a semisynthetic vinca alkaloid which binds to · and ß tubulin, thus inhibiting microtubule assembly and impairing metaphasic tumour cell division. Compared with different vinca alkaloids, VNR shows markedly improved clinical efficacy and reduced toxicity (13). This drug is now widely used and licensed for the treatment of non-small cell lung cancer, breast cancer and ovarian cancer (14) and shows promise in relapsed or refractory Hodgkin's disease (15) and prostatic carcinoma (16). Like other antimicrotubule agents, VNR is known to be a promoter of apoptosis in cancer cells. The precise mechanism b...

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“…For these eight successful phase 3 trials, there were nine preceding phase 2 trials [44][45][46][47][48][49][50][51][52]. For the 23 failed phase 3 trials there were 20 preceding phase 2 trials [53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72] (Table 1b). Trials were published from January 1994 to April 2017.…”

Section: Trial Characteristicsmentioning

confidence: 99%

Can RECIST response predict success in phase 3 trials in men with metastatic castration-resistant prostate cancer?

Brown

Sonpavde

Armstrong

2018

Prostate Cancer Prostatic Dis

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Background Intermediate endpoints are needed in early phase studies of men with metastatic castration-resistant prostate cancer (mCRPC) that can reliably predict success in phase 3 trials. Among men with measurable disease, objective response may provide information as to whether a treatment is likely to be successful. Methods We conducted a systematic review of systemic agents that have proceeded to phase 3 trials in men with mCRPC and examined the relationship between improvements in measurable disease response in phase 2 trials and successful phase 3 trials leading to regulatory approval. Only trials that included men with radiographically measurable disease were included. Results We examined 31 eligible mCRPC phase 3 trials between 1992 and 2017 and 29 of the preceding phase 2 trials for RECIST responses. Measurable tumor responses in phase 2 trials were higher for successful therapies in phase 3 trials in chemotherapy-naive men with mCRPC, but were less correlated with success in trials investigating docetaxel combination regimens or the post chemotherapy mCRPC setting. Many failed agents did not produce higher than expected response rates over control arms; however, several agents such as anti-angiogenic therapies or orteronel produced higher than expected responses without survival benefit. Conclusions Objective responses in men with mCRPC may be associated with prolonged survival, but this association is mechanism dependent and inconsistent across trials or disease states. These data support considering RECIST response as a supportive but not sole endpoint in phase 2 trials to support launching phase 3 trials.

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Vinorelbine in androgen-independent metastatic prostatic carcinoma—a phase II study

Cited by 26 publications

References 20 publications

Capecitabine in hormone-resistant metastatic prostatic carcinoma – a phase II trial

Capecitabine in hormone-resistant metastatic prostatic carcinoma – a phase II trial

Effect of Vinorelbine on cell growth and apoptosis induction in human osteosarcoma in vitro

Can RECIST response predict success in phase 3 trials in men with metastatic castration-resistant prostate cancer?

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