vinorelbine(navelbine)

Vinorelbine (Navelbine) and Vinorelbine Combinations

A Possible ≥ 2nd line chemotherapy

Author: Howard Hansen

Date: 12 February 2008

Introduction

Vinorelbine (Navelbine) is a cytotoxic anti-cancer agent classified as a vinca alkaloid. Vinca alkaloid's are derived from the Jamaican Periwinkile. Vinorelbine is a semi-synthetic vinca alkaloid which inhibits tumor cell growth by disrupting the function of microtubules in a manner different than docetaxel (taxotere.) More generally, vinorelbine is one of several mitotic inhibitors -- paclitaxel, docetaxel, etoposide, vinblastine, vincristine and vinorelbine are all mitotic inhibitors. Mitotic inhibitors are phase cycle specific -- they work in the "M" phase during which the cell wants to actually split into two new cells. By inhibiting mitosis (locking up the microtubules), cell division is inhibited.

Vinorelbine has been studied as a single agent as a doublet (combined with taxotere, emcyt, taxol) and as a triplet (combined with prednisone and doxorubicin and emcyt and mitoxantrone.) The lowest response rates are associated with single-agent vinorelbine. The synergism between docetaxel (taxotere) and vinorelbine suggests a possible use as a 2nd line chemotherapy if added when taxotere single agent fails. The synergism between vinorelbine and emcyt also appears to enhance the response rate (and may also provide an improved response rate as a 2nd line chemotherapy.)

For other evidence of activity as a 2nd line chemotherapy, the combination of taxol and vinorelbine and vinorelbine, emcyt and mitoxantrone should be considered. The latter triplet seems to provide an effective treatment for measurable disease.

The available data is summarized in Tables 1-4. Studies that provided 2nd line chemotherapy data are highlighted in color.

Vinorelbine - Single Agent - Chemo-Naive patients

Abratt RP et al(1) ran a phase III trial comparing vinorelbine and hydrocortisone vs hydrocortisone alone. Doses used were IV vinorelbine 30mg/m2 on days 1 and 8 of a 3 week cycle along with hydrocortisone 40mg/day or just hydrocortisone plus a placebo. There were 414 patients in the trial. Table 1 summarizes the results.

A phase II trial of single agent vinorelbine has also been run using the same dose and schedule as the phase III trial above. E. Silva and F. Silva(2) presented the results at the ASCO 2006 annual meeting and these results are also included in Table 1.

Table 1. Single Agent Vinorelbine
Study	Vinorelbine dose and schedule	PSA Response	Measurable Disease Response	Progression Free Survival(median)	Overall Survival at median 24 months followup
Abratt et al (1) No prior chemo.	Vinorelbine 30mg/m2 days 1, 8 every 3 weeks plus Hydrocortisone 40mg/day.	30.1%	5.9% (4 of 68)	3.7 months 6 mos rate 33.2%	14.7 months
Abratt et al (1) No prior chemo.	Hydrocortisone 40mg/day plus placebo.	19.2%	0%	2.8 months 6 mos rate 22.8%	15.2 months
E & F Silva (2) 38 of 44 had prior chemo.	Vinorelbine 30mg/m2 days 1, 8 every 3 weeks plus Hydrocortisone 40mg/day.	None; 39% PSA stable.	16%	Time to progression 7 mos.	-
M. Krainer et al (3) J. Urology 2007 No prior chemo. Crossover allowed.	25 mg/m(2) docetaxel (arm A) weekly.	62.5%, 1st line. 62.5% 2nd line (those who progressed on vinorelbine.)		14.5 Mos.	78.8% (during study)
	25 mg/m(2) vinorelbine (arm B) weekly.	11.1%, 1st line. 28.6% 2nd line (those who progressed on docetaxel.)		4.4 Mos.	75%(during study)

Single agent vinorelbine might be useful as part of a sequential chemotherapy after taxanes or instead of mitoxantrone or after mitoxantrone. However, the above phase III trial did not have patients with prior chemotherapy included. The phase II trial did indicate that stable PSA levels were achieved in 39% of the patients. The comparison to taxotere clearly illustrated the superiority of taxotere over vinorelbine, but does give some indication of vinorelbine as a 2nd line chemo after failure of taxotere 1st line -- with a 28.6% PSA RR.

Vinorelbine Combinations

If single agent vinorelbine is of marginal benefit (per overall survival) are there combinations that might enhance the effect of vinorelbine?

Vinorelbine plus Docetaxel

There are at least 4 studies of the combination of docetaxel and vinorelbine, but unfortunately they all allowed only chemo-naive patients. Weekly administration of this combination seems to provide a fairly high response rate. Synergism between docetaxel and vinorelbine has been observed in both pre-clinical models as well as several human trials (e.g., reference 5.)

Di Lorenzo et al (7) (2007) indicates that 82.5% of the patients on vinorelbine then had a 2nd line chemotherapy of mitoxantrone, gemcitabine or cyclophosphamide. Furthermore, 18 patients (45%) went on to a 3rd line of chemotherapy with thalidomide and cyclophosphamide.

See Table 9 at chemoupdt2004 which has taxotere plus vinorelbine combinations summarized.

Table 2. Docetaxel plus Vinorelbine
Study	Docetaxel	Vinorelbine	PSA RR (≥ 50% decrease)	Measureable Disease RR	Progression Free Survival	Overall Survival
Koletsky AJ et al Cancer J 2003 (4). Phase II. Chemo-naive. *	25mg/m2, days 1 and 8 of 21 day cycle.	20mg/m2, days 1 and 8 of 21 day cycle.	60%	60%
Di Lorenzo et al, Eur Urol 2004 (5) VIN-DOX. Chemo-naive. 19 patients. **	25mg/m2 6 weeks out of 8.	20mg/m2 6 weeks out of 8.	47% (9 of 19 patients)
Hahn NM et al. randomized phase II. Clin Cancer Res 2006 (6). 64 chemo-naive patients. ***	20mg/m2 days 1, 8 21 day cycle.	25mg/m2 days 1, 8 21 day cycle.	20%	4 of 12 (33.3%) partial or complete response.	Median 6.2 mos.	Median 16.2 mos.
	60-70mg/m2 day 1 q 3 weeks.	Emcyt: 280mg 3x/day, days 1-5	42.9%	6 of 9(66.7%) partial or complete response.	Median 5.7 mos.	Median of 19.2 mos.
Lorenzo GD et al Eur Urol 2007 (7). Phase II. 40 patients. Chemo-naive, except prior emcyt allowed. ****	25mg/m2 3 out of 4 weeks.	10mg/m2 3 out of 4 weeks.	50%; 34% had either < 50% PSA decline or stable disease.	18% complete; 32% partial.	Median of 7 months.	Median of 17 months.
Goodin S et al (8), 2005, phase II.	60mg/m2 day 1 of 21 day cycle.	15mg/m2 days 1 and 8 of 21 day cycle.	37% for chemo-naive 29% for prior chemo.

* Koletsky et al (4) found that 74% of the patients experienced grade 3 or 4 neutropenia.

** Di Lorenzo et al (5) had 48% grade 3-4 neutropenia with 16% febrile neutropenia and applied a 25% dose reduction in 38% of the patients.

*** In the docetaxel-vinorelbine arm, grade 3-4 toxicity occurred in 15.6% while in the docetaxel-emcyt arm, grade 3-4 toxicity occurred in 28.6%.

**** Zometa was also included, 4mg every 4 weeks.

Vinorelbine plus Emcyt

The combination of vinorelbine and estramustine phosphate (emcyt) are modestly active.

Table 3. Vinorelbine plus Estramustine Phosphate (Emcyt)
Study	Vinorelbine	Emcyt	PSA RR (≥ 50% decrease)	Measureable Disease RR	Progression Free Survival	Overall Survival
Smith, MR, et al (9) Cancer 2000. 25 patients.	25mg/m2 days 1, 8 on 21 day cycle.	140mg 3x/day days 1-14.	24%	0 of 5 patients	-	Median was 14 months.
Sweeney, C, et al (10). Phase II. Ann Oncol 2002. 23 patients, all Chemo-naive. *	20mg/m2 per week for 8 weeks, then every other week. 15mg/m2 if prior radiation to bone or pelvis.	280 mg 3x/day. Day before, day of and day after vinorelbine.	71%	1 of 8 had a partial response (12.5%); 6 of 7 had stable disease.	In the 8 patients with measurable disease, the median time to progression of the measurable disease was 5.75 months (2-52 wks).	Median was 15.1 months.
Nakabayashi M, et al (11), 2nd line, Cancer J. 2007. ** 39 patients, retrospective. Multiple prior chemo.	vinorelbine(25mg/m2), 21 patients	-	10%	-	Median duration of therapy was 1.2 mos.	Median 4.1 mos.
	vinorelbine(25mg/m2), 18 patients	emcyt(140mg 3x/day, days 1-14) 18 patients.	28%	-	Median duration of therapy was 2.3 mos.	Median 8.5 mos.

* Almost half the patients required diuretic therapy and 17% had thromboembolic complications (associated with emcyt.)

** The most common reversible adverse effect of VRL was grade 1 or 2 fatigue observed in 36% of patients and nausea in 28%. Neutropenia was more common in patients receiving both vinorelbine and emcyt(56%) compared to vinorelbine alone (24%.)

In the paper by Nakabayashi M et al, vinorelbine was used anywhere from a 2nd-line to a 4th line chemotherapy(85% received vinorelbine as 3rd or 4th line chemotherapy.) Treatment was either a 21 day cycle of vinorelbine on days 1 and 8 (62%) and 10% received vinorelbine on a 28 day cycle, days 1, 8, 15. Biweekly and weekly were also used. Ninety-percent received 25mg/m2.

Vinorelbine plus doxorubicin and prednisone (12)

LS Borden et al (12) studied the combination of weekly vinorelbine and doxorubicin (both 20 mg/m2 on days 1, 8, and 15 every 28 days) plus prednisone 5 mg twice daily. There were 46 patients, all chemo-naive. 42 percent had a PSA response within 3 cycles along with a significant improvement in quality of life over baseline. The use of pain medication decreased. Treatment was well tolerated overall; fatigue and gastrointestinal complaints were all grade 1 or 2, and only 17 (37 percent) had grade 3 or 4 neutropenia. Cardiac ejection fraction decreased to <50 percent in five men (11 percent), prompting discontinuation of doxorubicin.

Vinorelbine plus Taxol (13)

The combination of paclitaxel (Taxol) and vinorelbine, as administered in this phase II clinical trial looks promising as a 2nd line chemotherapy. Preclinical models showed synergy between paclitaxel and vinorelbine -- both are mitotic inhibitors. Previously, S. Sewak et al had run a phase I trial that showed this combination to be tolerable.

One previous line of chemotherapy (17% of patients had received one line of chemo,) strontium therapy, radiotherapy and bisphosphonate therapy were all allowed.

Table 4. Vinorelbine and Taxol (13)
Study	Vinorelbine	Taxol	PSA RR as 2nd line chemo.	Measurable Disease RR as 2nd line chemo.	Progression Free Survival	Overall Survival
S. Sewak et al, 2007 ASCO abstract # 15505 (13). Phase II, 30 patients. , *	20mg/m2 2 out of 3 weeks.	40 mg/m2 2 out of 3 weeks.	20% had ≥ 50% PSA decrease and 63% had stable disease.	10 patients, partial response rate was 20%; There was stable disease in 70%.	Median was 5.1 months	Median was 9.7 months

* 17% of the patients had had 1 prior chemotherapy and all had metastatic disease.

** Grade 3&4 toxicities were: neutropenia 8%, febrile neutropenia 4%, infection 2%, anemia 3%, lethargy 1%, and somnolescence 1%. 1 pt died as a result of neutropenic sepsis.

Vinorelbine, mitoxantrone and Emcyt (14)

This study used a chemotherapy triplet and is based on the synergy of vinorelbine and emcyt. The measurable disease response rate is notable -- there were complete responses in lymph nodes, lung and liver as well as partial responses.

Table 5. Vinorelbine, Emcyt and Mitoxantrone (14)
Study	Vinorelbine	Emcyt	Mitoxantrone	PSA RR	Measurable Disease RR	Progression Free Survival	Overall Survival
G. Fotios et al, Urology 2005; Phase II; 52 patients. (14) chemo-naive , *	25mg/m2 day 2 and 9 of 21 day cycle.	140mg 3x/day on days 1-3 and 8-10.	12mg/m2 day 2 of 21 day cycle.	56% (29 patients)	31% (6 complete, 10 partial in all organs, excluding bone.) 42% RR if bone included.	Median duration of response was 6.9 months	Median survival was 14.5 months.

* 5 patients were progressing on emcyt single-agent prior to joining this study.

** Grade 3-4 neutropenia in 63% of patients; Grad 1-2 in 27%. G-CSF used in 83% of patients. Neutropenic fever in 13.5% of patients.

References

1. Abratt, RP, Brune, D, Dimopoulos, MA, et al. Randomised phase III study of intravenous vinorelbine plus hormone therapy versus hormone therapy alone in hormone-refractory prostate cancer. Ann Oncol 2004; 15:1613.

2. E. Silva, F. Silva, Phase II study of intravenous vinorelbine plus hormone therapy in hormone-refractory prostate cancer, Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 14601.

3. Krainer M, Tomek S, Elandt K, Horak P, Albrecht W, Eisenmenger M, H�ltl W, Schramek P, Stackl W, Zielinski C, Reibenwein J, 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, J Urol. 2007 Jun;177(6):2141-5; discussion 2145.

4. Koletsky, AJ, Guerra, ML, Kronish, L. Phase II study of vinorelbine and low-dose docetaxel in chemotherapy-naive patients with hormone-refractory prostate cancer. Cancer J 2003; 9:286.

5. Di Lorenzo, G, Pizza, C, Autorino, R, et al. Weekly Docetaxel and Vinorelbine (VIN-DOX) as First Line Treatment in Patients with Hormone Refractory Prostate Cancer. Eur Urol 2004; 46:712.

6. Hahn, NM, Marsh, S, Fisher, W, et al. Hoosier Oncology Group randomized phase II study of docetaxel, vinorelbine, and estramustine in combination in hormone-refractory prostate cancer with pharmacogenetic survival analysis. Clin Cancer Res 2006; 12:6094.

7. Lorenzo GD, et al, Docetaxel, Vinorelbine, and Zoledronic Acid as First-Line Treatment in Patients with Hormone Refractory Prostate Cancer: A Phase II Study, European Urology xxx (2007) xxx-xxx.

8. Goodin s, Rao KV, Kane M, et al, A phase II trial of docetaxel and vinorelbine in patients with hormone refractory prostate cancer, Cancer Chemother Pharmacol 2005;56:199-204.

9. Smith, MR, Kaufman, D, Oh, W, et al. Vinorelbine and estramustine in androgen-independent metastatic prostate cancer. Cancer 2000; 89:1824.

10. Sweeney, C, Monaco, F, Jung, SH, et al. A phase II Hoosier Oncology Group study of vinorelbine and estramustine phosphate in hormone-refractory prostate cancer. Ann Oncol 2002; 13:435.

11. Nakabayashi M, Ling J, Xie W, Regan MM, Oh WK, Response to vinorelbine with or without estramustine as second-line chemotherapy in patients with hormone-refractory prostate cancer, Cancer J. 2007 Mar-Apr;13(2):125-9.

12. Borden, LS Jr, Clark, PE, Lovato, J, et al. Vinorelbine, doxorubicin, and prednisone in androgen-independent prostate cancer. Cancer 2006; 107:1093.

13. S. Sewak, S. Kosmider, V. Ganju, A. Woollett, B. Le, E. Yeo, M. Henry, R. Bell, A phase II study of paclitaxel and vinorelbine (Pac-Vin) in hormone-refractory metastatic prostate cancer (HRPC): A final update, Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 15505.

14. G. Fotios et al, The Combination of Estramustine, Vinorelbine, and Mitoxantrone in Hormone-Refractory Prostate Cancer: A Phase II Feasibility Study Conducted by the Hellenic Cooperative Oncology Group, Urology 66: 382-385, 2005.