See also the Sunitinib summary table of the results below.

Definitions

• Tyrosine kinase inhibitor - the NCI's definition is "A drug that interferes with cell communication and growth and may prevent tumor growth. Some tyrosine kinase inhibitors are used to treat cancer." Abbreviation is TKI.

• FLT3 - FMS-like tyrosine kinase-3 gene.

• PDGFRs - Platelet Derived Growth Factor Receptor - alpha and beta.

• RET - rearranged during transfection. An oncogene.

• VEGFRs - Vascular endothelial growth factor receptor. They are numbered 1, 2 and 3. VEGF is the key mediator of angiogenesis, endothelial cell growth and vascular permeability. It binds and activates its receptor.

• dysgeusia (impaired sense of taste).

• MDR - median duration of response.

• PFS - Progression Free Survival.

Introduction

Sunitinib malate (SUTENT®) is a small-molecule, oral, multitargeted tyrosine kinase inhibitor of VEGFRs (1,2 and 3), PDGFRs (α and β), KIT, RET and FLT3.  Of these, VEGFR overexpression contributes to prostate cancer progression, while PDGFR overexpression is related to bone metastasis progression. Sunitinib binds to both the VEGF receptor and the PDGFR receptor.  Sunitinib is approved for renal cell carcinoma and gastrointestinal stromal tumors. Sunitinib was previously known as SU11248.

Clinical Trial Results

Pre-Clinical Studies of Sunitinib and Docetaxel (1).

While one would not base a treatment in humans on only xenografts, such studies do indicate possibilities that then can be tested in human clinical trials.

A. Cumashi et al (1) studied docetaxel and sunitinib or sunitinib alone is DU-145 PCa xenografts. The following table summarizes their results.

• Both sunitinib and docetaxel inhibited tumor regrowth after initial treatment with the alternate drug.

• These results suggest that sunitinib alone or in combination with low-dose docetaxel may have a role in the treatment of HRPC

Phase I Combining Sunitinib Malate and Docetaxel (taxotere) in chemo-naive patients (2).

A. Zurita et al(2) presented the results of a phase I trial of Sutent® and taxotere in order to determine the optimum combination dose, safety and pharmacokinetic profile of the combination. Patients where chemo-naive, but were metastatic HRPC (CRPC).

• Suntinib and Docetaxel combined plus sunitinib alone for a lead in evaluation. Chemo-naive, mHRPC)

• Number of patients: 25.

• Taxotere Dose and Schedule: 60 and 75 mg/m2 every 3 weeks (plus prednisone 5mg 2x/day)

• Sunitinib Dose and Schedule: 12.5, 37.5, 50 mg/day 2 weeks on and 1 week off.

• Optimum Combined Dose: sunitinib 37.5 mg/d in combination with taxotere 75 mg/m2 and prednisone 5 mg 2x/day.

• PSA Response Rate: 40% (10 of 25 patients).

• Measurable disease: 20% (4 of the 20 patients) had a partial tumor response, based on RECIST criteria, and 11 (55%) had stable disease.

• Median duration of treatment at 12.5mg and 37.5mg/day plus 60mg/m2 were 6.3 months and 6.6 months. 3 patients had completed 1 year.

• The most common treatment-related Adverse Events were neutropenia (70%), fatigue (44%), anorexia (30%) and diarrhea (30%). Only 1 DLT was observed, a grade 3 hyponatremia in cohort 3 (50mg/day S and 60mg/m2 T). 6 patients discontinued this study due to disease progression and 6 left due to adverse events.

• Sutent alone (lead-in study).

• 50mg/day. 3 of 25 Patients had a greater than 50% PSA decrease, 7 patients had a mean PSA decline of 40% including the 3 with >50% drop. 12 patients showed a mean rise in PSA of 273% followed by a drop during the 2-week rest period. 6 showed steady mean increases of PSA of 73% but did not drop during the rest period.

• As to how to tell who will most likely respond to Sutent, the lead-in phase using 50mg/day of Sutent appeared to indicate that having a PSA reduction would predict for a later response to Sutent plus docetaxel.

Phase II Study of Metastatic Castration-Resistant Prostate Cancer (MCRPC) After Docetaxel-based chemotherapy (3).  Sunitinib monotherapy.

P.O. Periman et al (3) presented a study of Sunitinib malate in men who had failed 1st line docetaxel-based chemotherapy.  Currently there is no effective options for 2nd line chemotherapy or chemotherapy-like drugs for HRPC disease and none have been approved for this use. The study done by P.O. Periman et al examined the efficacy and toxicity of sunitinib in mCRPC (mHRPC) progressing after prior chemotherapy (actually the patients could have had 1-2 prior chemotherapy regimens including docetaxel.)

• Patients had to have been treated with 1-2 chemotherapies including docetaxel.

           36 patients total.

• Sunitinib dose: 50mg/day, oral, 4 weeks on and 2 weeks off in 6-week cycles.

• The primary objective was clinical progression-free survival (PFS) with a 12-week PFS >30% as a goal. Secondary objectives are PSA response, objective response, quality of life, pain, survival, and toxicities.

• Median clinical Progression Free Survival (RECIST, bone events, pain, obstruction, ECOG) was 21.1 weeks (4.9 months) and the 12 week PFS was attained in 78.9%.

• PSA 50% decrease response rate: 3 patients (9%).

• PSA 30% decrease response rate: 7 patients (21%).

• One patient had grade 3 anemia; 8 died due to disease progression with 2 deaths possibly related to sunitinib(non- neutropenic sepsis and hemorrhagic stroke, n=1 each).

Sunitinib and Docetaxel - Phase II (4), chemo-naive

Phase II has been completed and was reported at the ASCO 2009 annual meeting by AJ Zurita et al (4).  The phase I results were outlined above (2).  A summary follows.

• Sutent Dose and Schedule: 37.5mg daily po Days 1-14.

• Taxotere/Prednisone dose and schedule: 75mg/m2 IV on day 1, 5mg BID prednisone days 1-21 of 21 day cycle.

• 55 patients enrolled with 13 still on the study as of 1 Oct 08 with 36 discontinuing from the study for various reasons - 16 were due to disease progression, 13 adverse events, 6 consent withdrawal and 1 other.

• Dose reductions were permitted for treatment related toxicity.

• PSA RR (≥ 50% decrease) 31 pts (56%).

• Median time to PSA progression was 42.1 weeks (preliminary report).

• 33 patients had measurable disease. With RECIST criteria there were partial response in 13 (39%); 7 patients (21%) had an initial partial response.

• The probability of survival at 48 weeks is 92.4%. The median progression-free survival and overall survivals had not been reached at the time of submitting the abstract.

• Adverse events - the most common grade 3-4 were neutropenia in 75%, febrile neutropenia (15%), fatigue (15%), stomatitis (7%), and anorexia (7%).

While a randomized phase III clinical trial comparing docetaxel vs docetaxel/sunitinib would provide the best estimate of what sunitinib contributes to this combination, we can compare this trial's results to TAX327 phase III which defined the docetaxel portion of the current trial.

TAX327 (phase III) vs Taxotere/sunitinib phase II trial.

The potential improvement in measurable disease response rate is very encouraging and hopefully development will continue with this drug combination.

5. Phase II, Taxotere and Sutent Combined (continuation of ref. 4), chemo-naive patients.

In reference (5), A.J. Zurita et al provided another update on the phase II trial of combined docetaxel and sunitinib.

• 21 day cycle, oral sunitinib days 1-14, docetaxel on day 2 and prednisone bid DAYS 1-21.

• 45 Patients, on study median of 14 wks (range is 2-53 wks); 27% on study for > 6 mos; 2 pts (4%) for > 1 year.

• Confirmed PSA responses 18 patients (40%),

• Unconfirmed responses in 3 additional patients.

• 13 patients with measurable disease, 7 (54%) had a confirmed partial response.

• The most common treatment-related adverse events were diarrhea (50%), neutropenia (44%), fatigue (33%), nausea (33%) and dysgeusia (altered taste) (28%).

We can look forward to a final publication of these trial results.

Single Agent sunitinib in chemo-naive patients vs patients who have failed 1st line taxotere (7), Phase II.

M. Smith et al presented a paper at the 2008 ASCO GU conference comparing men with HRPC disease, who were chemotherapy naive vs men who were metastatic HRPC and taxotere-refractory.

• Sunitinib dose and schedule: 50mg daily 4 weeks on and 2 weeks off.

• Primary end point: PSA.

• Patients: Total of 34, 17 in each group.

Most common adverse effects were fatigue, myelosuppression and rectal bleeding. Treatment-related grade 4 toxicities were thrombocytopenia (n=1), anemia (n=1) and hyponatremia (n=1).

The authors concluded that some alternative endpoint other than PSA should be used that will correlate with clinical benefit.
 

The results of this trial contrast with the other trials discussed here. Perhaps the small number of patients was a factor.

Current Clinical Trials involving Sutent and HRPC Disease

Sutent Maintenance After Response to Taxotere (SMART) - Phase II.  SU011248 (study medication) will be given at 50 mg/day as a single agent for 4 consecutive weeks followed by a 2 week rest period to form a complete cycle of 6 weeks. Study medication will be orally self administered once daily without regard to meals beginning on Day 1 of the study. Cycles will be repeated in the absence of unacceptable toxicity or disease progression
http://clinicaltrial.gov/ct2/show/NCT00550810?term=sutent&recr=Open&rank=33

An Open-Label Phase II Study With SUTENT in Patients Suffering From Hormone Refractory Prostate Cancer (PROSUT). After docetaxel, study will investigate the efficacy of sunitinib (SUTENT) given orally at a dose of 37.5 mg continuously, for 6 cycles of 6 consecutive weeks. Patients who are still responders after 6 cycles will be treated until disease progression, pain progression, unacceptable toxicity or death due to any cause. Dose increase or reduction of 12.5 mg increments and change of schedule is recommended based on individual safety and tolerability.
http://clinicaltrial.gov/ct2/show/NCT00748358?term=sutent&recr=Open&rank=52

 A Multicenter, Randomized, Double-Blind, Phase III Study Of Sunitinib Plus Prednisone Versus Prednisone In Patients With Progressive Metastatic Hormone-Refractory Prostate Cancer After Failure Of A Docetaxel-Based Chemotherapy Regimen (SUN 1120). Sunitinib plus prednisone vs prednisone and a placebo.  Dose of sunitinib is 37.5mg administered on a continuous daily regimen. Prednisone 5mg 2x/day.

http://clinicaltrial.gov/ct2/show/NCT00676650?term=sutent&recr=Open&rank=63

Reference (6) by G. Sonpavde et al (6) outline a phase II clinical trial of sunitinib after previous docetaxel chemotherapy(1-2 total previous chemotherapies.) The trial enrolled 34 patients. Dose of sunitinib was planned to be 50mg, once daily for 4 weeks of every 6 week cycle. This trial might be that described in reference (3).

Are there any concerns with Sutent(sunitinib)?

There is some concern regarding heart problems.  See

http://professional.cancerconsultants.com/news.aspx?id=41130 for more information. Basically patients on Sutent should be monitored for LVEF reduction and hypertension.

Are there any other useage guidelines?

Even though HRPC trials involving Sutent with or without docetaxel have yet to be completed, some oncologists are already prescribing it for their patients. Myers at the 2007 PCRI PCa conference presented a talk on oral drugs -- among them was Sutent. He stated that it did not kill prostate cancer cells (which is one reason to combine drugs of this type with a cytotoxic chemotherapy such as docetaxel).  Therefore, he thought its best use might be in maintaining a complete remission.

Another side effect that one might watch out for is hypothyroidism. Measurement of TSH is recommended. See reference #8.

• The FDA has a patient information sheet on line for Sutent.

• See http://www.fda.gov/CDER/Drug/InfoSheets/patient/sunitinibPIS.htm

• Sutent might also make your skin yellow.

• Ketoconazole can increase the amount of Sutent in your body while dexmethasone may decrease the amount of Sutent.

Sutent is manufacturered by Pfizer. Pfizer has a website with prescribing information and more. See Pfizer for Oncology Professionals.

Discussion

Current development of Sutent in HRPC seems to be focusing on (1) improving the standard chemotherapy of 75mg/m2 plus 5mg bid prednisone by adding Sutent as a 1st line chemotherapy for HRPC (2,4,5 and 6) for which it presently looks fairly promising. Whether or not it will be better than taxotere/Avastin remains to be seen; (2) Using Sutent in HRPC patients who have failed 1st line Taxotere as a maintenance therapy (3, 6, 7.) P.O. Periman et al (3) had very good results for this use while that of M. Smith et al (7) did not.  Hopefully, the currently running clinical trials will result in better guidelines for use.

Author: Howard Hansen 21 November 2008; update 12/31/08.

Current update: 29 May 2009 with phase II results from ASCO 2009 (reference 4).

References

1. Cumashi A, Tinari N, Rossi C, Lattanzio R, Natoli C, Piantelli M, Iacobelli S., Sunitinib malate (SU-11248) alone or in combination with low-dose docetaxel inhibits the growth of DU-145 prostate cancer xenografts, Cancer Lett. 2008 Jun 27. [Epub ahead of print].

2. A. Zurita, N.D. Shore, M.F. Kozloff, C.W. Ryan, T.M. Beer, E. Chow Maneval, I. Chen, C.J. Logothetis, A phase I/II study of sunitinib in combination with docetaxel (dcx) and prednisone (pdn) in patients with metastatic castrate-resistant prostate cancer (mCRPC), European Journal of Cancer Supplements, Vol 5 No 4, Page 287, ECCO 14 - the European Cancer Conference Abstract # 4025, Barcelona, Spain, 23 - 27 September 2007.
 
3. P. O. Periman, G. Sonpavde, D. M. Bernold, D. J. Weckstein, A. Williams, F. Zhan, K. A. Boehm, L. Asmar, T. E. Hutson, Sunitinib malate for metastatic castration resistant prostate cancer following docetaxel-based chemotherapy, J Clin Oncol 26: 2008 (May 20 suppl; abstract # 5157). Information above was updated to what was presented at the conference.

4. A. J. Zurita, G. Liu, T. Hutson, M. Kozloff, N. Shore, G. Wilding, C. J. Logothetis, I. Chen, E. Chow Maneval, D. George, Sunitinib in combination with docetaxel and prednisone in patients (pts) with metastatic hormone-refractory prostate cancer (mHRPC), J Clin Oncol 27:15s, 2009 (suppl; abstr 5166).

5. A.J. Zurita, C.J. Logothetis, G. Liu, G. Wilding, T.E. Hutson, I. Chen, E. Chow-Maneval, D.J. George, SUNITINIB IN COMBINATION WITH DOCETAXEL AND PREDNISONE IN PATIENTS WITH METASTATIC HORMONE REFRACTORY PROSTATE CANCER (MHRPC), European Society of Medical Oncologists 2008 (ESMO 2008.) Supplement: Abstract Book of the 33rd ESMO Congress, Stockholm, Sweden 12-16 September 2008, Annals of Oncology, Volume 19, Supplement 8, September 2008, Abstract # 615P.

6. Sonpavde G, Hutson TE, Berry WR, Boehm KA, Asmar L., Phase II trial of sunitinib for the therapy of progressive metastatic castration-refractory prostate cancer after previous docetaxel chemotherapy, Clin Genitourin Cancer. 2008 Sep;6(2):134-7.

7. M. Smith, P. Kantoff, M. Regan, D. Kaufman, M. D. Michaelson, Phase II study of sunitinib malate in men with advanced prostate cancer, Meeting: ASCO 2008 Genitourinary Cancers Symposium, Abstract No: 198.

8. David H. Garfield, Pascal Wolter, Patrick Schöffski, Aleck Hercbergs, and Paul Davis, Documentation of Thyroid Function in Clinical Studies With Sunitinib: Why Does It Matter? JCO Nov 1 2008: 5131–5132. First published on Sep 29 2008; 10.1200/JCO.2008.18.8680.
In Reply
Harold J. Burstein, Kathy D. Miller, Mark A. Socinski, and Leonard B. Saltz
JCO Nov 1 2008: 5132–5133. First published on Sep 29 2008; 10.1200/JCO.2008.19.0645.