Docetaxel and Prednisone With or Without Cediranib in Treating Patients With Metastatic Prostate Cancer That Did Not Respond to Hormone Therapy

Phase 2

Terminated

Conditions: Adenocarcinoma of the Prostate
Stage IV Prostate Cancer

Interventions: Drug: cediranib maleate
Drug: docetaxel
Drug: prednisone
Other: laboratory biomarker analysis

Registration Number: NCT00527124

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: This randomized phase II trial is studying how well giving docetaxel and prednisone together with or without cediranib works in treating patients with metastatic prostate cancer that did not respond to hormone therapy. Drugs used in chemotherapy, such as docetaxel and prednisone, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Cediranib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Giving docetaxel together with prednisone, with or without cediranib, may kill more tumor cells.

Detailed Description: PRIMARY OBJECTIVE:

I. To determine the 6-month progression-free survival rate of patients with hormone refractory metastatic adenocarcinoma of the prostate treated with docetaxel and prednisone with vs without cediranib.

SECONDARY OBJECTIVES:

I. To evaluate the safety profile of cediranib, docetaxel, and prednisone in patients with metastatic hormone-refractory prostate cancer.

II. To determine the duration of prostate-specific antigen (PSA) response and PSA control in patients with metastatic hormone-refractory prostate cancer treated with cediranib, docetaxel, and prednisone.

III. To determine the partial and complete response rate in patients with measurable disease treated with cediranib, docetaxel, and prednisone.

IV. To determine time to progression in patients with metastatic hormone-refractory prostate cancer treated with cediranib, docetaxel, and prednisone.

V. To determine overall survival in patients with metastatic hormone-refractory prostate cancer.

VI. To perform correlative marker studies measuring serum levels of VEGF, PDGF, sICAM, bFGF, interleukin (IL)-6, and IL-8.

VII. To perform a pilot study of \[F18\]FMAU positron emission test (PET) imaging on patients receiving cediranib, docetaxel, and prednisone.

OUTLINE: This is a multicenter study. Patients are stratified by participating institution. Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive oral cediranib once daily on days 1-21, docetaxel IV over 1 hour on day 1, and oral prednisone twice daily on days 1-21.

ARM II: Patients receive docetaxel and prednisone as in arm I.

In both arms, courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Archival paraffin-embedded tissue blocks or slides from time of diagnosis (or subsequent, but prior to therapy) are evaluated for expression of molecular targets relevant to this study. Blood specimens from baseline, after courses 1 and 2, and after completion of study treatment are analyzed for protein markers. Samples are analyzed by ELISA and IHC for angiogenesis-associated plasma proteins, plasma levels of VEGF, tumor expression of PDGFR, and interleukin (IL)-6 and IL-8 plasma levels. Patients also undergo positron emission test (PET) scans utilizing fluorodeoxyglucose (FDG) at baseline and after course 1.

After completion of study treatment, patients are followed every 3 months for 52 weeks.

Recruitment & Eligibility

Status: TERMINATED

Sex: Male

Target Recruitment: 57

Inclusion Criteria

Clinical/radiologic metastases with objective evidence of disease progression by imaging or by rising prostate-specific antigen (PSA) despite androgen deprivation therapy
Rising PSA must be determined based on a rising trend with 2 successive elevations at a minimum interval of 1 week
Meets 1 of the following criteria: Measurable disease, with any level of PSA, at least 1 unidimensionally measurable lesion (longest diameter to be recorded) >= 20 mm by conventional techniques or >= 10 mm by spiral CT scan, nonmeasurable disease, PSA >= 5 ng/mL OR new areas of bony metastases on bone scan
Castrate levels of testosterone < 50 ng/dL must be maintained and documented
Luteinizing hormone-releasing hormone (LHRH) agonist therapy must be continued, if required to maintain castrate levels of testosterone
Total bilirubin normal
Patients with radiological evidence of stable brain metastases are eligible provided they are asymptomatic and do not require corticosteroids or have been treated with corticosteroids and show clinical and radiological evidence of stabilization at least 10 days after discontinuation of steroids
ECOG performance status (PS) =< 2 or Karnofsky PS 60-100%
Life expectancy > 12 weeks
Leukocytes >= 3,000/mcL
Absolute neutrophil count >= 1,500/mcL
Platelet count >= 100,000/mcL
Histologically confirmed adenocarcinoma of the prostate
AST and ALT =< 2.5 times upper limit of normal
Creatinine normal OR creatinine clearance >= 60 mL/min
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
Proteinuria =< 1+ and urine protein:creatinine ratio =< 1.0 OR 24-hour urine protein < 1,000 mg
Peripheral neuropathy >= grade 2
Uncontrolled intercurrent illness including, but not limited to, any of the following: ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, psychiatric illness/social situations that would limit compliance with study requirements
Congestive heart failure, second or third degree heart block, or recent myocardial infarction within the past 6 months
QTc prolongation > 500 msec OR other ECG abnormality noted within 14 days of treatment
New York Heart Association class III or IV cardiac disease; Class II disease controlled with treatment and monitoring allowed
History of poorly controlled hypertension (e.g., resting blood pressure > 150/90 mm Hg with or without hypertensive therapy)
History of a curatively treated malignancy with a survival prognosis of less than 5 years or concurrent malignancy except for adequately treated basal cell or squamous cell skin cancer or carcinoma in situ
History of significant gastrointestinal impairment, as judged by the investigator, that would significantly affect the absorption of cediranib
History of severe hypersensitivity reaction to docetaxel or other drugs formulated with polysorbate 80
Significant hemorrhage (30 mL bleeding/episode in previous 3 months) or hemoptysis (5 mL fresh blood in previous 4 weeks)
Prior enrollment or randomization of treatment in the present study
Patients must be off flutamide antiandrogen therapy for ≥ 4 weeks (6 weeks for bicalutamide or nilutamide)
No prior chemotherapy for metastatic prostate cancer
No major surgery within the past 14 days or a surgical incision that is not fully healed
No HIV-positive patients on combination antiretroviral therapy
No conditions requiring concurrent use of drugs or biologics with proarrhythmic potential
No other investigational agents within 30 days prior to study enrollment
No untreated unstable brain or meningeal metastases
Known hypersensitivity to cediranib or any of its excipients

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm II	prednisone	Patients receive docetaxel and prednisone as in arm I.
Arm II	laboratory biomarker analysis	Patients receive docetaxel and prednisone as in arm I.
Arm I	cediranib maleate	Patients receive oral cediranib maleate once daily on days 1-21, docetaxel IV over 1 hour on day 1, and oral prednisone twice daily on days 1-21.
Arm I	laboratory biomarker analysis	Patients receive oral cediranib maleate once daily on days 1-21, docetaxel IV over 1 hour on day 1, and oral prednisone twice daily on days 1-21.
Arm II	docetaxel	Patients receive docetaxel and prednisone as in arm I.
Arm I	prednisone	Patients receive oral cediranib maleate once daily on days 1-21, docetaxel IV over 1 hour on day 1, and oral prednisone twice daily on days 1-21.
Arm I	docetaxel	Patients receive oral cediranib maleate once daily on days 1-21, docetaxel IV over 1 hour on day 1, and oral prednisone twice daily on days 1-21.

Primary Outcome Measures

Name	Time	Method
6-month Progression-free Survival (PFS) Proportion	Followed for 52 weeks at 3 month intervals after coming off treatment, time period equal to the length of treatment + up to 12 months	The proportion of patients on each treatment arm who survive ≥ 6.00 months progression-free

Secondary Outcome Measures

Name	Time	Method
Prostate-specific Antigen (PSA) Response in Accordance With the Prostate Specific Antigen Working Group	Up to 52 weeks	PSA \< 4.0 ng/ml. is a CR. A 50% decline or better in PSA is a PR. Less than a 50% decline in PSA and less than a 25% increase in PSA is SD. A 25% or greater increase in PSA level by at least 5 ng/mL is PD by PSA only. The point estimate and 95% Wilson CI estimates of the proportion for the Prostate-specific antigen (PSA) response will be computed .
Overall Response Rate Evaluated by the RECIST Criteria	Up to 52 weeks	The overall response is determined by combining the patient's status on target lesions, PSA, non-target lesions, and new disease as defined in the following table. Target Lesions CR CR PR SD PD Any Any Any PSA Response CR PR PR Non-PD Any Any PD Any Non-Target Lesions CR Non-CR/Non-PD Non-PD Non-PD Any PD Any Any New Lesions No No No No Yes or No Yes or No Yes or No Yes Overall Response CR PR PR SD PD PD PD PD
Time to Progression	The time from registration date until documented clinical disease progression, or until date of death, whichever occurs first, assessed up to 52 weeks	Analyzed with standard K-M methodology. Both point and 95% CI estimates of the median and other statistics (e.g., the 3-month rate, 6-month rate, etc.) will be computed from the censored distribution of TTP. These point and CI estimates will be reported for all patients combined, and separately for each treatment arm.
Overall Survival	The time from registration date until death from any cause, assessed up to 52 weeks	Analyzed with standard K-M methodology. A 12 month survival rate will be calculated since median survival was not reached by the end of the study period.

Trial Locations

Locations (4): Barbara Ann Karmanos Cancer Institute
🇺🇸
Detroit, Michigan, United States
University of Wisconsin Hospital and Clinics
🇺🇸
Madison, Wisconsin, United States
Wayne State University
🇺🇸
Detroit, Michigan, United States
M D Anderson Cancer Center
🇺🇸
Houston, Texas, United States