Clinical trial NCT00436956: AZD2171 to Treat Prostate Cancer
Official title: A Phase II Study of AZD2171 in Metastatic Androgen Independent Prostate Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Prostate Cancer
Keywords: VEGF
Angiogenesis
Hormone-Refractory
Bone Metastases
Docetaxel-Resistant
Prostate Cancer
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2007-02-19
Enrollment: 59
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Background:

* AZD2171 (Cediranib) is an experimental drug that inhibits formation of new blood vessels.
* Tumors need new blood vessels to grow. Preventing the growth of new blood vessels with AZD2171 may inhibit tumor growth.

Objectives:

-To determine the effectiveness and side effects of AZD2171 in patients with prostate cancer that has metastasized (spread beyond the primary site).

Eligibility:

* Males 18 years of age and older with androgen-independent prostate cancer that has metastasized.
* Patients must have received prior treatment with docetaxel.

Design:

Patients take one AZD2171 by mouth every day in 28-day treatment cycles and undergo the following procedures:

* 1- to 2-day hospitalization at the start of the study for biopsies and blood measurements to determine the level of AZD2171 in the bloodstream. Blood is drawn immediately before the first dose, and 0.25 hr, 0.5 hr, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 12 hr, 24 hr, and 48 hours after the dose is taken.
* Blood tests before starting treatment and then monthly to determine the level of vascular endothelial growth factor receptor ( VEGFR), a protein involved in blood vessel formation.
* Magnetic resonance imaging (MRI) scans once a month to evaluate blood flow.
* Tumor biopsies (optional) both before and after the second and sixth treatment cycles.
* Clinic visits every 4 weeks, including various routine and research blood tests, urine test and electrocardiogram.
* Computed tomography (CT) scan of the chest, abdomen, and pelvis every 8 weeks
* Bone scan every 8 weeks

Patients record all doses of AZD2171 taken or missed in a pill diary. They record their blood pressure at least once daily in a blood pressure diary.

Treatment may continue as long as the patient tolerates the AZD2171 and the cancer does not worsen.

...

Detailed description: Background:

* AZD2171 (Cediranib) is an oral potent inhibitor of receptor tyrosine kinases which impact vascular endothelial growth factor-A (VEGF).
* VEGF appears important in blood vessel formation and disease progression in prostate cancer.
* No known effective therapy in patients with progressive androgen-independent prostate cancer after treatment with docetaxel.

Objectives:

* Primary objective of this study is to determine if AZD2171 is associated with a 30% 6 month probability of progression free survival in patients with metastatic androgen independent prostate cancer (AIPC) as determined by clinical and radiographic criteria.
* Secondary objective of this study will be demonstration of biologic effect by the drug in the patient and on the tumor (when possible). Correlative studies will be conducted on serially obtained tissue biopsies and white blood cell collections.
* Laboratory correlates will include elucidation of activation of components of the VEGFR2 and angiogenesis pathways and evaluation of endothelial cell adhesion molecules (released by damaged cells) using enzyme-linked immunosorbent assay (ELISA), pharmacogenetic analysis of kinase insert domain receptor (KDR) variants and single nucleotide polymorphisms, and pharmacokinetic characterization of AZD2171 activity.

Eligibility:

* Metastatic progressive androgen-independent prostate cancer.
* Prior treatment with docetaxel.
* May not have corrected QT interval (QTc ) greater than 470 msec or greater than 1+ proteinuria on 2 consecutive dipsticks no less than 1 week apart.

Design:

* Phase II trial with a two stage design. 12 patients enrolled in first cohort, if 2 or more are progression free at 6 months than enroll up to 35 evaluable patients. The ceiling will be set at 37 to allow for inevaluable patients.
* Starting dose 20 mg QD (every day) for all patients.
* Once two stage design is complete then prednisone 10 mg once per day will be given in combination with AZD2171. The total number of patients will be 23 for this portion of the protocol.

Eligibility criteria: * INCLUSION CRITERIA:

  1. Patients must have histopathological confirmation of prostate cancer by the Laboratory of Pathology of the National Cancer Institute (NCI), Pathology Department of the National Naval Medical Center or Pathology Department of Walter Reed Army Medical Center prior to entering this study. Patients whose pathology specimens are no longer available may be enrolled in the trial if the patient has a clinical course consistent with prostate cancer and available documentation from an outside pathology laboratory of the diagnosis. In cases where original tissue blocks or archival biopsy material is available, all efforts should be made to have the material forwarded to the research team for use in correlative studies.
  2. Patients must have metastatic progressive androgen-independent prostate cancer. There must be radiographic evidence of disease that has continued to progress despite hormonal agents. Progression requires that a measurable lesion is expanding, new lesions have appeared, and/or that prostatic specific antigen (PSA) is continuing to rise on successive measurements. Patients on flutamide must have disease progression at least 4 weeks after withdrawal. Patients on bicalutamide or nilutamide must have progression at least 6 weeks after withdrawal.
  3. Patients must have received prior therapy with docetaxel for androgen-independent prostate cancer. Any number of prior treatments are acceptable.
  4. Age greater than or equal to 18 years.
  5. Life expectancy of greater than 3 months.
  6. Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2 (Karnofsky greater than or equal to 60%).
  7. Patients must have normal organ and marrow function as defined below:

     Absolute neutrophil count greater than or equal to 1,500/mcL

     Platelets greater than or equal to 100,000/mcL

     Hemoglobin greater than or equal to 8 g/dL

     Total bilirubin within normal institutional limits (unless with clinical Gilbert's syndrome)

     Aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST(SGOT))/alanine aminotransferase/serum glutamic pyruvic transaminase (ALT(SGPT) less than or equal to 2.5 times institutional upper limit of normal

     Creatinine less than or equal to 1.5 times institutional upper normal institutional limits

     OR

     Creatinine clearance greater than 40 mL/min/1.3 m\^2 for patients with creatinin levels above institutional normal as calculated by the Cockcroft Gault formula.
  8. Patients must have recovered from any acute toxicity related to prior therapy, including surgery. Toxicity should be less than or equal to grade 1 or returned to baseline.
  9. All patients who have not undergone bilateral surgical castration must continue suppression of testosterone production by appropriate usage of gonadotropin releasing hormone (GnRH) agonists or antagonists.
  10. Patients must not have other invasive malignancies (within the past three years with the exception of non-melanoma skin cancers or non-invasive bladder cancer).
  11. AZD2171 has been shown to terminate fetal development in the rat, as expected for a process dependent on VEGF signaling. Enrolled patients must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, the duration of study participation and 3 months after the end of the treatment.
  12. Ability to understand and the willingness to sign a written informed consent document.
  13. Patients must have a blood pressure of less than 140/90 at the time of enrollment. Details of antihypertensive treatment, if required, will be left up to the primary care physician.

EXCLUSION CRITERIA:

1. Patients who have had chemotherapy, radiotherapy, or major surgery within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study.
2. Patients may not be receiving any agents not approved by the Food and Drug Administration (FDA) within the past four weeks.
3. Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
4. Mean QTc greater than 470 msec (with Bazett's correction) in screening electrocardiogram or history of familial long Q wave, T wave (QT) syndrome.
5. Greater than +1 proteinuria on two consecutive dipsticks taken no less than 1 week apart.
6. Uncontrolled intercurrent illness including, but not limited to hypertension, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
7. Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD2171.

Primary outcomes:
measure: Percent Probability of Participants With 6-month Progression-free Survival (PFS)
timeFrame: 6 months
Secondary outcomes:
measure: Number of Participants With Adverse Events
timeFrame: Date treatment consent signed to date off study, approximately 61.5 months
measure: Number of Grade 2 Toxicities
timeFrame: 61.5 months
measure: Number of Grade 3 Toxicities
timeFrame: 61.5 months
measure: Median Overall Survival
timeFrame: 44 months
measure: Median Progression Free Survival (PFS)
timeFrame: up to 14.9 months based on a Kaplan-Meier analysis.
measure: Response Per the Response Evaluation Criteria in Solid Tumors (RECIST)
timeFrame: Every 2 cycles (approximately 56 days)
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: William L Dahut, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Balbay MD, Pettaway CA, Kuniyasu H, Inoue K, Ramirez E, Li E, Fidler IJ, Dinney CP. Highly metastatic human prostate cancer growing within the prostate of athymic mice overexpresses vascular endothelial growth factor. Clin Cancer Res. 1999 Apr;5(4):783-9.
citation: Beedassy A, Cardi G. Chemotherapy in advanced prostate cancer. Semin Oncol. 1999 Aug;26(4):428-38.
citation: Belgore FM, Blann AD, Lip GY. Measurement of free and complexed soluble vascular endothelial growth factor receptor, Flt-1, in fluid samples: development and application of two new immunoassays. Clin Sci (Lond). 2001 May;100(5):567-75.
citation: Huang J, Jochems C, Talaie T, Anderson A, Jales A, Tsang KY, Madan RA, Gulley JL, Schlom J. Elevated serum soluble CD40 ligand in cancer patients may play an immunosuppressive role. Blood. 2012 Oct 11;120(15):3030-8. doi: 10.1182/blood-2012-05-427799. Epub 2012 Aug 28.
citation: Dahut WL, Madan RA, Karakunnel JJ, Adelberg D, Gulley JL, Turkbey IB, Chau CH, Spencer SD, Mulquin M, Wright J, Parnes HL, Steinberg SM, Choyke PL, Figg WD. Phase II clinical trial of cediranib in patients with metastatic castration-resistant prostate cancer. BJU Int. 2013 Jun;111(8):1269-80. doi: 10.1111/j.1464-410X.2012.11667.x. Epub 2013 Feb 18.