Clinical trial NCT00526591: Everolimus in Treating Patients With Newly Diagnosed Localized Prostate Cancer
Official title: Randomized Phase II Study of Two Different Doses of RAD-001 (Everolimus) as Neo-Adjuvant Therapy in Patients With Localized Prostate Cancer
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Prostate Cancer
Keywords: adenocarcinoma of the prostate
stage I prostate cancer
stage II prostate cancer
stage III prostate cancer
Lead sponsor: Case Comprehensive Cancer Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2007-09-10
Enrollment: 17
Sex: MALE
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: RATIONALE: Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving everolimus before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

PURPOSE: This randomized phase II trial is studying the side effects and how well everolimus works in treating patients with newly diagnosed localized prostate cancer.

Detailed description: OBJECTIVES:

Primary

* To determine the clinical effects of everolimus, in terms of pathologic response (i.e., histologic P0, margin status, or capsular penetration) and surgical outcome, in patients with newly diagnosed localized prostate cancer treated with two different doses of everolimus prior to radical prostatectomy.
* To evaluate the safety and tolerability of this drug in these patients.

Secondary

* To determine the effect of this drug on prostate-specific antigen (PSA) levels in these patients.
* To determine the effect of this drug on levels of expression of PTEN, Akt, phospho-mTOR (i.e., Se2448), phospho-p70 S6 kinase (i.e., Thre389), phospho-Smad3 (i.e., Ser433/435), phospho-Smads 1/5 (i.e., Ser463/465), AR, and TUNEL in these patients.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

* Arm I: Patients receive low-dose oral everolimus once daily for up to 8 weeks in the absence of unacceptable toxicity.
* Arm II: Patients receive high-dose oral everolimus once daily for up to 8 weeks in the absence of unacceptable toxicity.

Within 7 days after the last dose of everolimus, all patients undergo radical prostatectomy with bilateral pelvic lymphadenectomy.

Tumor biopsy specimens acquired prior to treatment and prostate tumor tissue acquired at the time of radical prostatectomy are evaluated for biomarker correlative studies. Tissue samples are assessed by immunohistochemistry (IHC) and tissue microarray analysis for expression of cellular and molecular biomarkers (i.e., p-S6, p-4E-BP1, and p-Akt) that correlate with response. Prostatectomy specimens are also assessed by pathologic analysis for histopathologic response (i.e., pathologic stage, Gleason score, margin status, and tumor size).

After completion of study therapy, patients are followed at 6 weeks.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically or cytologically confirmed newly diagnosed, localized adenocarcinoma of the prostate, meeting any of the following criteria:

  * Clinical stage T2a, T2b, T2c, or T3 disease (any grade or PSA)
  * Gleason score 7 (4+3 only) or ≥ 8 (any stage or PSA)
  * Serum PSA ≥ 10 ng/dL (any grade or stage)
  * Any stage, PSA, or Gleason score AND ≥ 35% chance of biochemical failure at 5 years based on Kattan's nomogram
* Recommended for radical prostatectomy
* Normal testosterone level
* No pure neuroendocrine or small cell prostate cancer
* No metastatic disease by CT scan, MRI, bone scan, or X-ray
* No clinical evidence of CNS metastases

PATIENT CHARACTERISTICS:

Inclusion criteria:

* ECOG performance status (PS) 0-1 or Karnofsky PS 70-100%
* ANC ≥ 1,500/μL
* Platelet count ≥ 100,000/μL
* Hemoglobin ≥ 8 g/dL
* AST and ALT ≤ 1.5 times upper limit of normal (ULN)
* Bilirubin ≤ 1.5 times ULN
* Creatinine ≤ 1.5 times ULN
* PT/PTT normal (no anticoagulants)
* No active unresolved infection
* No known HIV positivity
* Fertile patients must use effective contraception during and for 6 months after completion of study therapy

Exclusion criteria:

* Known hypersensitivity to everolimus or other rapamycins (e.g., sirolimus or temsirolimus) or to its excipients
* Gastrointestinal (GI) disease, condition, or symptoms that may significantly impair GI function and alter the absorption of everolimus, including any of the following:

  * Ulcerative disease
  * Uncontrolled nausea
  * Vomiting
  * Diarrhea
  * Malabsorption syndrome
* Other active malignancy or malignancy at ≥ 30% risk for relapse after completion of therapy, except nonmelanoma skin cancer
* Uncontrolled concurrent illness including, but not limited to, any of the following:

  * Ongoing or active infection (e.g., bacterial, viral or fungal)
  * Severely impaired lung function
  * Uncontrolled diabetes (fasting serum glucose \> 1.5 times ULN)
  * Liver disease (e.g., cirrhosis, chronic active hepatitis, or chronic persistent hepatitis)
  * Symptomatic congestive heart failure
  * Unstable angina pectoris
  * Cardiac arrhythmia
* Psychiatric illness or social situation that would limit study compliance
* Any underlying medical condition which, in the principal investigator's opinion, will make the administration of everolimus hazardous OR obscure the interpretation of adverse events

PRIOR CONCURRENT THERAPY:

* More than 4 weeks since major surgery
* More than 3 months since finasteride
* No prior or concurrent radiotherapy to the prostate gland or pelvis
* No prior hormones (e.g., luteinizing hormone-releasing hormone \[LHRH\] agonists, LHRH antagonists, or antiandrogens \[e.g., bicalutamide, flutamide, or nilutamide\]) and/or PC-SPES (or PC-x product) or estrogen-containing nutraceuticals
* No prior rapamycin mTOR inhibitor
* No prior small bowel resection that may significantly impair GI function and alter the absorption of everolimus
* No prior or concurrent immunotherapy, chemotherapy, or other investigational therapy for prostate cancer
* No other concurrent investigational or commercial agents
* No other concurrent anticancer agents
* No concurrent, chronic treatment with systemic steroids (except inhaled or topical steroids) or another immunosuppressive agent
* No concurrent live vaccines
* No concurrent strong inhibitors or inducers of the isoenzyme CYP3A administered as systemic therapy

Primary outcomes:
measure: Proportion of Patients Who Are P0 (i.e., no Clinically Detectable Tumor in the Pathologic Specimen) at Surgery
timeFrame: After 8 weeks of therapy at the time of prostatectomy
measure: Toxicity Profile of Each Dose (Number of Patients With Worst Grade Toxicity)
timeFrame: at daily dose for 8 weeks
Secondary outcomes:
measure: Change in PSA
timeFrame: Up to 16 weeks after start of study
Other outcomes:
measure: Effect of Treatment on Biological and Molecular Markers
timeFrame: After 8 weeks of therapy
Locations:
city: Cleveland
country: United States
facility: Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center
state: Ohio
Study officials:
affiliation: Case Comprehensive Cancer Center
name: Jorge A. Garcia, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Koshkin VS, Mir MC, Barata P, Gul A, Gupta R, Stephenson AJ, Kaouk J, Berglund R, Magi-Galluzzi C, Klein EA, Dreicer R, Garcia JA. Randomized phase II trial of neoadjuvant everolimus in patients with high-risk localized prostate cancer. Invest New Drugs. 2019 Jun;37(3):559-566. doi: 10.1007/s10637-019-00778-4. Epub 2019 Apr 30.