Everolimus in Treating Patients With Newly Diagnosed Localized Prostate Cancer

Randomized Phase II Study of Two Different Doses of RAD-001 (Everolimus) as Neo-Adjuvant Therapy in Patients With Localized Prostate Cancer

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.

Study Overview

• Status: Terminated
• Conditions: Prostate Cancer
• Intervention / Treatment: Drug: Everolimus; Procedure: conventional surgery

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.

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low-dose Everolimus Cohort; 5mg Everolimus daily continuously for 8 weeks and conventional surgery	Drug: Everolimus; Patients will receive arm-specific dosage of Everolimus daily continuously for 8 week; Other Names: RAD-001; Procedure: conventional surgery; Radical prostatectomy with bilateral pelvic lymphadenectomy will be performed within 10 days of the completion of week 8 on RAD-001 (Everolimus).
Active Comparator: High-dose Everolimus Cohort; 10mg Everolimus daily continuously for 8 weeks and conventional surgery	Drug: Everolimus; Patients will receive arm-specific dosage of Everolimus daily continuously for 8 week; Other Names: RAD-001; Procedure: conventional surgery; Radical prostatectomy with bilateral pelvic lymphadenectomy will be performed within 10 days of the completion of week 8 on RAD-001 (Everolimus).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Patients Who Are P0 (i.e., no Clinically Detectable Tumor in the Pathologic Specimen) at Surgery	Specimens are fixed in formalin for 24 hours.Specimens are the cut at 3 mm intervals perpendicular to the rectal surface and the sections are examined grossly and microscopically on routine Hematoxylin and Eosin stain (H&E) (pathologic complete response or P0) will be defined as responders.	After 8 weeks of therapy at the time of prostatectomy
Toxicity Profile of Each Dose (Number of Patients With Worst Grade Toxicity)	Toxicity will be assessed using the NIH-NCI Common Terminology Criteria for Adverse Events, version 3.0 (CTCAEv3.0)	at daily dose for 8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in PSA	Time-to-event data, such as change in PSA will be summarized using the method of Kaplan and Meier.	Up to 16 weeks after start of study

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of Treatment on Biological and Molecular Markers	Immunohistochemical Staining of Cellular and Molecular Markers in Prostate Tumor Tissue	After 8 weeks of therapy

Collaborators and Investigators

• Sponsor: Jorge A. Garcia, MD
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Jorge A. Garcia, MD, Case Comprehensive Cancer Center

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: September 1, 2007
• Primary Completion (Actual): July 1, 2011
• Study Completion (Actual): August 1, 2011

Study Registration Dates

• First Submitted: September 5, 2007
• First Submitted That Met QC Criteria: September 5, 2007
• First Posted (Estimate): September 10, 2007

Study Record Updates

• Last Update Posted (Actual): December 6, 2018
• Last Update Submitted That Met QC Criteria: November 14, 2018
• Last Verified: November 1, 2018

More Information

Terms related to this study

• Keywords: stage III prostate cancer; adenocarcinoma of the prostate; stage I prostate cancer; stage II prostate cancer
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Everolimus
• Other Study ID Numbers: CASE21806; P30CA043703 (U.S. NIH Grant/Contract); CASE-21806 (Other Identifier: Case Comprehensive Cancer Center); CASE-21806-CC256 (Other Identifier: Cancer Center IRB)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No