Everolimus as First-Line Therapy in Treating Patients With Prostate Cancer

Everolimus First-line Therapy in Non-rapidly Progressive Castration Resistant Prostate Cancer (CRPC). A Multicenter Phase II Trial.

RATIONALE: Everolimus 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.

PURPOSE: This phase II trial is studying the side effects of everolimus and to see how well it works as first-line therapy in treating patients with prostate cancer.

Study Overview

• Status: Completed
• Conditions: Prostate Cancer
• Intervention / Treatment: Drug: everolimus

Detailed Description

OBJECTIVES:

Primary

• Determine the progression-free survival at 12 weeks of patients with non-rapidly progressive castration-resistant prostate cancer treated with everolimus as first-line therapy.
• Assess the activity and safety of this regimen in these patients.

Secondary

• Determine the progression-free survival at 24 weeks of patients treated with this regimen.
• Determine the percentage of PSA response from baseline to 12 weeks in patients treated with this regimen.
• Determine the changes in PSA-doubling time in patients treated with this regimen.
• Determine the overall survival of patients treated with this regimen.

OUTLINE: This is a multicenter study.

Patients receive oral everolimus once daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed up at 28 days and then every 3 months.

• Study Type: Interventional
• Enrollment (Actual): 37
• Phase: Phase 2

Contacts and Locations

Study Locations

• Switzerland
  • Aarau, Switzerland, CH-5001
    • Kantonspital Aarau
  • Baden, Switzerland, 5404
    • Kantonsspital Baden
  • Basel, Switzerland, CH-4031
    • Universitaetsspital-Basel
  • Bern, Switzerland, CH-3010
    • Inselspital Bern
  • Biel, Switzerland, CH-2501
    • Spitalzentrum Biel
  • Chur, Switzerland, 7000
    • Kantonsspital Graubuenden
  • Geneva, Switzerland, CH-1211
    • Hôpital Cantonal Universitaire de Genève
  • Lausanne, Switzerland, CH-1011
    • Centre Hospitalier Universitaire Vaudois
  • Luzern, Switzerland, 6000
    • Kantonsspital Luzern
  • St. Gallen, Switzerland, CH-9007
    • Kantonsspital - St. Gallen
  • Winterthur, Switzerland, 8401
    • Kantonsspital Winterthur
  • Zurich, Switzerland, CH-8091
    • Universitaetsspital Zuerich
  • Zurich, Switzerland, 8091
    • Universitaetsspital Zuerich

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 confirmed metastatic or locally advanced adenocarcinoma of the prostate

  • No curative therapy available
  • Oligosymptomatic or asymptomatic patients

• Tumor progression after ≥ 1 hormonal treatment (orchiectomy or luteinizing-hormone releasing-hormone [LHRH] agonist) with documented total testosterone levels ≤ 1.7 nmol/L (≤ 50 ng/dL)

  • Concurrent LHRH agonist therapy is required for patients who have not been surgically castrated
  • Must have stopped antiandrogen therapy ≥ 6 weeks before the start of trial treatment without withdrawal response

• PSA progression defined as an increase in PSA ≥ 25% (and an absolute increase of 2 ng/mL or more) over nadir value on hormonal therapy measured on 3 successive occasions ≥ 1 week apart

  • If the third measurement is not higher than the second, a fourth measurement will be taken (patient allowed if the fourth measurement is higher than the second)
  • PSA doubling time ≥ 55 days
• No known or suspected CNS metastases

PATIENT CHARACTERISTICS:

• WHO performance status 0-1
• ANC ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• Hemoglobin ≥ 90 g/L
• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• AST ≤ 2.5 times ULN
• Creatinine clearance ≥ 40 mL/min

• Fasting serum cholesterol ≤ 7.75 mmol/L AND fasting triglycerides ≤ 2.5 times ULN

  • Appropriate lipid-lowering medication allowed in case one or both of these thresholds are exceeded
• Patient compliance and geographic proximity that would allow proper staging and follow-up are required
• No malignancy within the past 5 years except curatively treated localized nonmelanoma skin cancer or Ta and Tis bladder cancer
• No known history of HIV
• No serologically confirmed hepatitis B or C

• No serious underlying medical condition that, in the judgment of the investigator, could impair the ability of the patient to participate in the trial including, but not limited to, any of the following conditions:

  • Uncontrolled or acute severe infection
  • Uncontrolled diabetes
  • Advanced chronic obstructive pulmonary disease
• No psychiatric disorder precluding understanding of information on trial-related topics, giving informed consent, or interfering with compliance for oral drug intake
• No known hypersensitivity to trial drug or hypersensitivity to any of its components

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No prior chemotherapy, radioisotopes, small molecules, immunotherapy, or investigational drug therapy for prostate cancer
• No local radiotherapy within the past 2 weeks
• No major surgery within the past 4 weeks
• No concurrent radiotherapy
• No concurrent angiotensin converting enzyme inhibitors
• No concurrent chronic immunosuppressive therapy including high-dose corticosteroids (i.e., > 25 mg prednisone equivalent per day)
• No products known to affect PSA levels (e.g., PC Calm, PC Plus, PC SPES, finasteride, or fluconazole) within the past 4 weeks or concurrently
• No strong CYP3A4 inhibitors (e.g., itraconazole, erythromycin, clarithromycin, diltiazem, verapamil, or grapefruit or its juice) within the past 2 weeks or concurrently
• No strong CYP3A4 inducers (e.g., phenytoin, rifampicin, carbamazepine, phenobarbital, or St. John wort) within the past 2 weeks or concurrently

• No concurrent bisphosphonates

  • Patients must continue to receive bisphosphonates regularly if it was started prior to entering the trial
• No concurrent experimental drugs or other anticancer therapy in a clinical trial within the past 30 days
• No concomitant drugs contraindicated for use with the trial drug according to the investigator's drug brochure

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A: Everolimus; Everolimus: 10mg daily	Drug: everolimus; Everolimus: 10mg daily; Other Names: RAD001; Afinitor®; Votubia®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS) at 12 weeks	PFS at 12 weeks is defined as the absence of disease progression or death at 12 weeks after start of treatment.	at 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PFS at 24 weeks	PFS at 24 weeks is defined as the absence of any disease progression or death at 24 weeks after start of treatment.	at 24 weeks
Progression-free survival	from start of treatment until progression or death of any cause, whereas it will be censored at the last follow-up visit or initiation of a different treatment.	from start of treatment until progression or death of any cause
Adverse events (AEs) according to NCI CTCAE v. 3.0	All AEs will be assessed according to NCI CTCAE v3.0	from start of treatment until progression or death of any cause
PSA response	50% PSA response is defined as a decrease in PSA level of at least 50% (compared to baseline PSA). 30% PSA response is defined as a decrease in PSA level of at least 30% (compared to baseline PSA). Best response is defined as the percentage of change in PSA from baseline to the maximum decline in PSA at any point under treatment. Response at 12 weeks is defined as the percentage of change in PSA from baseline to 12 weeks (or earlier for those patients who discontinue therapy, in this case last PSA values recorded should be taken).	50% and 30%, best and at 12 weeks
Changes in PSA-doubling time	PSA-DT is calculated by natural log of 2 divided by the slope of the relationship between the log of PSA and time of PSA measurement for each patient.	Time points for later calculations include: after 12 weeks, after 24 weeks and at best PSA response
Tumor assessment of measurable disease according to RECIST v1.1 criteria	For patients with measurable disease at baseline RECIST v1.1 will be used to define CR, PR, SD and PD.	The first assessment will be performed after 12 weeks of treatment, or earlier if clinically indicated.
Tumor assessment of bone lesions	Bone metastases can be assessed by radionuclide bone scan.	at 12 weeks.

Collaborators and Investigators

• Sponsor: Swiss Group for Clinical Cancer Research
• Investigators: Study Chair: Silke Gillessen, MD, Cantonal Hospital of St. Gallen; Principal Investigator: Arnoud Templeton, MD, Cantonal Hospital of St. Gallen

Publications and helpful links

General Publications

• Templeton A, Rothermundt C, Cathomas R, et al.: Everolimus as first-line therapy in nonrapidly progressive metastatic castration-resistant prostate cancer (mCRPC): A multicenter phase II trial (SAKK 08/08). [Abstract] J Clin Oncol 29 (Suppl 15): A-4588, 2011.
• Templeton AJ, Dutoit V, Cathomas R, Rothermundt C, Bartschi D, Droge C, Gautschi O, Borner M, Fechter E, Stenner F, Winterhalder R, Muller B, Schiess R, Wild PJ, Ruschoff JH, Thalmann G, Dietrich PY, Aebersold R, Klingbiel D, Gillessen S; Swiss Group for Clinical Cancer Research (SAKK). Phase 2 trial of single-agent everolimus in chemotherapy-naive patients with castration-resistant prostate cancer (SAKK 08/08). Eur Urol. 2013 Jul;64(1):150-8. doi: 10.1016/j.eururo.2013.03.040. Epub 2013 Apr 6.

Study record dates

Study Major Dates

• Study Start (Actual): September 14, 2009
• Primary Completion (Actual): November 29, 2012
• Study Completion (Actual): August 8, 2019

Study Registration Dates

• First Submitted: September 11, 2009
• First Submitted That Met QC Criteria: September 11, 2009
• First Posted (Estimate): September 14, 2009

Study Record Updates

• Last Update Posted (Actual): August 9, 2019
• Last Update Submitted That Met QC Criteria: August 8, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: stage III prostate cancer; stage IV prostate cancer; adenocarcinoma of the prostate; hormone-resistant 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: SAKK 08/08; SWS-SAKK-08/08; EU-20967; CDR0000649049

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO