Carboplatin, Everolimus, and Prednisone in Treating Patients With Metastatic Prostate Cancer That Progressed After Docetaxel

November 6, 2020 updated by: Elisabeth Heath, Barbara Ann Karmanos Cancer Institute

Phase II Trial of Carboplatin and Everolimus (RAD001) in Metastatic Castrate Resistant Prostate Cancer (CRPC) Pretreated With Docetaxel Chemotherapy.

RATIONALE: Drugs used in chemotherapy, such as carboplatin and prednisone, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. 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. Giving carboplatin together with everolimus and prednisone may kill more tumor cells.

PURPOSE: This phase II trial is studying how well giving carboplatin together with everolimus and prednisone works in treating patients with metastatic prostate cancer that progressed after docetaxel.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

OBJECTIVES:

Primary

  • To evaluate the time to progression (TTP) achieved with carboplatin and everolimus in patients with castrate resistant metastatic prostate cancer that progressed after docetaxel-based chemotherapy.

Secondary

  • To evaluate the safety of this regimen.
  • To assess the PSA response rate in patients treated with this regimen.
  • To evaluate the overall survival (OS) outcome in these patients.
  • To investigate the association of TTP and PSA response rate with correlative markers, such as phospho mTOR, pAKT, and p70S6.
  • To evaluate the pharmacokinetics of this regimen.
  • To explore the association of TTP, OS, and circulating tumor tumor cell count.

OUTLINE: Patients receive carboplatin IV over 30-60 minutes on day 1, oral prednisone twice daily on days on days 1-21, and oral everolimus once daily on days 2-21 of course 1 and on days 1-21 of subsequent courses. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Blood and tumor tissue samples are collected periodically for pharmacodynamic, pharmacokinetic, and biomarker analysis.

After completion of study treatment, patients are followed up every 3 months.

Study Type

Interventional

Enrollment (Actual)

26

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Illinois
      • Evanston, Illinois, United States, 60201
        • NorthShore University Health System
    • Michigan
      • Detroit, Michigan, United States, 48201-1379
        • Barbara Ann Karmanos Cancer Institute
      • Farmington Hills, Michigan, United States, 48334
        • Weisberg Cancer Treatment Center
    • New Jersey
      • New Brunswick, New Jersey, United States, 08903
        • Cancer Institute Of New Jersey

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

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 adenocarcinoma of the prostate
  • Objective disease progression or rising PSA despite androgen deprivation therapy and antiandrogen withdrawal (when applicable)

  • Progressed after ≥ 1 prior docetaxel-based chemotherapy regimen for metastatic disease

    • Patients with measurable disease* must have either rising PSA, increase in size of the lesion(s), or both

      • Patients with rising PSA as the only evidence of disease progression must demonstrate a rising trend with 2 successive elevations ≥ 1 week apart
    • Patients with no measurable disease must have a PSA ≥ 5 ng/mL or new areas of bony metastases on bone scan NOTE: *There is no minimum PSA requirement for patients with measurable disease

  • Documented to be castrate with a testosterone level of ≤ 0.5 ng/mL

    • Leuteinizing hormone-releasing hormone agonist therapy must be continued, if required to maintain castrate levels of testosterone
  • No uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases

PATIENT CHARACTERISTICS:

  • Zubrod performance status 0-1
  • ANC ≥ 1,500/mm^3
  • Hemoglobin ≥ 9.0 g/dL
  • Platelet count ≥ 100,000/mm^3
  • Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
  • Calculated creatinine clearance ≥ 50 mL/min OR serum creatinine ≤ 2 mg/dL
  • AST and/or ALT ≤ 2.5 times ULN if alkaline phosphatase normal OR alkaline phosphatase ≤ 4 times ULN if AST and/or ALT normal (for patients without documented bone metastases or for patients with liver metastases)
  • AST and/or ALT < 2.5 times ULN, without regard to alkaline phosphatase levels (for patients with documented bone metastases)
  • Fasting serum cholesterol ≤ 300 mg/dL OR ≤ 7.75 mmol/L AND fasting triglycerides ≤ 2.5 times ULN (in the case that one or both of these thresholds are exceeded, the patient is eligible only after initiation of appropriate lipid-lowering medication)
  • Fertile patients must use effective contraception during and for ≥ 6 months after completion of study treatment
  • Willing and able to comply with this study
  • Able to ingest oral medication
  • No other malignancies except non-melanoma skin cancer or any other adequately treated cancer in complete remission for ≥ 2 years
  • No significant traumatic injury within the past 4 weeks
  • No active (acute or chronic) or uncontrolled severe infections

  • No severe and/or uncontrolled medical conditions or other conditions that could affect study participation, including the following:

    • NYHA class III-IV symptomatic congestive heart failure
    • Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within the past 6 months, serious uncontrolled cardiac arrhythmia, or any other clinically significant cardiac disease
    • Severely impaired lung function as defined by spirometry and DLCO that is 50% of the normal predicted value and/or oxygen saturation that is ≤ 88% at rest on room air
    • Uncontrolled diabetes as defined by fasting serum glucose > 1.5 times ULN
    • Liver disease such as cirrhosis, chronic active hepatitis, or chronic persistent hepatitis
    • Known history of HIV seropositivity, hepatitis B or C
    • Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of everolimus (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
    • Active, bleeding diathesis
  • No known hypersensitivity to everolimus or other rapamycins (sirolimus, temsirolimus) or to their excipients
  • No history of noncompliance to medical regimens
  • No uncontrolled diabetes mellitus

PRIOR CONCURRENT THERAPY:

  • See Disease Characteristics

  • At least 1 prior docetaxel based regimen for metastatic disease

    • Docetaxel based combination therapy or docetaxel alone considered as 1 regimen
  • No more than 2 prior chemotherapy regimens for metastatic disease
  • No prior treatment with an mTOR inhibitor (sirolimus, temsirolimus, everolimus)
  • At least 6 weeks since prior bicalutamide or nilutamide
  • At least 4 weeks since prior flutamide
  • More than 4 weeks since prior and no other concurrent investigational drugs
  • More than 4 weeks since prior and no other concurrent anticancer therapies (including chemotherapy, radiotherapy, or antibody-based therapy)
  • More than 4 weeks since prior and no concurrent major surgery (defined as requiring general anesthesia) and recovered
  • More than 1 week since prior and no concurrent immunization with attenuated live vaccines

  • No concurrent chronic, systemic treatment with corticosteroids or other immunosuppressive agents

    • Topical or inhaled corticosteroids are allowed
  • No concurrent prophylactic growth factors
  • Concurrent bisphosphonate therapy allowed

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Carboplatin, RAD 001 & Prednisone

Carboplatin: AUC=4 by Calvert's formula (max dose 600 mg)*IV over 30-60 min, Day 1 of a 21 day cycle

RAD 001: 5 mg Orally daily, starting from Day 2 continuously

Prednisone 5 mg Orally twice daily, continuously
Drug: carboplatin
AUC = 5 by Calvert's formula, day 1 of each 21 day cycle
Other Names:
  • Paraplatin®
Drug: RAD 001
5 mg orally starting on Day 2 then continuous
Other Names:
  • Zortress
  • Afinitor®
  • Everolimus
Drug: prednisone
5 mg orally twice a day starting on Day 1 then continuous
Other Names:
  • Deltasone
  • Orasone
  • Meticorten
  • Prednicen-M
  • Liquid Pred
  • Prednicot
  • Sterapred
  • Sterapred DS
Other: laboratory biomarker analysis
Samples will be collected from archival tissue.
Other: pharmacological study
Samples will be collected Cycle 1, day 1, 2 & 8 and Cycle 2, Day 1 & 2

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Time to Progression (TTP)
Time Frame: Up to 63 days while on treatment, then up 90 days thereafter. From date of registration to date of progressive disease.
Progression defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions taking as references the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.
Up to 63 days while on treatment, then up 90 days thereafter. From date of registration to date of progressive disease.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Participants With Toxicity as Measured by NCI CTCAE v3.0 Criteria
Time Frame: Day 1 of each cycle (every 21 days), through study completion, an average of 6 months
Number of Participants with Grade 3/4 Toxicity as measured by NCI CTCAE v3.0 criteria
Day 1 of each cycle (every 21 days), through study completion, an average of 6 months
PSA Response Rate
Time Frame: Day 1 of each cycle (every 21 days), through study completion, an average of 6 months
PSA response rate with response defined as => a 30% reduction in PSA
Day 1 of each cycle (every 21 days), through study completion, an average of 6 months
Association of PSA Response Rate With Correlative Markers (Phospho mTOR, pAKT, and p70S6)
Time Frame: Archival tissue will be collected if available. Optional biopsies pre-treatment and 24 hours after first everolimus and carboplatin dose
PSA response defined as a decrease of 30% or more will be tabled against mTOR, pAKT, and p70S6 (1+, 2+, 3+ vs ND)
Archival tissue will be collected if available. Optional biopsies pre-treatment and 24 hours after first everolimus and carboplatin dose
Pharmacokinetics: Observed Carboplatin AUC Was Estimated Based on the Concentration in the 2.75-h Sample.
Time Frame: Samples were collected Cycle 2, Day 1
Using a limited sampling model (i.e., AUC = 0.52 × C2.75h + 0.92) (Sorensen et al., 1993), observed carboplatin AUC was estimated based on the concentration in the 2.75-h sample.
Samples were collected Cycle 2, Day 1
Overall Survival
Time Frame: After treatment, participants will be contacted every 3 months up to 4 years
Overall Survival as measured by the Kaplan-Meier method
After treatment, participants will be contacted every 3 months up to 4 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Barbara Ann Karmanos Cancer Institute

Collaborators

National Cancer Institute (NCI)

Investigators

  • Principal Investigator: Ulka N. Vaishampayan, M.D., Barbara Ann Karmanos Cancer Institute

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

February 1, 2010

Primary Completion (Actual)

September 1, 2013

Study Completion (Actual)

September 1, 2013

Study Registration Dates

First Submitted

January 15, 2010

First Submitted That Met QC Criteria

January 15, 2010

First Posted (Estimate)

January 18, 2010

Study Record Updates

Last Update Posted (Actual)

December 1, 2020

Last Update Submitted That Met QC Criteria

November 6, 2020

Last Verified

November 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CDR0000663630
  • P30CA022453 (U.S. NIH Grant/Contract)
  • WSU-2009-087
  • NOVARTIS-WSU-2009-087

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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