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

• ClinicalTrials.gov Identifier: NCT01051570
• Recruitment Status: Completed
• First Posted: January 18, 2010
• Results First Posted: August 25, 2014
• Last Update Posted: December 1, 2020
• Sponsor: Barbara Ann Karmanos Cancer Institute
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Elisabeth Heath, Barbara Ann Karmanos Cancer Institute

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Prostate Cancer	Drug: carboplatin; Drug: RAD 001; Drug: prednisone; Other: laboratory biomarker analysis; Other: pharmacological study	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 26 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Trial of Carboplatin and Everolimus (RAD001) in Metastatic Castrate Resistant Prostate Cancer (CRPC) Pretreated With Docetaxel Chemotherapy.
• Study Start Date: February 2010
• Actual Primary Completion Date: September 2013
• Actual Study Completion Date: September 2013

Arms and Interventions

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 Name: Paraplatin®; Drug: RAD 001; 5 mg orally starting on Day 2 then continuous; Other Names: Afinitor®; Zortress; Everolimus; Drug: prednisone; 5 mg orally twice a day starting on Day 1 then continuous; Other Names: Deltasone; Liquid Pred; Meticorten; Orasone; Prednicen-M; 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

Outcome Measures

Primary Outcome Measures :

1. 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.

Secondary Outcome Measures :

1. 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
2. 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
3. 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)
4. 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.
5. 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

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, Illinois

Northshore University Health System

Evanston, Illinois, United States, 60201

United States, Michigan

Barbara Ann Karmanos Cancer Institute

Detroit, Michigan, United States, 48201-1379

Weisberg Cancer Treatment Center

Farmington Hills, Michigan, United States, 48334

United States, New Jersey

Cancer Institute of New Jersey

New Brunswick, New Jersey, United States, 08903

Sponsors and Collaborators

Barbara Ann Karmanos Cancer Institute

National Cancer Institute (NCI)

Investigators

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

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ&#174; database 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Vaishampayan U, Shevrin D, Stein M, Heilbrun L, Land S, Stark K, Li J, Dickow B, Heath E, Smith D, Fontana J. Phase II Trial of Carboplatin, Everolimus, and Prednisone in Metastatic Castration-resistant Prostate Cancer Pretreated With Docetaxel Chemotherapy: A Prostate Cancer Clinical Trial Consortium Study. Urology. 2015 Dec;86(6):1206-11. doi: 10.1016/j.urology.2015.08.008. Epub 2015 Sep 12.

• Responsible Party: Elisabeth Heath, Principal Investigator, Barbara Ann Karmanos Cancer Institute
• ClinicalTrials.gov Identifier: NCT01051570
• Other Study ID Numbers: CDR0000663630; P30CA022453 ( U.S. NIH Grant/Contract ); WSU-2009-087; NOVARTIS-WSU-2009-087
• First Posted: January 18, 2010
• Results First Posted: August 25, 2014
• Last Update Posted: December 1, 2020
• Last Verified: November 2020

Keywords provided by Elisabeth Heath, Barbara Ann Karmanos Cancer Institute:

hormone-resistant prostate cancer; recurrent prostate cancer; stage IV prostate cancer; adenocarcinoma of the prostate

Additional relevant MeSH terms:

Prostatic Neoplasms; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Prostatic Diseases; Prednisone; Carboplatin; Everolimus; Antineoplastic Agents; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Antineoplastic Agents, Hormonal; Immunosuppressive Agents; Immunologic Factors