A Phase 2 Trial of Bevacizumab, Lenalidomide, Docetaxel, and Prednisone (ART-P) for Treatment of Metastatic Castrate-Resistant Prostate Cancer

NCT00942578 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 09019509-C-0195
• Study Type: interventional
• Target: 63
• Locations: 1 country
• Sites: 1

Brief Summary

Background:

• Prednisone and docetaxel have been used successfully in treating patients with prostate cancer, either when used alone or in combination with other agents. Researchers believe that these anticancer effects can be increased by giving them in this specific combination.
• A previous study at the National Cancer Institute combined docetaxel and prednisone with bevacizumab and thalidomide. The results of this study were promising; however, most patients in the study required a dose reduction of thalidomide because of its side effects.
• Lenalidomide, a drug similar to thalidomide, may have less severe side effects. Based on previous studies, lenalidomide is well tolerated in patients with solid tumors when used alone or in combination with docetaxel, and it may be a good substitute for thalidomide. Objectives:
• To determine if lenalidomide is an appropriate and effective substitute for thalidomide in treating prostate cancer.
• To evaluate the safety and effectiveness of bevacizumab, lenalidomide, docetaxel, and prednisone as a prostate cancer treatment, and to study any side effects. Eligibility: \- Men 18 years of age and older who have been diagnosed with metastatic prostate cancer that has not responded to standard treatment, including surgical removal of the testicles or treatment with androgen (sex-hormone) suppressing drugs. Design:
• Participants will have a complete medical history and physical examination before beginning the study.
• Patients will be treated with 21-day cycles with a combination of four drugs:
• (1) Docetaxel, which will be given into a vein for 60 minutes on the first day of each 21-day cycle. Patients will take dexamethasone (a steroid agent) before and after taking docetaxel.
• (2) Prednisone, which will be taken by mouth daily.
• (3) Bevacizumab, which will be given through a vein over 30 to 90 minutes on the first day of each 21-day cycle following the infusion of docetaxel.
• (4) Lenalidomide, which will be taken by mouth during the first 2 weeks of each 21-day cycle. The dose of lenalidomide may be adjusted if side effects develop.
• Patients will also receive enoxaparin, a subcutaneous injection administered daily, to prevent blood clots and/or pegfilgrastim, a subcutaneous injection on day 2 of each cycle, to improve white blood cell counts, as directed by researchers.

Conditions

Metastatic Prostate Cancer

Keywords

Dual Antiangiogenic Combination Therapy for mCRPC; Efficacy and Toxicity Profile; Single Stage Phase 2 With Early Stopping, Run In Phase For Toxicity; Correlative Measurements; Overall Survival Assessment; Metastatic Prostate Cancer; Prostate Cancer

Outcome Measures

Primary Outcomes (3)

• Recommended Phase 2 Dose (RP2D)

  The RP2D is the dose at which there are no dose-limiting toxicities (defined as a ≥grade 3 hematological toxicity related to lenalidomide).

  3 weeks

• Count of Participants With Dose-Limiting Toxicities (DLT)

  DLT is defined as a ≥grade 3 non-hematological toxicity related to lenalidomide.

  First 28 days of treatment.

• Median Time to Progression (TTP)

  TTP is evaluated from the on-study date until the date of progression or last follow-up after progression.

  median time of potential follow-up of 47.5 months

Secondary Outcomes (8)

• Median Overall Survival of Patients Studied

  median time of potential follow-up of 47.5 months

• Count of Participants With Changes in Circulating Apoptotic Endothelial Cells (CAEC) From Baseline After Drug Administration

  After drug administration, an average of 3 months

• Changes in the Molecular Markers of Angiogenesis (i.e Serum VEGF) Before and After Administration of Docetaxel, Prednisone,Lenalidomide and Bevacizumab

  median time of potential follow-up of 47.5 months

• Survival Based on Expression of Programmed Cell Death Protein 1 (PD-1) on Cluster of Differentiation 8 (CD8) + T Cells

  median time of potential follow-up of 47.5 months

• Survival Based on Expression of T Cell Immunoglobulin and Mucin Domain (TIM-3) on Cluster of Differentiation 8 (CD8) + T Cells

  46.5 months

Study Arms (1)

Single Arm - 4 Drug Combination

EXPERIMENTAL

A two dose level escalation of Lenalidomide from 15mg to 20mg to 25mg- standard 3+3 dose escalation approach in combination with docetaxel, Bevacizumab and prednisone.

Drug: Bevacizumab; Drug: Lenalidomide; Drug: Docetaxel; Drug: Prednisone

Interventions

Bevacizumab DRUG

15 mg/kg cycle 1 day 1, repeated every 21 days

Also known as: Avastin

Single Arm - 4 Drug Combination

Lenalidomide DRUG

Once daily days 1-14 of every 21

Also known as: Revlimid

Single Arm - 4 Drug Combination

Docetaxel DRUG

75 mg/m\^2 intravenous (IV) over 60 minutes on cycle 1 day 1, repeated every 21 days (a 3-week cycle)

Also known as: Taxotere

Single Arm - 4 Drug Combination

Prednisone DRUG

10 mg orally every day

Also known as: Deltasone

Single Arm - 4 Drug Combination

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Castrate-resistant metastatic adenocarcinoma of the prostate defined as progressive metastatic disease (see below) while on GnRH agonists or post surgical castration. All patients enrolled will be required to have evaluable disease on imaging studies.
• Histopathological documentation of prostate cancer confirmed in the NCI Laboratory of Pathology at the National Institutes of Health, the Pathology Department at Walter Reed Medical Center, or the Pathology Department at National Naval Medical Center, prior to starting this study. In addition, patients whose slides are lost or unavailable will be eligible for the study if they provide documentation of prostate cancer and if they meet criteria of clinically progressive prostate cancer as outlined (see below).
• Clinically progressive prostate cancer documented prior to entry. Progression must be evidenced and documented by any of the following parameters:
• i) Two consecutively rising prostatic specific-antigen (PSA) levels apart of 2 weeks
• ii) At least one new lesion on bone scans.
• iii) Progressive measurable disease.
• Patients must have undergone bilateral surgical castration or must continue on GnRH agonist.
• Those patients receiving an anti-androgen agent for at least 6 months and are entering the trial due to a rise in PSA must demonstrate a continued rise in PSA 4 weeks after stopping flutamide and 6 weeks after stopping bicalutamide or nilutamide.
• May not have received any chemotherapy or antiangiogenic therapy (including thalidomide, lenalidomide, bevacizumab and its targets receptor inhibitors) for metastatic prostate cancer. (Prior immunotherapy/vaccine, experimental hormonal therapy, radiation and (neo)adjuvant chemotherapy is permitted)
• Age greater than or equal to 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2
• Must have adequate organ and marrow function as defined below:
• Laboratory Test and Required Value:
• Leukocytes greater than or equal to 3,000/microL
• Absolute neutrophil count greater than or equal to 1,500/ microL

You may not qualify if:

• Present clinical signs or symptoms of current active brain and/or leptomeningeal metastases confirmed by computed tomography (CT) or magnetic resonance imaging (MRI) brain scan. Patients with previously treated brain metastases are allowed to participate in the study.
• Treated brain metastases are defined as having no ongoing requirement for steroids and no evidence of progression or hemorrhage after treatment for at least 3 months, as ascertained by clinical examination and brain imaging (MRI or CT). (Stable dose of anticonvulsants are allowed). Treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS; Gamma Knife, term linear accelerator (LINAC), or equivalent) or a combination as deemed appropriate by the treating physician. Patients with central nervous system (CNS) metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to Day 1 will be excluded.
• Uncontrolled, intercurrent illness including, but not limited to, symptomatic congestive heart failure (American Heart Association (AHA) Class II or worse), unstable angina pectoris
• Psychiatric illness/social situations that would limit compliance with study requirements.
• Prior history of hypertensive crisis or hypertensive encephalopathy
• Proteinuria, as demonstrated by a 24 hour protein of greater than or equal to 2000 mg. Urine protein should be screened by urine analysis. If urine dipstick is greater than 1.0+, then a 24 hour urine collection for total protein will need to be obtained and the level should be less than 2000 mg for patient enrollment.
• Serious, non-healing wound, active ulcer, or untreated bone fracture, including tumor-related pathological fracture
• Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)
• Human immunodeficiency virus (HIV)-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with docetaxel, bevacizumab, and/or the combination.
• Greater than Grade 2 peripheral neuropathy at baseline
• History of allergic reaction to docetaxel, prednisone, lenalidomide and/or bevacizumab or related products.
• Patients who are unable to ingest oral medication.
• Patients on treatment for venous thromboembolism (VTE).
• History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months prior to day 1
• Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to Day 1 therapy

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Hudes GR, Greenberg R, Krigel RL, Fox S, Scher R, Litwin S, Watts P, Speicher L, Tew K, Comis R. Phase II study of estramustine and vinblastine, two microtubule inhibitors, in hormone-refractory prostate cancer. J Clin Oncol. 1992 Nov;10(11):1754-61. doi: 10.1200/JCO.1992.10.11.1754.

  PMID: 1383436 BACKGROUND

• Hudes GR, Nathan F, Khater C, Haas N, Cornfield M, Giantonio B, Greenberg R, Gomella L, Litwin S, Ross E, Roethke S, McAleer C. Phase II trial of 96-hour paclitaxel plus oral estramustine phosphate in metastatic hormone-refractory prostate cancer. J Clin Oncol. 1997 Sep;15(9):3156-63. doi: 10.1200/JCO.1997.15.9.3156.

  PMID: 9294479 BACKGROUND

• Pienta KJ, Redman BG, Bandekar R, Strawderman M, Cease K, Esper PS, Naik H, Smith DC. A phase II trial of oral estramustine and oral etoposide in hormone refractory prostate cancer. Urology. 1997 Sep;50(3):401-6; discussion 406-7. doi: 10.1016/S0090-4295(97)00228-8.

  PMID: 9301705 BACKGROUND

MeSH Terms

Conditions

Prostatic Neoplasms

Interventions

Bevacizumab; Lenalidomide; Docetaxel; Prednisone

Condition Hierarchy (Ancestors)

Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Phthalimides; Phthalic Acids; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Piperidones; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Diterpenes; Terpenes; Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Results Point of Contact

• Title: Dr. Ravi Madan
• Organization: National Cancer Institute

rm480i@nih.gov

301-480-7168

Study Officials

• Ravi A Madan, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: July 18, 2009
• First Posted: July 21, 2009
• Study Start: July 16, 2009
• Primary Completion: July 31, 2017
• Study Completion: July 31, 2017
• Last Updated: October 11, 2018
• Results First Posted: October 11, 2018

Record last verified: 2018-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)