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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT00942578
First received: July 18, 2009
Last updated: November 20, 2014
Last verified: November 2014
  Purpose

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.

Condition Intervention Phase
Metastatic Prostate Cancer
Drug: Bevacizumab
Drug: Lenalidomide
Drug: Docetaxel
Drug: Prednisone
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 2 Trial of Bevacizumab, Lenalidomide, Docetaxel, and Prednisone (ART-P) for Treatment of Metastatic Castrate-Resistant Prostate Cancer

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Safety of adding lenalidomide to a regimen containing bevacizumab,docetaxel and prednisone [ Time Frame: Dose Limiting Toxicity ] [ Designated as safety issue: Yes ]
  • Efficacy of lenalidomide with this drug regimen [ Time Frame: Disease progression ] [ Designated as safety issue: No ]

Enrollment: 63
Study Start Date: July 2009
Estimated Study Completion Date: June 2015
Estimated Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Single Arm
A two dose level escalation of Lenalidomide from 15mg to 20mg to 25mg- standard 3+3 dose escalationapproach in combination with docetaxel, Bevacizumab and prednisone.
Drug: Bevacizumab
15 mg/kg cycle 1 day 1, repeated every 21 days
Drug: Lenalidomide
Once daily days 1-14 of every 21
Drug: Docetaxel
75 mg/m2 IV over 60 minutes on cycle 1 day 1, repeated every 21 days (a 3-week cycle)
Drug: Prednisone
10 mg orally every day

  Hide Detailed Description

Detailed Description:

Background:

The dual antiangiogenic therapy with bevacizumab and thalidomide in combination with docetaxel and prednisone (ATTP) is highly active in patients with metastatic castration resistant prostate cancer (mCRPC), associated with unprecedented results (90% patients had PSA declines of greater than or equal to 50% and 64% ORR in measurable disease).

Most patients in the ATTP trial required dose reduction due to thalidomide toxicities.

Lenalidomide, an analogue of thalidomide, possesses both antiangiogenesis and inhibition of TNF-alpha, but has a favorable toxicity profile. Lenalidomide is well tolerated in patients with solid tumors when used alone or in combination with docetaxel.

To preserve the efficacy of ATTP and to potentially reduce toxicity, lenalidomide may be a good substitute for thalidomide.

Objectives

Primary:

To assess if lenalidomide at its approved dosing schedule can be safely combined with docetaxel, bevacizumab, and prednisone in patients with mCRPC (less than 25% Grade 4 toxicity)

To evaluate the efficacy of the combination

Secondary:

To evaluate overall survival of the enrolled patients and the toxicity profile of the combination

To evaluate circulating prostate cancer cells before and after drug administration

To measure circulating apoptotic endothelial cells before and after drug administration and to correlate with efficacy of the combination

To determine whether there are changes in the molecular markers of angiogenesis before and after administration of the combination

To analyze the patients genotype with regard to genes involved in transport and metabolization of these agents to correlate that with efficacy

Eligibility:

Patients with progressive mCRPC who have not received any chemotherapy or antiangiogenic therapy for mCRPC

Design:

A single-stage Phase 2 study, with an early stopping rule for excessive toxicity: the goal is to enroll 45 patients at the 25-mg dose level of lenalidomide. However, if 7 in the first 18 or fewer patients receiving lenalidomide at 25 mg develop grade 4 non-hematologic toxicity at anytime during study, no further patients will be enrolled. With respect to the stopping rule, a grade 4 hematologic toxicity will be considered if the episode has lasted for greater than or equal to 5 days. Grade 4 lymphopenia of any duration will not be counted. If less than 7 of the first 18 patients experience the above level of toxicity, accrual will continue until 45 patients have been enrolled at the 25 mg dose level of lenalidomide.

A run-in phase with lenalidomide at 15 mg will be conducted in the first three patients and at 20mg for the next three patients for assessing its tolerability within the combination prior to dosing at 25 mg thereafter.

An expansion cohort of a lower dose of lenalidomide (15 mg) in combination with docetaxel and and Avastin will be conducted to asses if this lower dose of lenalidomide could have similar efficacy with less toxicity.

Treatment Schema of ART-P

Dex -Dexamethasone 8 mg. po 12 hours pre, 3 hours pre, and 1 hour pre infusion of docetaxel (patients who were on prior regimen which included a lower dose of decadron and did not have a reaction do not have to increase their decadron to the 8 mg dose)

Len - Lenalidomide 25 mg po, days 1-14. Lenalidomide 15 mg and 20mg for the proposed run-in phase. Lenalidomide 15 mg for the expansion cohort.

Doc - Docetaxel 75 mg/m2 IV

Bev - Bevacizumab 15 mg/kg IV

Pre - Prednisone 10 mg PO daily throughout cycle

E - Enoxaparin given SQ daily based on weight (see dosing chart in section 4.2)

Peg - Pegfilgrastim 6mg SQ given at least 24 hours after docetaxel administration

Baseline screening evaluations are to be conducted within 15 days prior to protocol enrollment. Baseline scans and x-rays must be performed 4 weeks prior to protocol enrollment. Patients must be evaluated at the NCI clinic each cycle for treatment continuation. Staging scans will be performed after the first 2 cycles of treatment and then every three cycles. All follow-up evaluations can be done on the last week of the prior cycle.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

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 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 target s 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

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
  • Platelets greater than or equal to 100,000/ microL
  • Total bilirubin less than or equal to 1.5 times the institutional upper limits of normal, or less than or equal to 3 mg/dl in a subject with Gilbert Syndrome
  • AST (SGOT) and ALT (SGPT) less than or equal to 2.5 times the institutional upper limit of normal
  • Creatinine less than or equal to 1.5 times the institutional upper limits of normal

OR

-Creatinine clearance greater than or equal to 50 mL/min/1.73 m(2) for patients with creatinine levels above institutional normal.

Recovered from any acute toxicity from surgery or radiotherapy, with minimum 4 weeks from major surgical procedures and 2 weeks from radiotherapy

Must be willing to travel from their home to the NIH for follow-up visits

Able and willing to follow instructions and conform to protocol.

Patients may have had no other active malignancy within the past 2 years with the exception of non-melanoma skin cancer and superficial bladder carcinoma.

No history of myocardial infarction within the past 6 months, uncontrolled CHF or uncontrolled angina pectoris

Patients must agree to use adequate contraception (abstinence; hormonal or barrier method of birth control) prior to the study, during the study, and at least six months after completion. Males must agree to use a latex condom during sexual contact with females of childbearing potential while participating in the study and for at least six months following, even if a man has undergone a successful vasectomy. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure as indicated in the consent.

Subjects must agree not to share study drug and not donate blood, sperm, or semen. A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).

Ability to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

Present clinical signs or symptoms of current active brain and/or leptomeningeal metastases confirmed by CT or 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, LINAC, or equivalent) or a combination as deemed appropriate by the treating physician. Patients with 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 (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)

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 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

Anticipation of need for major surgical procedures during the course of the study

Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to Day 1

Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair, aortic dissection or recent peripheral arterial thrombosis) within 6 months prior to Day 1

Patients with clinically significant cardiovascular disease are excluded

  • Inadequately controlled HTN (SBP greater than 160 mmHg and/or DBP greater than 90 mmHg despite antihypertensive medication)
  • History of CVA within 6 months (see additional requirement for adjuvant protocols), myocardial infarction or unstable angina within 6 months (see additional requirement for adjuvant protocols)
  • New York heart association grade II or greater congestive heart failure
  • Serious and inadequately controlled cardiac arrhythmia
  • Clinically significant vascular disease as stated above

Patients with known hypersensitivity of Chinese hamster ovary cell products or other recombinant human antibodies

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00942578

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
Investigators
Principal Investigator: William L Dahut, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier: NCT00942578     History of Changes
Other Study ID Numbers: 090195, 09-C-0195
Study First Received: July 18, 2009
Last Updated: November 20, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
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

Additional relevant MeSH terms:
Prostatic Neoplasms
Genital Diseases, Male
Genital Neoplasms, Male
Neoplasms
Neoplasms by Site
Prostatic Diseases
Urogenital Neoplasms
Bevacizumab
Docetaxel
Lenalidomide
Prednisone
Thalidomide
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Anti-Bacterial Agents
Anti-Infective Agents
Anti-Inflammatory Agents
Antimitotic Agents
Antineoplastic Agents
Antineoplastic Agents, Hormonal
Glucocorticoids
Growth Inhibitors
Growth Substances
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Immunologic Factors
Immunosuppressive Agents
Leprostatic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on November 20, 2014