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

Phase 2
18 Years
Open (Enrolling)
Metastatic Prostate Cancer

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Trial Information

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


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.



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

To evaluate the efficacy of the combination


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

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


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


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

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

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

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


-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.


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

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

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

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To assess safety of Lenalidomide at approved dosing schedule when combined with Docetaxel, Bevacizumab, and Prednisone in patients with mCRPC as measured by less than 25% Grade 4 toxicity and evaluation of the efficacy of the drug combination.

Principal Investigator

William L Dahut, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)


United States: Federal Government

Study ID:




Start Date:

July 2009

Completion Date:

July 2013

Related Keywords:

  • Metastatic Prostate Cancer
  • 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
  • Prostatic Neoplasms



National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892