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

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

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.

- 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 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

- 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

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase (SGOT) and
alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase (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 National Institutes of Health (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 congestive heart
failure (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 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

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 hypertension (HTN) (systolic blood pressure (SBP) greater than
160 mmHg and/or diastolic blood pressure (DBP) greater than 90 mmHg despite
antihypertensive medication)

- History of cerebrovascular accident (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