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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Metastatic Prostate Cancer

Intervention / Treatment
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* Drug: Bevacizumab
* Drug: Lenalidomide
* Drug: Docetaxel
* Drug: Prednisone


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm - 4 Drug Combination<br>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<br>* 15 mg/kg cycle 1 day 1, repeated every 21 days<br>* Other names: Avastin;Drug: Lenalidomide<br>* Once daily days 1-14 of every 21<br>* Other names: Revlimid;Drug: Docetaxel<br>* 75 mg/m^2 intravenous (IV) over 60 minutes on cycle 1 day 1, repeated every 21 days (a 3-week cycle)<br>* Other names: Taxotere;Drug: Prednisone<br>* 10 mg orally every day<br>* Other names: Deltasone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Overall Survival of Patients Studied | OS is evaluated from the on-study date until the date of death or last follow-up. | 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 | The definition of an increase is any increase (any number greater than zero) in the percent CAEC among total peripheral blood mononuclear cells comparing each patient's percent CAEC among total peripheral blood mononuclear cells at baseline to each patient's percent CAEC among total peripheral blood mononuclear cells at cycle 3 day 1. The definition of a decrease is any decrease (any number less than zero) in the percent CAEC among total peripheral blood mononuclear cells comparing each patient's percent CAEC among total peripheral blood mononuclear cells at baseline to each patient's percent CAEC among total peripheral blood mononuclear cells at cycle 3 day 1. | 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 | Serum and urine samples were collected before and after administration of Docetaxel, Prednisone, Lenalidomide and Bevacizumab to measure VEGF levels. | 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 | Expression of PD-1 on CD8 + T cells was evaluated by flow cytometry. High and low expression are based on the median values. Patients with a low expression of PD-1 proteins had better survival than those with a high expression. | 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 | Expression of TIM-3 on CD8 + T cells was evaluated by flow cytometry. | 46.5 months | 
| Count of Participants With a Radiologic Response | Radiologic response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.0 criteria. Complete response is disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Progressive disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). Stable disease is neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. | median time of potential follow-up of 47.5 months | 
| Count of Participants With Prostatic Antigen-Specific (PSA) Declines | PSA decline is defined as a ≥50% decline in measurable disease. Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥20 mm by chest x-ray, as ≥10 mm with computed tomography, or ≥10 mm with calipers by clinical exam. | median time of potential follow-up of 47.5 months | 
| Count of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) Who Were Administered the Four-Drug Combination | Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. | Date treatment consent signed to date off study, approximately 93 months and 22 days. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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