Metastatic Prostate CancerPhase 2NCT00942578
A Phase 2 Trial of Bevacizumab, Lenalidomide, Docetaxel, and Prednisone (ART-P) for Treatment of Metastatic Castrate-Resistant Prostate Cancer
A Phase 2 study testing Bevacizumab, Lenalidomide and Docetaxel in people with Metastatic Prostate Cancer, run by National Cancer Institute (NCI) at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 100 years, men only
- Conditions the study is for
- Metastatic Prostate Cancer
- What is being tested?
- Bevacizumab, Lenalidomide and Docetaxel
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 63 participants
- Where
- 1 siteUnited States
- Study dates
- 16 Jul 2009to 31 Jul 2017
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 100 years
- Men only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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:
- Two consecutively rising prostatic specific-antigen (PSA) levels apart of 2 weeks
- At least one new lesion on bone scans.
- Progressive measurable disease.
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- 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.
Who cannot join
- 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.
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- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
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.
Read more
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.
Read the 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
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.
- Conditions
- Metastatic Prostate Cancer
- Being tested
- Bevacizumab, Lenalidomide, Docetaxel, Prednisone
- 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
- Medical subject headings
- Prostatic Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
BevacizumabDrug
Also called Avastin
15 mg/kg cycle 1 day 1, repeated every 21 days
LenalidomideDrug
Also called Revlimid
Once daily days 1-14 of every 21
DocetaxelDrug
Also called Taxotere
75 mg/m^2 intravenous (IV) over 60 minutes on cycle 1 day 1, repeated every 21 days (a 3-week cycle)
PrednisoneDrug
Also called Deltasone
10 mg orally every day
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: Bevacizumab; Drug: Lenalidomide; Drug: Docetaxel; Drug: Prednisone |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: 3 weeks
Count of Participants With Dose-Limiting Toxicities (DLT)
DLT is defined as a ≥grade 3 non-hematological toxicity related to lenalidomide.
Measured: 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.
Measured: median time of potential follow-up of 47.5 months
Secondary outcomes (8)
Median Overall Survival of Patients Studied
OS is evaluated from the on-study date until the date of death or last follow-up.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Date treatment consent signed to date off study, approximately 93 months and 22 days.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Jul 2009 (estimated)
- Study start16 Jul 2009
- Primary completion31 Jul 2017
- Study completion31 Jul 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Metastatic Prostate CancerStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 63 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Principal investigator, Ravi A. Madan, M.D., National Institutes of Health Clinical Center (CC)
- Investigators
- Ravi A Madan, M.D., Principal investigator, National Cancer Institute (NCI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00942578
- Sponsor's protocol ID
- 090195
- Other IDs
- 09-C-0195
- Status last verified
- Sep 2018
- First submitted
- 18 Jul 2009
- Last updated
- 11 Oct 2018
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 1383436Hudes 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.
PubMed 9294479Pienta 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.
PubMed 9301705
Study at a glance
From the registry record, last updated by the sponsor on 11 Oct 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 2 Trial of Bevacizumab, Lenalidomide, Docetaxel, and Prednisone (ART-P) for Treatment of Metastatic Castrate-Resistant Prostate Cancer
- ClinicalTrials.gov ID
- NCT00942578
- Acronym / sponsor ID
- 090195
- 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
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 63 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- 16 Jul 2009 (actual)
- Primary completion
- 31 Jul 2017 (actual)
- Study completion
- 31 Jul 2017 (actual)
- First posted
- 21 Jul 2009 (estimated)
- Results
- Posted 11 Oct 2018
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Single Arm - 4 Drug Combination | Experimental | Drug: Bevacizumab, Drug: Lenalidomide, Drug: Docetaxel, Drug: PrednisoneA 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. |
Who may qualify
- Ages
- 18 to 100 years
- Sex
- Male only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (29 listed)
- 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:
- Two consecutively rising prostatic specific-antigen (PSA) levels apart of 2 weeks
- At least one new lesion on bone scans.
Key exclusion criteria (25 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| BevacizumabAlso: Avastin15 mg/kg cycle 1 day 1, repeated every 21 days | Drug | Single Arm - 4 Drug Combination |
| LenalidomideAlso: RevlimidOnce daily days 1-14 of every 21 | Drug | Single Arm - 4 Drug Combination |
| DocetaxelAlso: Taxotere75 mg/m^2 intravenous (IV) over 60 minutes on cycle 1 day 1, repeated every 21 days (a 3-week cycle) | Drug | Single Arm - 4 Drug Combination |
| PrednisoneAlso: Deltasone10 mg orally every day | Drug | Single Arm - 4 Drug Combination |
Primary outcome
Recommended Phase 2 Dose (RP2D)
Time frame: 3 weeks
The RP2D is the dose at which there are no dose-limiting toxicities (defined as a ≥grade 3 hematological toxicity related to lenalidomide).
Count of Participants With Dose-Limiting Toxicities (DLT)
Time frame: First 28 days of treatment.
DLT is defined as a ≥grade 3 non-hematological toxicity related to lenalidomide.
Median Time to Progression (TTP)
Time frame: median time of potential follow-up of 47.5 months
TTP is evaluated from the on-study date until the date of progression or last follow-up after progression.
8 secondary outcomes
Median Overall Survival of Patients Studied
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 46.5 months
Count of Participants With a Radiologic Response
Time frame: median time of potential follow-up of 47.5 months
Count of Participants With Prostatic Antigen-Specific (PSA) Declines
Time frame: 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
Time frame: Date treatment consent signed to date off study, approximately 93 months and 22 days.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Oct 2018.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 1383436Hudes 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.
- Background: PubMed 9294479Hudes 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.
- Background: PubMed 9301705Pienta 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ravi A Madan, M.D. principal investigator
National Cancer Institute (NCI)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Bevacizumab, Lenalidomide and Docetaxel in people with Metastatic Prostate Cancer, run by National Cancer Institute (NCI) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 29 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 11 Oct 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 11 Oct 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Recommended Phase 2 Dose (RP2D) (time frame: 3 weeks). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00942578, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Oct 2018.