A Phase 2 Trial of Bevacizumab, Lenalidomide, Docetaxel, and Prednisone (ART-P) for Treatment of Metastatic Castrate-Resistant Prostate Cancer
|First Received Date ICMJE||July 18, 2009|
|Last Updated Date||November 27, 2013|
|Start Date ICMJE||July 2009|
|Estimated Primary Completion Date||July 2014 (final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||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.|
|Original Primary Outcome Measures ICMJE
||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.@@@|
|Change History||Complete list of historical versions of study NCT00942578 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
||Overall survival of the enrolled patients. Measurement of circulating prostate cancer cells and apoptotic endothelial cells before and after drug administration. Assessment of molecular markers of angiogenesis before and after drug administrati...|
|Original Secondary Outcome Measures ICMJE
||Overall survival of the enrolled patients. Measurement of circulating prostate cancer cells and apoptotic endothelial cells before and after drug administration. Assessment of molecular markers of angiogenesis before and after drug administration.|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||A Phase 2 Trial of Bevacizumab, Lenalidomide, Docetaxel, and Prednisone (ART-P) for Treatment of Metastatic Castrate-Resistant Prostate Cancer|
|Official Title ICMJE||A Phase 2 Trial of Bevacizumab, Lenalidomide, Docetaxel, and Prednisone (ART-P) for Treatment of Metastatic Castrate-Resistant Prostate Cancer|
- 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.
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 toxicity)
To evaluate the efficacy of the combination
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
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 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 Type ICMJE||Interventional|
|Study Phase||Phase 2|
|Study Design ICMJE||Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Condition ICMJE||Metastatic Prostate Cancer|
|Study Arm (s)||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Active, not recruiting|
|Estimated Completion Date||July 2014|
|Estimated Primary Completion Date||July 2014 (final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
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:
-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 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
Patients with known hypersensitivity of Chinese hamster ovary cell products or other recombinant human antibodies
|Ages||18 Years and older|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Location Countries ICMJE||United States|
|NCT Number ICMJE||NCT00942578|
|Other Study ID Numbers ICMJE||090195, 09-C-0195|
|Has Data Monitoring Committee||Not Provided|
|Responsible Party||National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )|
|Study Sponsor ICMJE||National Cancer Institute (NCI)|
|Collaborators ICMJE||Not Provided|
|Information Provided By||National Institutes of Health Clinical Center (CC)|
|Verification Date||December 2012|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP