A Phase I/II Clinical Trial of Lenalidomide in Combination With Oral Cyclophosphamide in Patients With Previously Treated Hormone Refractory Prostate Cancer
Overview
- Phase
- Phase 1
- Intervention
- laboratory biomarker analysis
- Conditions
- Adenocarcinoma of the Prostate
- Sponsor
- University of Nebraska
- Enrollment
- 25
- Locations
- 1
- Primary Endpoint
- Maximum Tolerated Dose of Lenalidomide Administered in Combination With Oral Cyclophosphamide (Phase I)
- Status
- Terminated
- Last Updated
- 2 years ago
Overview
Brief Summary
This phase I/II trial studies the side effects and best dose of lenalidomide when given together with cyclophosphamide and to see how well they work in treating patients with previously treated hormone-refractory prostate cancer. Lenalidomide may stop the growth of prostate cancer by blocking blood flow to the tumor. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving lenalidomide together with cyclophosphamide may kill more tumor cells.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) and the dose limiting toxicities (DLT) of lenalidomide administered in combination with oral cyclophosphamide. SECONDARY OBJECTIVES: I. To evaluate the objective prostate-specific antigen (PSA) response (50% decrease in PSA levels sustained for at least 4 weeks) as defined by PSA working group criteria; or a decrease in absolute PSA or a decrease in PSA velocity, increase in PSA doubling time, duration of any responses. II. To explore the anti-tumor activity of the combination of lenalidomide plus oral cyclophosphamide in patients with previously treated hormone refractory prostate cancer. III. To evaluate baseline and change of quality of life, particularly, bone pain and analgesic consumption, of the patients on this combination chemotherapy. TERTIARY OBJECTIVES: I. To determine whether related cytokines and biomarkers (serum levels of tumor necrosis factor-alpha, basic fibroblast growth factor, vascular endothelial growth factor \[VEGF\], T cell inhibitory activity, phytohemagglutinin \[PHA\] and interleukin \[IL\]-2, mononuclear cell isolation, VEGF, basic fibroblast growth factor \[bFGF\], IL-6) can help predict response to patients undergoing treatment with lenalidomide and cyclophosphamide. OUTLINE: This is a phase I, dose-escalation study of lenalidomide followed by a phase II study. Patients receive lenalidomide orally (PO) once daily (QD) on days 1-21 and cyclophosphamide PO QD on days 1-28. Treatment repeats every 28 days for at least 4 courses in the absence of disease progression or unacceptable toxicity. Treatment modifications may apply according to response. After completion of study treatment, patients are followed up periodically.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Able to provide written informed consent
- •Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less
- •Men with histologically documented previously treated hormone refractory adenocarcinoma of the prostate; mixed histology and rare subtypes histology of prostate cancer are allowed only in phase 1 portion of trial
- •Patients must be on an luteinizing-hormone-releasing hormone (LHRH) agonist or have undergone surgical castration
- •Patients must have already failed or progressed after treatment with a docetaxel-based regimen; patients who were unable to tolerate docetaxel are eligible in phase 1 portion of trial
- •Creatinine clearance \>= 45 by Cockcroft-Gault formula
- •Total bilirubin =\< upper limit of normal (ULN)
- •Aspartate aminotransferase (AST) \< 2 x ULN
- •Alanine aminotransferase (ALT) \< 2 x ULN
- •Hepatic alkaline phosphatase \< 2 x ULN (\< 5.0 x ULN for subjects with known bone metastases)
Exclusion Criteria
- •Treatment with a cytotoxic chemotherapy or investigational drug within 30 days before day 1 of study treatment; palliative radiation therapy is allowed, as long as a radiated lesion is not used to assess response rate, and the radiation occurred greater than 4 weeks prior to enrollment
- •Known positive for human immunodeficiency virus (HIV) or infectious hepatitis, type A, B or C or active hepatitis
- •Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form
- •Known hypersensitivity to thalidomide, lenalidomide or cyclophosphamide
- •Active infection at the start of lenalidomide
- •Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any EKG abnormality at screening has to be documented by the investigator as not medically relevant
- •History of life threatening or recurrent thrombosis/embolism; patients may participate if they are adequately anti-coagulated during the treatment
- •Patient has \> grade 2 peripheral neuropathy within 14 days before enrollment
- •Any evidence of severe or uncontrolled systemic disease (e.g., unstable or uncompensated respiratory, cardiac, hepatic, or renal disease)
- •Any unresolved chronic toxicity greater than Common Terminology Criteria (CTC) grade 2 from previous anticancer therapy (except alopecia)
Arms & Interventions
Treatment (lenalidomide and cyclophosphamide)
Patients receive lenalidomide PO QD on days 1-21 and cyclophosphamide PO QD on days 1-28. Treatment repeats every 28 days for at least 4 courses in the absence of disease progression or unacceptable toxicity. Treatment modifications may apply according to response.
Intervention: laboratory biomarker analysis
Treatment (lenalidomide and cyclophosphamide)
Patients receive lenalidomide PO QD on days 1-21 and cyclophosphamide PO QD on days 1-28. Treatment repeats every 28 days for at least 4 courses in the absence of disease progression or unacceptable toxicity. Treatment modifications may apply according to response.
Intervention: lenalidomide
Treatment (lenalidomide and cyclophosphamide)
Patients receive lenalidomide PO QD on days 1-21 and cyclophosphamide PO QD on days 1-28. Treatment repeats every 28 days for at least 4 courses in the absence of disease progression or unacceptable toxicity. Treatment modifications may apply according to response.
Intervention: cyclophosphamide
Treatment (lenalidomide and cyclophosphamide)
Patients receive lenalidomide PO QD on days 1-21 and cyclophosphamide PO QD on days 1-28. Treatment repeats every 28 days for at least 4 courses in the absence of disease progression or unacceptable toxicity. Treatment modifications may apply according to response.
Intervention: questionnaire administration
Treatment (lenalidomide and cyclophosphamide)
Patients receive lenalidomide PO QD on days 1-21 and cyclophosphamide PO QD on days 1-28. Treatment repeats every 28 days for at least 4 courses in the absence of disease progression or unacceptable toxicity. Treatment modifications may apply according to response.
Intervention: quality-of-life assessment
Outcomes
Primary Outcomes
Maximum Tolerated Dose of Lenalidomide Administered in Combination With Oral Cyclophosphamide (Phase I)
Time Frame: 28 days
Defined to be the dose cohort below which 2 of 3 or 3 of 6 patients experience dose-limiting toxicities in course 1 or the highest dose cohort of 25 mg.
Secondary Outcomes
- Number of Patients Achieving Objective PSA Response (50% Decrease in PSA Levels Sustained for at Least 4 Weeks) as Defined by PSA Working Group Criteria(4 weeks)
- Anti-tumor Activity as Assessed by the Sum of Complete Response (CR), Partial Response (PR), and Stable Disease (SD)(Up to 4 months)
- Proportion of Patients Achieving CR(At 4 months)
- Overall Survival(Up to 4 years)