Lenalidomide and Cyclophosphamide in Treating Patients With Previously Treated Hormone-Refractory Prostate Cancer

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase I/II Clinical Trial of Lenalidomide in Combination With Oral Cyclophosphamide in Patients With Previously Treated Hormone Refractory Prostate Cancer

Conditions
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Adenocarcinoma of the Prostate, Hormone-resistant Prostate Cancer, Recurrent Prostate Cancer

Intervention / Treatment
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* Drug: lenalidomide
* Drug: cyclophosphamide
* Other: laboratory biomarker analysis
* Other: questionnaire administration
* Other: quality-of-life assessment


Participation Criteria
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Eligibility Criteria
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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) Absolute neutrophil count greater than 1,500/mm^3 Platelets greater than 100,000/mm^3 Hemoglobin >= 9.0 g/dL Able to adhere to the study visit schedule and other protocol requirements No serious disease or condition that, in the opinion of the investigator, would compromise the patient's ability to participate in the study All study participants must be registered into the mandatory Revlimid REMS program, and be willing and able to comply with the requirements of Revlimid REMS Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to acetylsalicylic acid [ASA] may use warfarin or low molecular weight heparin) Men must agree to use a latex condom during sexual contact with females of childbearing potential (FCBP) even if they have had a successful vasectomy Male subject agrees to use an acceptable method for contraception for the duration of the study Electrocardiogram (EKG) at baseline, if abnormal, not medically relevant 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) Evidence of any other significant clinical disorder or laboratory finding that makes it undesirable for the subject to participate in the trial

Ages Eligible for Study
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Minimum Age: 19 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: Treatment (lenalidomide and cyclophosphamide)<br>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. | Drug: lenalidomide<br>* Given PO<br>* Other names: Revlimid;Drug: cyclophosphamide<br>* Given PO<br>* Other names: Endoxana;Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: questionnaire administration<br>* Ancillary studies<br>Other: quality-of-life assessment<br>* Ancillary studies<br>* Other names: quality of life assessment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose of Lenalidomide Administered in Combination With Oral Cyclophosphamide (Phase I) | 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. | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | As measured by Response Evaluation Criteria In Solid Tumors (RECIST version 1.1), in which CR is defined as disappearance of target lesions and a partial response (PR) is defined as at least a 30% decrease in the sum of the longest diameter of target lesions. PD is defined as 20% increase over smallest sum on study (including baseline if that is smallest) and at least 5 mm increase or new lesions. SD is defined as not enough response to be PR and not enough progression to be PD. | Up to 4 months | 
| Proportion of Patients Achieving CR |  | At 4 months | 
| Overall Survival |  | Up to 4 years |