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

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

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.

Study Overview

• Status: Terminated
• Conditions: Recurrent Prostate Cancer; Hormone-resistant Prostate Cancer; Adenocarcinoma of the Prostate
• Intervention / Treatment: Drug: lenalidomide; Other: laboratory biomarker analysis; Other: questionnaire administration; Other: quality-of-life assessment; Drug: cyclophosphamide

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.

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: lenalidomide; Given PO; Other Names: CC-5013; IMiD-1; Revlimid; Other: laboratory biomarker analysis; Correlative studies; Other: questionnaire administration; Ancillary studies; Other: quality-of-life assessment; Ancillary studies; Other Names: quality of life assessment; Drug: cyclophosphamide; Given PO; Other Names: Cytoxan; Endoxan; CPM; CTX; Endoxana

What is the study measuring?

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
Overall Survival		Up to 4 years
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

Collaborators and Investigators

• Sponsor: University of Nebraska
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: James K Schwarz, MD, University of Nebraska

Study record dates

Study Major Dates

• Study Start (Actual): March 4, 2010
• Primary Completion (Actual): May 19, 2015
• Study Completion (Actual): May 19, 2015

Study Registration Dates

• First Submitted: March 24, 2010
• First Submitted That Met QC Criteria: March 24, 2010
• First Posted (Estimated): March 25, 2010

Study Record Updates

• Last Update Posted (Actual): September 13, 2023
• Last Update Submitted That Met QC Criteria: August 21, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases, Male; Genital Diseases; Prostatic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Cyclophosphamide; Lenalidomide
• Other Study ID Numbers: 0479-09-FB; P30CA036727 (U.S. NIH Grant/Contract); 479-09 (Other Identifier: University of Nebraska Medical Center); NCI-2010-00363 (Registry Identifier: CTRP (Clinical Trial Reporting Program))