Exisulind and Intermittent Androgen Suppression (ADT) in Biochemical Relapsed Prostate Cancer

Study Overview
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Brief Summary
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The purpose of this research study is to determine if an investigational drug called Exisulind will extend the off-treatment period of patients receiving Intermittent Androgen Suppression (ADT). There is evidence suggesting that alternating between periods of treatment and no treatment with androgen suppressants may delay the time to develop androgen-insensitive progression and improve overall quality of life. During intermittent androgen suppression (IAS) treatments, men receive a luteinizing hormone-releasing hormone (LHRH) agonist and antiandrogen for a fixed period of time (approximately 9 months) and then enter an off-treatment period, whose length will vary, depending on the rate of rise in the patient's Prostate-Specific Antigen (PSA). Once the PSA reaches an established threshold (1 ng/mL in men who have had a prostatectomy or 4 ng/ml in men with an intact prostate), androgen suppression will be re-initiated for another 9 months. These cycles of on-treatment/off-treatment will be repeated until patient no longer responds to the androgen suppression and it is clear that their cancer is progressing. It has been observed that off-treatment periods tend to become shorter with each successive cycle of androgen suppression, presumably due to the emergence of androgen-independent clones. This study proposes to look at exisulind, a pro-apoptotic drug, which may extend the off-treatment period in patients receiving IAS.

Detailed Description
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A study doctor will meet with you and ask you about your medical history, examine you, and explain the study. We will draw some blood for tests (about 4-6 tablespoons), including Prostate-Specific Antigen (PSA). If not already obtained, you will have a bone scan and a computed tomography scan (CT scan) to establish a baseline. You will be receiving hormone suppression treatment with monthly injections of a luteinizing hormone-releasing hormone (LHRH) analog such as Lupron or Zoladex and an antiandrogen such as Eulexin or Casodex as part of your standard care for prostate cancer. About 3 months before your next off-treatment period, you will start 1 Exisulind pill 250 mg (2 x 125mg capsules) by mouth twice a day. It is necessary for you to start the Exisulind treatment 3 months prior to your next off-treatment period so that the medication can build up in your system enough to be effective. Per our standard follow-up procedures, we will ask you to have blood draws every 2 weeks for up to 12 weeks after starting Exisulind to check liver function. Thereafter you will be asked to have monthly blood draws, and return to the clinic every 3 months for a physical examination, to determine how well you are tolerating the study medication, how your cancer is responding to the treatment, and to give you more study medication. You will continue taking Exisulind during your off-treatment period until your PSA reaches a threshold level. PSA threshold is defined by your primary treatment. If you have had your prostate removed, the threshold is 1.0 ng/dL. If you have an intact prostate, your threshold is 4 ng/dL. Once your PSA reaches this level, you will restart your hormone suppression treatment as directed by your doctor.

Official Title
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Evaluation of the Effect of Exisulind on the Duration of the Off-Treatment Interval on Patients With Biochemical Relapse of Prostate Cancer Who Are Treated With Intermittent Androgen Suppression (ADT)

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Exisulind
* Drug: luteinizing hormone-releasing hormone (LHRH) agonist
* Drug: Antiandrogen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A willingness and ability to sign an informed consent document; 21 years or of legal age; Histologically or cytologically documented prostate cancer. ECOG Performance status score of 0 or 1. Received at least one cycle of IAS with an LHRH agonist and anti-androgen Willingness to remain off chronic NSAIDs (with the exception of ibuprofen or naproxen), including COX 2 inhibitors and salicylates (e.g., aspirin, mesalamine, azodisalicylate, salsalate, sulfasalazine) for duration of the study. Patients on low dose aspirin for cardiovascular prevention may be included in the study. Have not taken sulindac (Clinoril™) on regular basis for any indication for one week prior to enrollment and willing to remain off of sulindac for the duration of the study. Patients with prior radiation must be 2 weeks from their last radiation-treatment and have recovered from all associated toxicity. Exclusion Criteria: Known hypersensitivity to sulindac (Clinoril™) ECOG Performance status score > 1; Patients previously on SWOG 9346 or 9921 trials, or any other trials using IAS for which adding exisulind may be confounding. Patients may not have any evidence of hormone-refractory prostate cancer, i.e. 2 consecutive rises in PSA on LHRH agonist and anti-androgen Active peptic ulcer disease; Use of an investigational medication or device within one month of initiating study therapy; Elevations of serum creatinine to above the upper limit of normal; Platelet count < 100,000/L; hgb < 9.0 g/dL; absolute neutrophil count < 1500/mm3 Known hepatic, biliary tract, renal or hematologic dysfunction which in the opinion of the Investigator or Sponsor are clinically significant or would obscure laboratory analyses or are associated with lab abnormalities; Any condition or any medication that may interfere with the conduct of the study. Bilirubin > ULN. Patients with elevated indirect bilirubin due to Gilbert's Syndrome will be eligible. AST or ALT >2.5 X ULN

Ages Eligible for Study
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Minimum Age: 21 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: IAS and Exisulind<br>Patients will receive intermittent dosing of hormone therapy with commercially supplied luteinizing hormone-releasing hormone (LHRH) agonist and anti-androgen to be chosen by physician per standard of care. Exisulind will be started 3 months prior to the end of the second cycle of hormone therapy. Patients will continue treatment with Exisulind beyond the completion of the second cycle of hormone therapy until they meet criteria for discontinuation. | Drug: Exisulind<br>* Oral antineoplastic agent that induces apoptosis in cancerous cells.<br>* Other names: Aptosyn;Drug: luteinizing hormone-releasing hormone (LHRH) agonist<br>* Hormonal therapy to suppress testosterone as a standard treatment for Prostate Cancer.<br>* Other names: Zoladex;Drug: Antiandrogen<br>* Hormonal therapy used as lead in treatment with luteinizing hormone-releasing hormone (LHRH) agonist to prevent the initial rise in testosterone (testosterone flare) seen during the first dose of LHRH agonists.<br>* Other names: Casodex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of the First Off-treatment Cycle in Patients Who Have Completed One Cycle of Intermittent Androgen Suppression With the Addition of Exisulind. | Patients were monitored for the amount of time (number of weeks) that passed between the completion of a cycle of Intermittent Androgen Suppression with Exisulind and the need to re-initiate treatment with Intermittent Androgen Suppression. It was hoped that adding Exisulind to standard Androgen Suppression would extend the amount time before disease progression. | From date of first treatment until the date of first documented progression or study withdrawal, whichever came first, assessed up to 10 years. | 
| Time to Hormone-refractory Diseases in Patients Treated With Intermittent Androgen Suppression and Exisulind | Patients were monitored for continued hormonal sensitivity of their disease from the time of the first treatment with Intermittent Androgen Suppression and Exisulind and the time at which point they were considered hormone-refractory (castrate resistant). The development of hormone-refractory disease was one of the criteria for withdraw from study treatment. For this protocol, hormone-refractory was defined as 2 consecutive rising PSAs at least 2 weeks apart while on an LHRH agonist (with or without an anti-androgen). | From date of first treatment until the date of first documented progression or study withdrawal, whichever came first, assessed up to 10 years. | 
| Number of Participants With Dose Hold, Dose Reduction, or Treatment Withdrawal for Toxicity. | Patients were monitored for toxicity related treatment modifications from the start of Exisulind through the time that there were withdrawn from study. | From date of first treatment until study withdrawal, assessed up to 10 years. |