Bicalutamide With or Without Akt Inhibitor MK2206 in Treating Patients With Previously Treated Prostate Cancer

Study Overview
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Brief Summary
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This phase II trial studies how well giving bicalutamide with or without Akt inhibitor MK2206 works in treating patients with previously treated prostate cancer. Androgens can cause the growth of prostate cancer cells. Antihormone therapy, such as bicalutamide, may lessen the amount of androgens made by the body. Akt inhibitor MK2206 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether bicalutamide is more effective with or without Akt inhibitor MK2206 in treating prostate cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To compare the two regimens on the proportion of patients with undetectable prostate-specific antigen (PSA) level (< 0.2 ng/mL) at 44 weeks. SECONDARY OBJECTIVES: I. To assess the proportion of patients with PSA decline >= 85% at 44 weeks on the combination therapy arm compared to that of bicalutamide monotherapy arm. II. To assess the distribution of best PSA response in each study arm. III. To assess the time to PSA progression in each arm of the study. IV. To assess the time to PSA nadir in each arm of the study. V. To assess the duration of PSA response in each arm of the study. VI. To characterize the PSA slope pre-study, during treatment, and off treatment. VII. To evaluate the safety and tolerability of MK-2206 (Akt inhibitor MK2206) in this patient population. VIII. To determine whether Gleason score has any effect on PSA response to treatment. IX. To determine whether prior hormonal therapy has any effect on PSA response to treatment. TERTIARY OBJECTIVES: I. Samples of the primary tumor specimen will be retrieved for banking and future analysis of the molecular profile of the primary prostate cancer (PC) tissues with emphasis on the androgen receptor (AR) and protein kinase B (Akt) upstream and downstream signaling pathways. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM A: Patients undergo observation on weeks 1-12. Patients then receive bicalutamide* orally (PO) once daily (QD) on weeks 13-44. Patients with a PSA decline of >= 50% may continue on bicalutamide until week 72 in the absence of disease progression or unacceptable toxicity. ARM B: Patients receive Akt inhibitor MK2206** PO once per week on weeks 1-44 and bicalutamide* PO QD on weeks 13-44. Patients with a PSA decline of >= 50% may continue on MK2206 and bicalutamide until week 72 in the absence of disease progression or unacceptable toxicity. NOTE: *Patients may begin bicalutamide on weeks 4-11 if the disease worsens. NOTE: **Patients on Akt inhibitor MK2206 with a PSA < 0.2 ng/mL by week 12 do not receive bicalutamide until PSA rises to >= 0.2 ng/mL. After completion of study therapy, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then every year for up to 10 years.

Official Title
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Androgen Receptor Modulation Phase II, Randomized Study of MK-2206 - Bicalutamide Combination in Patients With Rising PSA at High-Risk of Progression After Primary Therapy

Conditions
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Recurrent Prostate Carcinoma, Stage I Prostate Cancer AJCC v7, Stage IIA Prostate Cancer AJCC v7, Stage IIB Prostate Cancer AJCC v7, Stage III Prostate Cancer AJCC v7

Intervention / Treatment
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* Drug: Akt Inhibitor MK2206
* Drug: Bicalutamide
* Other: Clinical Observation
* Other: Laboratory Biomarker Analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient must have histologically confirmed diagnosis of prostate cancer Patient must have had previous treatment with definitive surgery or radiation therapy or cryoablation Patient may have prior salvage therapy (surgery, radiation or other local ablative procedures) within 4 weeks prior to randomization if the intent was for cure; prophylactic radiotherapy to prevent gynecomastia within 4 weeks prior to randomization is allowed Patient must have no evidence of metastatic disease on physical exam, computed tomography (CT) abdomen/pelvis (or magnetic resonance imaging [MRI]), chest x-ray (or CT chest) and bone scan within 8 weeks prior to randomization Patient may have had prior neoadjuvant and/or adjuvant therapy (chemotherapy, vaccines or experimental agents) within 4 weeks prior to randomization, if the PSA rise and PSA doubling time (PSADT) were documented after the testosterone level was > 150 ng/dL Patient may not have had therapy modulating testosterone levels (such as luteinizing-hormone, releasing-hormone agonists/antagonists and antiandrogens) within 1 year prior to randomization, unless it was in the neoadjuvant and/or adjuvant setting; agents such as 5 alpha reductase inhibitors, ketoconazole, abiraterone, systemic steroids, or herbal supplements known to decrease PSA levels including any dose of megestrol acetate, finasteride (e.g., Saw Palmetto and PC-SPES, African pygeum extract, lycopene, alanine, glutamic acid and glycine, beta-sitosterol, lycopene, nettle root extract, quercitin, Belizian Man Vine extract, mulra puama extract and epimedium extract campesterol, beta-sitosterol, stigmasterol, sitostanol and brassicasterol) are not permitted at any time during the period that the PSA values are being collected Patient must have hormone-sensitive prostate cancer as evident by a serum total testosterone level > 150 ng/dL within 12 weeks prior to randomization Patient must have evidence of biochemical failure after primary therapy and subsequent progression Biochemical failure is declared when the PSA reaches a threshold value after primary treatment and it differs for radical prostatectomy or radiation therapy For radical prostatectomy the threshold for this study is PSA >= 0.4 ng/mL For radiation therapy the threshold is a PSA rise of 2 ng/mL above the nadir PSA achieved post radiation with or without hormone therapy (2006 Radiation Therapy Oncology Group [RTOG]-American Society for Radiation Oncology [ASTRO] Consensus definition) PSA progression requires a PSA rise above the threshold (PSA1) measured at any time point since the threshold was reached The PSADT must be < 12 months; requires two consecutive PSA rises (PSA2 and PSA3) above the PSA1; PSA2 and PSA3 must be obtained within 6 months of study entry; all baseline PSAs should be obtained, preferably, at the same reference lab PSADT calculation needs 3 PSA values: PSA1 is any PSA value that is equal or greater than the threshold PSA (0.4 ng/mL for radical prostatectomy or 2 ng/mL above the nadir for primary radiation therapy) indicating biochemical relapse PSA2 must be higher than PSA1, obtained at least 2 weeks after PSA1 and within 6 months or less from randomization PSA3 must be higher than PSA2 and obtained at least 2 weeks after PSA2 Baseline PSA must have reached a minimum of 2 ng/mL but be no greater than 50 ng/mL and equal or higher than PSA3; PSA3 may be used as baseline PSA if obtained within 1 week of randomization Patient's PSA doubling time (PSADT) must be less than 12 months Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Granulocytes >= 1,500/mm^3 Platelet count >= 100,000/mm^3 Serum creatinine within normal institutional limits or creatinine clearance >= 50 ml/min for patients with creatinine levels above institutional normal Serum total bilirubin =< 1.5 times upper limit of normal (ULN) Alkaline phosphatase (ALP) =< 2.5 x ULN Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 2.5 x institutional upper limit of normal Human immunodeficiency virus (HIV)-positive patients are excluded from this study Patient cannot receive concurrent therapeutic administration of anticoagulant therapy; low dosage aspirin =< 325 mg per day is allowed Patients with impaired cardiac function including any one of the following will be excluded from entry on study: Baseline corrected QT interval (QTc) > 450 msec (male) (patients with QTc 450-480 msec will be allowed to participate in this trial if they do not have any of the other cardiac conditions mentioned in this section) Patients with congenital long QT syndrome History of sustained ventricular tachycardia Any history of ventricular fibrillation or torsades de pointes Concomitant use of drugs with a risk of causing torsades de pointes Bradycardia defined as heart rate < 50 beats per minute; patients with a pacemaker and heart rate >= 50 beats per minute are eligible Myocardial infarction or unstable angina within 6 months of study entry Congestive heart failure (New York Heart Association class III or IV) Right bundle branch block and left anterior hemi-block (bifascicular block) Patient must not have gastrointestinal (GI) tract disease resulting in an inability to take oral medication, malabsorption syndrome, a requirement for intravenous (IV) alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn's, ulcerative colitis) Patient may not be receiving any other investigational agents or receiving concurrent anticancer therapy (chemotherapy, immunotherapy, radiation therapy, surgery for cancer, or experimental medications) at time of randomization Patient may not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to MK-2206 or bicalutamide Patient must not have any uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Patients with diabetes or at risk for hyperglycemia MUST not be excluded from trials with MK-2206, but the hyperglycemia should be well controlled before the patient enters the trial Patients receiving any medications or substances that are inhibitors or inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) are ineligible Patient must NOT have previous or concurrent malignancy; exceptions are made for patients who meet any of the following conditions: Basal cell or squamous cell carcinoma of the skin OR Prior malignancy has been adequately treated and patient has been continuously disease free for >= 2 years Patient must agree to use barrier contraception during and for 3 months after discontinuation of study treatment; if patient impregnates a woman while on treatment or within 3 months of discontinuing treatment, he should inform his treating physician immediately Patients must discontinue use of enzyme-inducing anti-epileptic drugs (EIAEDs) >= 14 days prior to study enrollment; the investigator may prescribe non-EIAEDs; patients who must begin EIAED therapy while on study will be allowed to remain Patients must not be taking cytochrome P450 enzyme-inducing antiepileptic drugs (phenytoin, carbamazepine or phenobarbital), St John's Wort, ketoconazole, dexamethasone, the dysrhythmic drugs (terfenadine, quinidine, procainamide, sotalol, probucol, bepridil, indapamide or flecainide), haloperidol, risperidone, rifampin, grapefruit, or grapefruit juice within two weeks of randomization and during the course of therapy Patients may have received targeted agents (angiogenesis inhibitors, epidermal growth factor receptor [EGFR] inhibitors, mammalian target of rapamycin [mTOR] inhibitors, phosphatidylinositol 3 kinase [PI3K] inhibitors, etc.), however patients must have discontinued treatment with the targeted agent(s) at least 4 weeks prior to enrollment; if the patient stopped targeted agent(s) due to unresolved or persistent grade 3 or 4 toxicity, patient cannot be enrolled onto the study regardless of the length of time since discontinuation of treatment with targeted agent(s)

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A (observation and bicalutamide)<br>Patients undergo observation on weeks 1-12. Patients then receive bicalutamide PO QD on weeks 13-44. Patients with a PSA decline of >= 50% may continue on bicalutamide until week 72 in the absence of disease progression or unacceptable toxicity. | Drug: Bicalutamide<br>* Given PO<br>* Other names: ICI 176334;Other: Clinical Observation<br>* Undergo clinical observation<br>* Other names: observation;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|
| Experimental: Arm B (Akt inhibitor MK2206 and bicalutamide)<br>Patients receive Akt inhibitor MK2206 PO once per week on weeks 1-44 and bicalutamide PO QD on weeks 13-44. Patients with a PSA decline of >= 50% may continue on Akt inhibitor MK2206 and bicalutamide until week 72 in the absence of disease progression or unacceptable toxicity. | Drug: Akt Inhibitor MK2206<br>* Given PO<br>* Other names: MK2206;Drug: Bicalutamide<br>* Given PO<br>* Other names: ICI 176334;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Proportion of Patients With Undetectable PSA Level (< 0.2 ng/mL) at 44 Weeks | The proportion of patients with undetectable PSA level (< 0.2 ng/mL) at 44 weeks, defined as number of patients with undetectable PSA level at 44 weeks divided by number of patients randomized. | 44 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients With PSA Decline > 85% at 44 Weeks | Proportion of patients with PSA decline > 85% at 44 weeks from baseline, defined as number of patients with PSA decline > 85% at 44 weeks from baseline divided by number of patients randomized. | 44 weeks | 
| Proportion of Patients With PSA Response | PSA complete response (CR) is defined as a PSA <0.2 ng/mL confirmed on two consecutive additional determinations taken at least 4 weeks apart. PSA partial response (PR) is defined as a reduction in PSA ≥ 50% from baseline without evidence of progression (confirmed on two consecutive additional determinations taken at least 4 weeks apart). Either CR or PR is considered as a PSA response. | Assessed every 3 months for 2 years, every 6 months for 3 years, and then annually up to 10 years | 
| Time to PSA Progression | Time to PSA progression was defined as the time from randomization to PSA progression or date of last disease assessment showing progression-free. Development of clinical progression is also considered as an event. For patients (pts) who achieved a ≥ 50% decline in PSA (confirmed on two consecutive determinations taken at least 4 weeks apart), progression is defined as an increase in PSA by 50% above baseline or nadir, whichever is lowest, confirmed by a 2nd PSA rise at least two weeks later. The PSA rise must be >= 5 ng/mL. For pts with an undetectable PSA nadir (< 0.2 ng/mL confirmed on two consecutive determinations taken at least 4 weeks apart), progression is defined as PSA ≥ 0.2 ng/mL confirmed by a 2nd PSA rise at least 2 weeks later. For pts whose PSA has not decreased by 50%, progression is defined as an increase in PSA of ≥ 50% of baseline or nadir PSA, whichever is lowest, confirmed by a repeat PSA at least 2 weeks later. The PSA must have risen by >= 5 ng/mL | Assessed every 3 months for 2 years, every 6 months for 3 years, and then annually up to 10 years | 
| Time to PSA Nadir | Time to PSA nadir was defined as the time from randomization to the date that PSA nadir, the lowest PSA value achieved after randomization, was documented. This analysis was performed among patients whose PSA level decreased after randomization compared to baseline. | Assessed every 3 months for 2 years, every 6 months for 3 years, and then annually up to 10 years | 
| Duration of PSA Response | Duration of PSA response was defined as the time from the date PSA criteria were met for complete response (CR) or partial response (PR), whichever status was recorded first, to the date of PSA progression. Patients without documented PSA progression were censored at the date of last disease assessment. Duration of PSA response is analyzed among responders (PSA CR or PR). | Assessed every 3 months for 2 years, every 6 months for 3 years, and then annually up to 10 years | 
| PSA Slope Prior to Randomization | PSA slopes were assessed by multiple PSA values prior to randomization. Linear regression was used to calculate PSA slope using natural log-transformed PSA values on the time of PSA measurements for each patient. | Baseline (pre-randomization) | 
| PSA Slope After Randomization and Before Starting Bicalutamide | PSA slopes were assessed by multiple PSA values from randomization to starting bicalutamide treatment. Linear regression was used to calculate PSA slope using natural log-transformed PSA values on the time of PSA measurements for each patient. | After randomization and prior to starting bicalutamide | 
| PSA Slope After Starting Bicalutamide Treatment | PSA slopes were assessed by multiple PSA values after starting bicalutamide treatment. Linear regression was used to calculate PSA slope using natural log-transformed PSA values on the time of PSA measurements for each patient. | Assessed every 3 months for 2 years, every 6 months for 3 years, and then annually up to 10 years | 
| The Association Between Gleason Score and PSA Response | The association between PSA response (responder vs non-responder) and Gleason score (<7, 7 vs. >7) was evaluated by logistic regression with adjustment for treatment assignment. Based on the biopsy sample, a Gleason grade is assigned to the most predominant pattern in the biopsy and a second Gleason grade is assigned to the second most predominant pattern. The two grades will then be added together to determine the Gleason score. Gleason scores range from 2-10. The higher the Gleason score, the more aggressive the cancer is likely to be. | Assessed every 3 months for 2 years, every 6 months for 3 years, and then annually up to 10 years | 
| The Association Between Prior Hormonal Therapy and PSA Response | The association between PSA response (responder vs non-responder) and prior hormonal therapy (yes vs. no) was evaluated by logistic regression with adjustment for treatment assignment. | Assessed every 3 months for 2 years, every 6 months for 3 years, and then annually up to 10 years |