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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

Phase 2
18 Years
Open (Enrolling)
Recurrent Prostate Cancer, Stage I Prostate Cancer, Stage IIA Prostate Cancer, Stage IIB Prostate Cancer, Stage III Prostate Cancer

Thank you

Trial Information

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


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.


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.


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

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: 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

ARM II: 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

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.

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 RTGO-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

- 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 normal 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 =< 2.5 times ULN

- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and
serum glutamic pyruvic 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 Fridericia 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 (CYP 450) 3A4 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

- The effect of the study medications on the developing human fetus are unknown; for
this reason, 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)

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Proportion of patients with undetectable PSA level (< 0.2 ng/mL)

Outcome Time Frame:

44 weeks

Safety Issue:


Principal Investigator

Anna Ferrari

Investigator Role:

Principal Investigator

Investigator Affiliation:

Eastern Cooperative Oncology Group


United States: Food and Drug Administration

Study ID:




Start Date:

December 2010

Completion Date:

Related Keywords:

  • Recurrent Prostate Cancer
  • Stage I Prostate Cancer
  • Stage IIA Prostate Cancer
  • Stage IIB Prostate Cancer
  • Stage III Prostate Cancer
  • Prostatic Neoplasms



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