| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with Rising PSA at high risk of Prostate cancer progression |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with Rising PSA at high risk of Prostate cancer progression |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10071119 |
| E.1.2 | Term | Hormone-dependent prostate cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare the two regimens on the proportion of patients with undetectable PSA level (< 0.2 ng/mL) at 44 weeks |
|
| E.2.2 | Secondary objectives of the trial |
- 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.
- To assess the distribution of best PSA response in each study arm.
- To assess the time to PSA progression in each arm of the study.
- To assess the time to PSA nadir in each arm of the study.
- To assess the duration of PSA response in each arm of the study.
- To characterize the PSA slope pre-study, during treatment, and off treatment.
- To evaluate the safety and tolerability of MK-2206 in this patient population.
- To determine whether Gleason score has any effect on PSA response to treatment.
- To determine whether prior hormonal therapy has any effect on PSA response to treatment. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient must be at least 18 years of age.
2. Patient must have histologically confirmed diagnosis of prostate cancer.
3. Patient must have had previous treatment with definitive surgery or radiation therapy or cryoablation.
4. 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.
5. Patient must have no evidence of metastatic disease on physical exam, CT abdomen/pelvis (or MRI), chest x-ray (or CT chest) and bone scan within 8 weeks prior to randomization.
6. 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 PSADT were documented after the testosterone level was > 150 ng/dL.
7. Patient may not have had therapy modulating testosterone levels (such as luteinizinghormone, 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, MDV31000 megestrol acetate, 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.
8. Patient must have hormone-sensitive prostate cancer as evident by a serum total testosterone level > 150 ng/dL within 12 weeks prior to randomization.
9. 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 lab.
10. 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 50ng/mL and equal or higher than PSA3. PSA3 may be used as baseline PSA if obtained within 1 week of randomization.
11. Patient's PSA doubling time (PSADT) must be less than 12 months.
12. Patient must have an ECOG Performance Status of 0 or 1.
13. Patient must have adequate end-organ function as evident by the following lab values obtained within 4 weeks prior to randomization:
o Granulocytes ≥ 1500/mm3
o Platelet count ≥ 100,000/mm3
o Serum creatinine within normal institutional limits or creatinine clearance ≥ 50 mL/min for patients with creatinine levels above institutional normal.
o Serum total bilirubin ≤1.5 times the upper limit of normal (ULN), and alkaline phosphatase (ALP) ≤2.5 × ULN
o SGOT (AST) and SGPT (ALT) < 2.5 x institutional upper limit of normal.
|
|
| E.4 | Principal exclusion criteria |
14. HIV-positive patients are excluded from this study because of possible pharmacokinetic interactions with MK-2206.
15. Patient cannot receive concurrent therapeutic administration of anticoagulant therapy. Low dosage aspirin ≤ 325 mg per day is allowed
16. Patients with impaired cardiac function including any one of the following will be excluded from entry on study:
o Baseline 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). A list of medications that may cause QTc interval prolongation are listed in Appendix VII, and should be avoided by patients entering on trial.
o Patients with congenital long QT syndrome
o History of sustained ventricular tachycardia
o Any history of ventricular fibrillation or torsades de pointes
o Concomitant use of drugs with a risk of causing torsades de pointes
o Bracardia defined as heart rate < 50 beats per minute. Patients with a pacemaker and heart rate ≥ 50 beats per minute are eligible.
o Myocardial infarction or unstable angina within 6 months of study entry
o Congestive heart failure (NY Heart Association class III or IV)
o Right bundle branch block and left anterior hemi-block (bifasicular block)
17. Patient must not have GI tract disease resulting in an inability to take oral medication, malabsorption syndrome, a requirement for IV alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn’s, ulcerative colitis).
18. 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.
19. Patient may not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to MK-2206 or bicalutamide.
20. 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.
21. 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. Please follow Section 5.4.4 for glucose monitoring during study for this patient population.
22. Patients receiving any medications or substances that are inhibitors or inducers of CYP 450 3A4 are ineligible. Lists including medications and substances known or with the potential to interact with the CYP 450 3A4 isoenzymes are provided in Appendix VI.
23. Patient must NOT have other current malignancies. 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.
24. 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.
25. 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. (Appendix VI has a list of additional medications which have the potential for interaction.)
26. 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
27. Patients may have received targeted agents (angiogenesis inhibitors, EGFR inhibitors, mTOR inhibitors, 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).
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary objective of this study is to compare the proportion of patients with undetectable PSA level (<0.2 ng/mL) at 44 weeks from study entry between two regimens (combination therapy-Arm B vs. bicalutamide monotherapy-Arm A). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Patients randomized to Arm A will be observed for 12 weeks followed by a 32-week bicalutamide treatment, while patients randomized to Arm B will be treated with MK-2206 for 12 weeks followed by a 32-week combination therapy with bicalutamide and MK-2206. The primary comparison will be an intention to treat analysis of all randomized patients. Although patients will be stratified based on Gleason score and prior hormonal therapy, no subgroup analyses are planned.
|
|
| E.5.2 | Secondary end point(s) |
Our secondary objectives include comparison of the proportion of patients that achieve a ≥ 85% PSA decline at 44 weeks between the two arms, and evaluation of PSA response, time to PSA progression, time to PSA nadir, duration of PSA response, as well as PSA slope pre-treatment, during treatment, and off treatment. In addition, this study will evaluate whether Gleason score, and prior hormonal therapy have any effect on PSA response to treatment.
Exact binomial confidence intervals will be used to describe the proportion of patients with ≥85% PSA decline at 44 weeks and the distribution of best PSA response (defined in section 6). Patients who withdraw from the study prior to treatment completion will be considered non-responders for the analysis regarding 85% PSA decline at 44 weeks. Given 52 patients per arm, there will be 88% power to test the proportion of patients with ≥85% PSA decline of 75% in the combination arm vs. 50% in bicalutamide monotherapy arm based on a 0.10 level one-sided Fisher’s exact test.
Duration of PSA response is defined as time from PSA response to PSA progression. Time to PSA progression, time to PSA nadir from registration, and duration of PSA response will be estimated on each arm and characterized using the method of Kaplan and Meier. Because patients with PSA rise greater than or equal to 50% above baseline confirmed on a second measurement at least 2 weeks later will be allowed to proceed to take bicalutamide before the end of 12 weeks, the analysis of time to PSA nadir will be restricted to patients who do not start bicalutamide treatment early. Additionally, the percentage of patients who start bicaltamide treatment early in both arms will be reported.
PSA slope will be assessed by multiple PSA values for four phases, prior to registration, from registration to starting bicalutamide treatment, from starting bicalutamide treatment until PSA nadir, and within a year after going off treatment; all values are required to be obtained from the same laboratory. Linear regression will be used to calculate PSA slope using natural log-transformed PSA values on the time of PSA measurements for each patient. This endpoint is exploratory and the analysis is descriptive in nature.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
As for the relationship between Gleason score, prior hormonal therapy and PSA response, we will fit a logistic regression to determine whether Gleason score and prior hormonal therapy have any effect on PSA response to treatment. Another important objective is to evaluate the safety and tolerability of MK-2206 in this patient population. All patients who receive treatment, regardless of eligibility, will be evaluated for toxicity. The 90% confidence interval for the true probability of observing a toxicity of Grade 4 or higher on a given arm will be no wider than 25%. The probability of observing one or more toxicities on a given arm with a true rate of 5% is 93%.
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
For this protocol, all patients, including those who discontinue protocol therapy early, will be followed for response until clinical metastatic progression and for survival for 10 years from
the date of registration. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 11 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 11 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
