E2809: Androgen Receptor Modulation: A Phase II randomized study of MK-2206 - Bicalutamide combination in patients with rising PSA at high-risk of progression after primary therapy

Summary

It is proposed that a global strategy to modulate androgen receptor (AR) activation without testosterone deprivation can be implemented to successfully prevent the progression of androgen-dependent and preexisting androgen-independent clones in patients with recurrent prostate cancer (PC) at high-risk of progression. We propose utilizing combinations of agents to simultaneously block the AR ligand binding domain (LBD) with anti-androgens and the cross-talk with activated PKs using specific inhibitors or agents that decrease the levels of AR expression. We predict that this combined approach will reduce expression and function of AR in PC and target tissues that will reduce PSA to undetectable levels. We expect a marked antitumor response with a prolonged period of remission or cure. By preserving testosterone, we expect patients to experience a better quality of life (QOL) compared to historical controls treated with androgen deprivation. Furthermore, in cases of progression, we predict that the recurrent tumor in a non-castrate environment will remain androgen-sensitive and responsive to androgen ablation. Finally, we predict that this prolonged hormone sensitive state will be associated with increased survival.

Participant Eligibility

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 must have hormone-sensitive prostate cancer as evident by a serum total testosterone level > 150 ng/dL within 12 weeks prior to randomization.

8. 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; obtained within 6 months of study entry and preferably at the same reference lab

9. PSADT calculation needs 3 PSA values: PSA1, PSA2, PSA3 and Baseline PSA

10. Patient's PSA doubling time (PSADT) must be less than 12 months calculated using the following formula: PSADT in days = 0.693 (t) / In (PSA3) – In (PSA2)

11. Patient must have an ECOG Performance Status of 0 or 1.
12. Patient must have adequate end-organ function as evident by the following lab values obtained within 4 weeks prior to randomization:

12.1. Granulocytes ≥1500/mm3

12.2. Platelet count ≥ 100,000/mm3

12.3. Serum creatinine within normal institutional limits or creatinine clearance ≥ 50 mL/hr for patients with creatinine levels above institutional normal.

12.4. Serum total bilirubin ≤1.5 times the upper limit of normal (ULN), and alkaline phosphatase (ALP) ≤2.5 x ULN

12.5. SGOT (AST) and SGPT (ALT) < 2.5 x institutional upper limit of normal.

13. Patients may have received targeted agnets (angiogenesis inhibitors, EGFR inhibitors, mTOR inhibitors, P13K 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).