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Clinical Trials Monthly - December 2012

This month we’ve focused on genitourinary cancers with a feature article titled: Another Victory in Prostate Cancer Treatment – Enzalutamide as well as several clinical trials for prostate and bladder cancer.

Another Victory in Prostate Cancer Treatment —Enzalutamide

Prostate cancer is generally very sensitive to testosterone, which binds to the androgen receptor (AR) on prostate cancer cells to spur their growth and spread. Many current treatments interfere with the testosterone-AR pathway, but the disease often becomes resistant to this hormonal pathway (“castration-resistant”) after prolonged treatment.

Recently, new treatments for metastatic castration-resistant prostate cancer have led to improved survival outcomes. Examples include docetaxel, abazetaxel, and sipuleucel-T. In 2011, abiraterone was approved by the FDA for its ability to inhibit production of testosterone, improving survival even in very advanced patients who had received prior docetaxel.

A new agent called enzalutamide (MDV3100) potently and irreversibly binds to AR and shuts down the process of prostate cancer cell activation. Successful Phase I/II studies at Seattle Cancer Care Alliance (SCCA) and other institutions led to a large randomized Phase III trial, called AFFIRM, that evaluated men who had already received prior docetaxel for metastatic, castration-resistant prostate cancer.

In this study, enzalutamide was shown to reduce the risk of death by 37 percent with a median survival benefi t of fi ve additional months. All other important study endpoints, such as decrease in PSA, time to progression, and decrease in tumor size were all in favor of those who received enzalutamide. A small number of men (fi ve, 0.6 percent) experienced seizure.

Figuring out the best timing and combinations

With this growing tool chest of survival-prolonging agents, the question now is how best to initiate, sequence, and combine these multiple drugs to achieve the best long-term outcome. SCCA physician researchers are now developing and conducting clinical studies to do exactly that.

One example is the work of Evan Yu, MD, and Heather Cheng, MD, who are determining whether the new agents should be combined or sequenced with other chemotherapies. Specifically, they are evaluating how well enzalutamide works for patients who have already received prior abiraterone. They plan to develop an enzalutamide trial for the large patient population that develops PSA rise after surgery or radiation therapy. This trial will enroll hundreds of patients and follow them for years with a potential goal of moving enzalutamide very early in the future treatment paradigm.

SCCA’s Celestia Higano, MD, is also investigating enzalutamide in earlier disease states for men with castration-resistant prostate cancer. The PREVAIL trial and the STRIVE trial, opening soon, will test enzalutamide against bicalutamide, an older drug that also blocks AR. These trials will enroll patients with radiographically detectable metastasis and those who do not have detectable metastatic disease but only rising PSA.

Because prostate cancer cells can become resistant to treatment, researchers are also closely examining cells during treatment to identify mechanisms of resistance. This line of study might help in determining how to select the most appropriate treatment for individual patients. Toward this end, Elahe Mostaghel, MD, and Peter Nelson, MD, along with SCCA medical oncologist Bruce Montgomery, MD, are leading efforts to acquire tumor tissue from patients at all stages of treatment with agents like abiraterone and enzalutamide.

Looking ahead, even newer advances such as radium-223 are coming to the field of prostate cancer treatment. Figuring out how and when to use the growing arsenal of treatments, and how to individualize therapy, will ensure the maximum benefi t for the greatest number of patients.

A Patient's Experience with Enzalutamide

Jim Conaty is a retired orthopedic surgeon from Spokane, Wash., who underwent surgery to treat prostate cancer in 1999 at age 61. After a year, his PSA began to rise, and Jim received radiation therapy. His PSA rose four-fold after just a few weeks.

Celestia Higano, MD, UW professor of medical oncology and prostate cancer specialist, treated Jim with nonsteroidal anti-androgens, which block the effect of androgens, along with leuprolide, which reduces testosterone levels. These agents stopped the growth and spread of his cancer.

The treatment held fast for six years but then Jim’s PSA began rising again. That’s when he became one of the fi rst people to be treated in a Phase I/II clinical trial for MDV-3100, now known as enzalutamide. Jim has been taking this medication since January 2008 and remains on it today. His PSA has been nearly undetectable and his lymph nodes have been stable ever since.

“I’m 73 now and find this particularly remarkable because of my PSA doubling in just a few weeks before starting the drug. Usually that means a poor prognosis,” Jim says. Side effects from his treatments haven’t been too bad. He gained more weight than he liked while on the study drug and androgen suppression “has its own issues,” he says. “But I’m surviving nicely with my loving, caring wife Patty. My retirement has been made positive by Dr. Higano and Seattle Cancer Care Alliance.”

Prostate Cancer

MDV3100 for Patients Undergoing Prostatectomy for Prostate Cancer

A Randomized, Open-label, Phase II Study of MDV3100 as a Neoadjuvant Therapy for Patients Undergoing Prostatectomy for Localized Prostate Cancer (NCT01547299)

The purpose of this study is to assess response rates following therapy with MDV3100—either alone or in combination with leuprolide and dutasteride—as neoadjuvant therapy for six months prior to prostatectomy in patients with localized prostate cancer. Secondary outcome measures include PSA level, rate of positive surgical margins, effects on specific pharmacodynamics markers, and others. This study opened in March 2012 and is estimated to be completed by August 2013.

Investigator: Robert Bruce Montgomery, MD.

Abiraterone for Metastatic, Castration Resistant Prostate Cancer

Open-Label Pharmacodynamic Study of Abiraterone in the Treatment of Metastatic, Castration-Resistant Prostate Cancer

The purpose of this study is to evaluate the molecular effects of abiraterone acetate and prednisone on prostate cancer. While taking these drugs, patients will undergo sampling of cancer—one before treatment and one during treatment—to measure tumor responses and other cellular effects of abiraterone acetate. The study also follows patients for PSA levels, cancer symptoms, and side effects.

Investigator: Robert Bruce Montgomery, MD.

Degarelix Acetate Prior to Radiation Therapy

Radiation with Androgen Deprivation (RAD2): Degarelix Acetate Prior to Radiation Therapy (NCT01731912)

Sponsored by Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium, this is a trial testing degarelix acetate prior to radiation therapy for adenocarcinoma of the prostate (stage IIA, IIB, III, or IV prostate cancers). This medication, a hormonal therapy once known as FE200486, binds to gonadotropin-releasing hormone (GnRH) receptors in the pituitary gland. By blocking GnRH binding, degarelix induces a rapid reduction in luteinizing hormone and follicle-stimulating hormone and thereby profoundly suppresses testosterone production.

Degarelix may be better hormone therapy than traditional luteinizing hormone-releasing hormone (LHRH) agonists such as leuprolide. This study will examine potential biological mechanisms behind this hypothesis. The goal is to determine the best androgen deprivation therapy possible so it can be employed as early as possible in the treatment of locally advanced prostate cancer.

Investigator: Robert Bruce Montgomery, MD.

GTx-758 for Castration Resistant Prostate Cancer

Phase II, Open-Label Study of the Effect of GTx-758 as Secondary Hormonal Therapy on Serum PSA and Serum-Free Testosterone Levels in Men with Prostate Cancer Maintained on Androgen Deprivation Therapy (NCT01615120)

GTx-758 performs some of the roles of an estrogenic agent against prostate cancer, but it also increases sex hormone-binding globulin (SHBG). This protein binds to testosterone in the blood, making the hormone less available to fuel activity in prostate tumors. Early studies have shown signifi cant decreases in PSA. This trial will enroll men with early metastatic castration-resistant prostate cancer yet to be treated with chemotherapy or other second-line hormonal therapies. Patients will be divided into three cohorts to test the efficacy and safety of three different dose levels of GTx-758.

Investigator: Evan Ya-Wen Yu, MD.

BKM120 for Metastatic Castration-resistant Prostate Cancer

Phase II Study of BKM120 in Men with Metastatic, Castration-Resistant Prostate Cancer

BKM-120 inhibits PI3kinase, is an intracellular signaling protein implicated in prostate cancer resistance to potent hormonal therapies. This novel agent is being tested in chemotherapyresistant and castration-resistant metastatic prostate cancer patients, many of whom have received prior hormonal therapies. This trial is in collaboration with Duke University Medical Center.

Investigator: Evan Ya-Wen Yu, MD.

Bladder Cancer Trials

OGX-427 Plus Chemotherapy for Advanced Bladder Cancer

A Randomized, Double-Blind Phase II Study Comparing Gemcitabine and Cisplatin in Combination with OGX-427 or Placebo in Patients with Advanced Transitional Cell Carcinoma (NCT01454089)

This is an advanced bladder cancer study evaluating the safety and efficacy of standard chemotherapy in combination with the investigational drug OGX-427. From OncoGeneX, OGX-427 has been shown to inhibit production of heat shock protein 27 (Hsp27), a protective multi-functional protein that is elevated in many cancers. Expression of this protein is further enhanced by various cancer treatments. By inhibiting the production of Hsp27, OGX-427 may reduce tumor resistance to therapy and improve treatment outcomes for advanced bladder cancer patients.

Investigator: Evan Ya-Wen Yu, MD.


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