A Multicenter Phase I/II Trial of Abiraterone Acetate + BEZ235 in Metastatic, Castration-Resistant Prostate Cancer
Prostate Cancer Overview:
Prostate cancer is the second most common cancer in men representing approximately 30% of
all cancers diagnosed in men. When confined to the prostate gland the disease is curable
with local therapy. However approximately 50% of men fail local therapy and develop
incurable metastatic disease. Androgen deprivation (AD) therapy remains the mainstay of
treatment, not only for advanced disease but also in the adjuvant and neo-adjuvant settings.
Androgen deprivation therapy induces a remission in 80 to 90% of patients with advanced
disease and results in a median progression-free survival of 12 to 33 months, at which time
an androgen-independent phenotype usually emerges. This accounts for the median overall
survival of 23 to 37 months from the initiation of androgen deprivation.
Androgen deprivation can be achieved surgically with orchiectomy, or using some form of drug
treatment. Current approaches to AD utilize leutinizing hormone releasing hormone (LHRH)
agonists. These act by continuous stimulation of the anterior pituitary resulting in
inhibition of leutinizing hormone (LH) secretion, and hence a fall in testicular production
of testosterone. Although AD is clinically effective in the majority of patients, studies
have shown that extratesticular sources of testosterone represent an important alternative
source of androgen stimulation in a significant proportion of prostate cancer patients. As
much as 10% of baseline circulating testosterone remains in castrate men, due to the
peripheral conversion of adrenal steroids to testosterone. Increased levels of androgen
receptor confer resistance to antiandrogens in prostate cancer xenograft models. This could
result in amplified signal output from circulating low levels of adrenal androgens and
suggests a role for agents that target the adrenal androgen synthesis pathway.
As prostate cancer progresses to castration-resistant prostate cancer genetic events
accumulate. One of the most consistent genetic findings in CRPC is amplification and
over-expression of the androgen receptor (AR). Multiple groups have demonstrated that
up-regulation of AR expression along with de novo synthesis of androgens by the adrenals
and/or prostate cancer cells themselves is perhaps the most common mechanism by which
prostate cancer cells progress despite castrate levels of circulating testosterone. This
underlying biology is likely the mechanism explaining the recent success of Abiraterone
Acetate.
An important genetic event found to be associated with progression of prostate cancer is
loss of heterozygosity and subsequent homozygous deletion at the 10q23 locus containing the
PTEN tumor suppressor gene. PTEN functions, in part, as a negative regulator of the
phosphatidylinositol 3' (PI3) kinase - AKT pathway. Targeting the PI3K pathway and/or
downstream targets of PI3K has been recognized as an important therapeutic strategy for some
time. An important aspect of PI3K signaling is the PTEN mutation and the downstream events
associated with PI3K signaling are not mutually exclusive with the aforementioned AR
signaling pathway aberrancies that have yielded important therapeutic consequences.
Preclinical data has demonstrated that PI3K inhibition upregulates AR expression, but that
the net effect is antiproliferative and that concomitant anti androgen therapy is
synergistic.
Introduction to BEZ235 and Abiraterone Acetate:
Preclinical data has demonstrated that PI3K inhibition upregulates AR expression, and that
concomitant anti-androgen therapy has synergistic anti-tumor effects with PI3K inhibition.
This study seeks to enhance the efficacy of Abiraterone Acetate in CRPC by concomitantly
targeting PI-3Kinase activity with the novel agent BEZ-235.
BEZ235 is a potent pan-class I PI3K and mammalian target of rapamycin (mTOR) inhibitor
belonging to the class of imidazoquinoline derivatives. BEZ235 is the investigational agent
utilized in this study.
Abiraterone Acetate is now considered a standard of care for the treatment of Castration
Resistant Prostate Cancer (CRPC) following docetaxel, and is likely to be considered such in
the pre-chemotherapy setting based on recent results. Despite benefits in survival
resistance to this therapy develops in virtually all patients.
Study rationale and purpose:
It is hypothesized that signaling through the PI3Kinase pathway is a major mechanism of
resistance to Abiraterone Acetate therapy (and castration based therapy in general) and that
inhibition of this pathway will enhance the clinical benefit of Abiraterone Acetate.
The addition of BEZ 235 to Abiraterone Acetate provides an opportunity to test if inhibition
of PI3K along with TORC1 will attenuate the survival mechanisms co-opted by CRPC when
treated with Abiraterone Acetate. We will conduct a Phase I study to determine the MTD for
this combination and use that dose for this Phase II study. Biopsies of metastatic disease
prior to and during treatment with BEZ235 plus Abiraterone Acetate will allow for the
determination if mutations in the PTEN and/or PI3kinase axis in biopsied tumors are
associated with response to therapy with the combination of BEZ235 and Abiraterone Acetate.
While PSA decline remains an imperfect surrogate marker for overall survival it remains a
useful means of determining whether a positive clinical "signal" exists for a given
treatment strategy and can be an efficient means of determining if an approach could proceed
to more definitive testing according the standards of the Prostate Cancer Working Group 2
(PCWG2).
Interventional
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Number of reported Dose Limiting Toxicities when combining BEZ235 with Abiraterone Acetate (Phase I).
Up to 15 months
Yes
Charles Ryan, MD
Study Chair
University of California, San Francisco
United States: Food and Drug Administration
UCSF CC#125510
NCT01717898
January 2013
June 2016
Name | Location |
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University of California, San Francisco | San Francisco, California 94143 |