A Multicenter Phase I/II Trial of Abiraterone Acetate + BEZ235 in Metastatic, Castration-Resistant Prostate Cancer
|ClinicalTrials.gov Identifier: NCT01717898|
Recruitment Status : Terminated (Dose limiting toxicities on lowest dose level)
First Posted : October 31, 2012
Results First Posted : March 27, 2018
Last Update Posted : March 27, 2018
There will be two parts to this clinical research study. The purpose of each part is:
- Phase 1: This part of the study will determine what dose of BEZ235 is safe to give with a standard dose of abiraterone acetate and prednisone by administering different doses of BEZ235. This will help to find out what effects, good and/or bad, this combination has on CRPC.
- Phase 2: This part of the study will measure the treatment effect of the combination of BEZ235 and abiraterone acetate/prednisone on CRPC.
|Condition or disease||Intervention/treatment||Phase|
|Castrate-resistant Prostate Cancer||Drug: BEZ235 Drug: Prednisone Drug: Abiraterone acetate||Phase 1 Phase 2|
Hide Detailed Description
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).
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||6 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Multicenter Phase I/II Trial of Abiraterone Acetate + BEZ235 in Metastatic, Castration-Resistant Prostate Cancer|
|Actual Study Start Date :||January 31, 2013|
|Actual Primary Completion Date :||September 3, 2013|
|Actual Study Completion Date :||August 29, 2016|
Experimental: Abiraterone/prednisone + BEZ235
In Phase I, a dose escalation of BEZ235 will be performed using a standard 3 + 3 design to determine the maximum tolerated dose (MTD) of BEZ235 given in combination with continuous fixed doses of Abiraterone Acetate and prednisone. This BEZ235 dose will be used in the phase II portion of the study.
BEZ235 - 200 mg, 300 mg, or 400 mg; po, BID. BEZ235 will be supplied in 200 mg, 300 mg, and 400 mg sachets packaged in boxes.
10/mg po daily. Prednisone can be modified at the investigator's discretion, but should not be discontinued.
Drug: Abiraterone acetate
1000 mg, po. Abiraterone Acetate is supplied in 250 mg white tablets, four tablets are to be taken with a full glass of water on an empty stomach once daily.
Other Name: CB7630
- Number of Reported Dose Limiting Toxicities When Combining BEZ235 With Abiraterone Acetate (Phase I). [ Time Frame: Beginning of study up to 15 months ]
- Anti-tumor Responses as Defined by a Decline in PSA of > 50% [ Time Frame: From day 1 of therapy initiation up to 12 weeks ]Anti-tumor responses as defined by a decline in PSA of > 50% following 12 weeks of therapy to the combination of Abiraterone Acetate plus BEZ-235 occur in a cohort of patients who have received prior therapy with Abiraterone Acetate therapy
- Response Proportion as Defined by a Decline in PSA of > 50% [ Time Frame: From day 1 of therapy initiation up to 12 weeks ]
Response proportion as defined by a decline in PSA of > 50% following 12 weeks of therapy for patients treated with the combination of BEZ235 and Abiraterone Acetate plus Prednisone (Phase II outcome measure).
Study was terminated during Phase I, Dose level 1 due to toxicity, therefore no Phase II data is available.
- Maximum Tolerated Dose for BEZ235 + Abiraterone Acetate (Phase I). [ Time Frame: Beginning of study up to 15 months ]Maximum Tolerated Dose (MTD) for BEZ235 + Abiraterone Acetate (to be determined during Phase I). The MTD of BEZ235 will be the dose when given in combination results in less than 33% dose limiting toxicities (DLT).
- Trough Concentrations of BEZ235 and Abiraterone Acetate Plus Prednisone When Used in Combination [ Time Frame: Beginning of study up to 15 months ]Trough concentrations of BEZ235 and Abiraterone Acetate plus Prednisone when used in combination during Phase I.
- Progression Free Survival (PFS) in Phase II [ Time Frame: Beginning of Phase II up to 15 months ]Progression Free Survival (PFS) of the combination of BEZ235 plus Abiraterone Acetate/prednisone as determined by Prostate-Specific Antigen Working Group 2 criteria (PSAWG2 ) during Phase II.
- Determination of the Time to PSA Progression in Phase II [ Time Frame: Beginning of Phase II up to 15 months ]Determination of the time to PSA progression in Phase II based on PSAWG2 criteria.
- Objective Response Rate (ORR) in Phase II [ Time Frame: From beginning of Phase II up to 15 months ]Proportion of patients achieving an objective response to BEZ235 + Abiraterone Acetate/prednisone according to RECIST criteria.
- Safety of BEZ235 and Abiraterone Acetate Plus Prednisone When Used in Combination [ Time Frame: Beginning of Phase II up to 15 months ]Number of reported Adverse Events in BEZ235 and Abiraterone Acetate plus Prednisone when used in combination (Phase II).
- Determination of Whether the Pre-treatment Status of pS6, pAKT, p4EBP1 and PTEN, Determined by IHC in the Optional Biopsies of Metastatic Tumors, Are Associated With Response to BEZ235 Plus Abiraterone Acetate/Prednisone. [ Time Frame: post study ]
- Determination of Whether Specific Pathway Changes Are Predictive of Clinical Benefit (Improved PFS) or Resistance Prior to Treatment or During Treatment Using Microarray Analysis. [ Time Frame: post study ]
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01717898
|United States, California|
|University of California, San Francisco|
|San Francisco, California, United States, 94115|
|Study Chair:||Charles Ryan, MD||University of California, San Francisco|