Study of Dose Escalation of Abiraterone Actetate in Prostate Cancer

The purpose of this study is to test whether a dose escalation up to 2000 mg per day of abiraterone acetate is feasible and lead to disease stabilization in castration-resistant metastatic prostate cancer patients who experience disease progression within the first 6 months of abiraterone actetate at standard dose (1000 mg/d) and have a plasma abiraterone concentration below 8.5 ng/mL.

It is a non-comparative phase 2 study in which patients will be included in two successive steps. Patients with mCRPC will be included in the first step and treated with standard dose (1000 mg/day) of ABI + prednisone /prednisolone (10 mg/d) according to the summary of product characteristics and monitored for trough ABI plasma level each month for 3 months.

In the second step intrapatient ABI dose escalation (2000 mg/day) + prednisone/prednisolone (10 mg/d) will be realized for patients from the first step experiencing progressive disease within 6 months of ABI standard dose and with mean ABI plasma level during the first three months \< 8.5 ng/mL

Metastatic castration-resistant prostate cancer (mCRPC) causes approximately 307,500 deaths annually worldwide. mCRPC has been defined as a clinical state in which, despite suppressed circulating testosterone levels lower than 50 ng/dL, the androgen receptor axis is reactivated. This reactivation is mainly due to the multiple signaling mechanisms in prostate cancer cells along with their microenvironment.

Thus, research efforts aimed at identifying new strategies to inhibit the androgen receptor axis. Abiraterone acetate (ABI) is a first-in-class inhibitor of cytochrome (CYP) 17A1, a critical enzyme for extra-gonadal and testicular androgen syntheses. ABI has shown impressive efficacy in treatment of mCRPC. ABI plus low-dose prednisone was first shown to improve survival in mCRPC patients pre-treated with docetaxel, and the combination therapy has since been approved for this purpose. Moreover, ABI plus low-dose prednisone resulted in prolonged overall survival (OS) as compared with placebo plus prednisone in docetaxel-naive patients. In these patients, ABI was associated with a median progression free survival of 16 months and median overall survival of 35 months. However, around 40% of patients do not experience PSA response to ABI therapy at 3 months. This parameter has been consistently identified as a surrogate parameter of time to progression.

As ABI is an oral agent that is subject to both inter- and intra-individual variability in bioavailability, its pharmacokinetics might be a critical parameter for its anticancer activity.

Investigators first established a simple method to mesure plasma ABI concentration by HPLC. They then conducted a prospective observational study in which they aimed to explore the relationship between ABI trough concentration and PSA response in mCRPC patients and to identify the critical determinants for its activity.

73 mCRPC patients, in whom treatment with ABI was indicated, were recruited from December 2012 to December 2014 in the oncology department of Cochin Hospital in Paris, France. The plasma concentration of ABI was determined at baseline, and then one (M1), two (M2) and three (M3) months after treatment initiation. The primary study objective was to investigate the relationship between ABI mean plasma trough concentration (ABI Cmin) and PSA response. PSA response was defined as a PSA decline of at least 50% after receiving ABI for 3 months.

In multivariate analysis, ABI Cmin was the only factor independently associated with PSA response: OR=1.12, \[1.0-1.3\], P=0.03. Based on these results, they established an optimal threshold of ABI C min by building a ROC curve. The treshold value of 8.45 ng/mL was associated with a specificity of and sensitivity of 70% \[49-84\] and 79% \[63-81\], respectively.

As plasma ABI exposure is a key element of PSA response, it supports the exploration of benefits of a pharmacokinetically-guided dosing strategy for ABI.

In a phase I trial, the recommended dose of ABI was 1000 mg per day as a plateau of endocrine effects was reported at doses greater than 750 mg. However, to their knowledge, no data regarding the effect of ABI on tissue androgens are available, and no dose limiting toxicity was identified up to 2000 mg per day which support the rational of a dose-escalation strategy. In a phase 2 study, 41 mCRPC patients received 1000 mg twice a day of ABI (2000 mg/day) and the tolerance profile appeared similar than with lower dose.

In this phase II trial, investigators aim to confirm the preliminary results presented above in a larger population. Moreover, their objective is to test whether a dose escalation up to 2000 mg per day is feasible and lead to disease stabilization in progressive patients within the first 6 months of treatment.

Eligibility Criteria:
Inclusion Criteria:

Step 1

* Male 18 years and older.
* Voluntary signed informed consents of the patient before any study-specific procedure.
* Histologically confirmed prostate adenocarcinoma.
* Presence of bone and/or soft-tissue and/or visceral metastases through CT scan, MRI, scintigraphy scan.
* Progressive disease assessed by PSA, CT scan, MRI or bone scan according to the PCGW3 criteria PSA progression is defined as a 25% or greater increase and an absolute increase of 2 ng/mL or more from the nadir, which is confirmed by a second value obtained 1 or more weeks later. Bone scan: at least two or more new lesions are seen on bone scan compared with a prior scan.
* Patient with no or moderate symptoms (no need for continuous opioid treatment)
* Effective castration confirmed by testosterone plasma level \< 50 ng/dL
* ECOG performance status: 0-2
* Life expectancy \> 3 months
* Patient affiliate to french social assurance
* Laboratory criteria within 14 days before inclusion:

  * SGPT and SGOT \< 5 fold the upper normal value
  * Kaliemia \> 3 mM
* Patient using an effective contraceptive method during treatment

Step2

* Patients receiving ABI 1000 mg/day + prednisone/prednisolone 10 mg once a day through step 1 for at least two months
* At least two measures of ABI plasma concentrations available within the first three months of treatment
* Mean of ABI concentration \< 8,5 ng/mL.
* Progressive disease occuring within 28 weeks following starting of ABI in the step 1. A progressive disease is assessed by PSA increase or bone scan according to PCWG3 criteria (15) or to CT scan according to RECIST 1.1 criteria (see § 2).
* Inclusion in step 2 must occur within 2 months following the first observation of cancer progression while in step 1.
* Patient using an effective contraceptive method during treatment

Exclusion Criteria:

Step 1

* Pure small cell carcinoma of the prostate or predominant histology of neuro-endocrine carcinoma.
* Confirmed brain and/or leptomeningeal metastases
* Previous treatment with docetaxel or any other anticancer treatment for castration-resistant prostate carcinoma (previous docetaxel for hormone-sensitive metastatic disease is allowed)
* Previous treatment with ABI or any other 17 B hydroxylase inhibitor or enzalutamide
* Treatment with first-generation antiandrogen (ciproterone acetate, bicalutamide, flutamide, nilutamide) performed on the day of baseline or within previous four weeks, due to possible anti-androgen withdrawal response. (This criterion does not apply for subjects, who have never responded to anti-androgen treatment).
* Patient co-morbidities:

  * Patients with the following hereditary diseases: galactose hypersensitivity, Lapp lactase deficiency.
  * Cirrhosis Child-Pugh B or C
  * Active or symptomatic viral hepatitis
  * Heart failure stage NYHA III or IV
  * Cardiac arythmia, heart failure stage NYHA II, ischemic cardiopathy or uncontroled hypertension, except if left ventricular ejection fraction is \> 50%
  * Patients with left ventricular ejection fraction (LVEF) \< 50%
  * Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or puts the patient at high risk for treatment related complications.Prior or concurrent malignant disease in complete remission for less than 3 years, except T1N0 vocal cord carcinoma, basal or squamous cell skin carcinoma and in situ transitional cell bladder carcinoma
* Limitation of the patient's ability to comply with the treatment or to follow-up the protocol.

Step 2 Grade 3-4 toxicities related to ABI. In case of persistent grade 2 toxicity, inclusion in step 2 must be discussed in a case by case basis with the study coordinating Investigator.

* All non-inclusion criteria for step 1 applied
* Patient who is not adherent to ABI treatment at the investigator opinion
* Patient with a symptomatic and/or visceral tumor progression that would be an indication to start chemotherapy immediately according to the opinion of the investigator