Study of Dose Escalation of Abiraterone Actetate in Prostate Cancer
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.
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