Phase Ib of Abiraterone Acetate Plus BEZ235 or BKM120 in Castration-resistant Prostate Cancer (CRPC) Patients

Phase Ib Dose Finding Study of Abiraterone Acetate Plus BEZ235 or BKM120 in Patients With Castration-resistant Prostate Cancer.

This is an open label study of abiraterone acetate in combination with BEZ235 and abiraterone acetate in combination with BKM120 in CRPC patients with abiraterone acetate failure.

Study Overview

• Status: Completed
• Conditions: Castration-resistant Prostate Cancer
• Intervention / Treatment: Drug: BEZ235; Drug: BKM120

Detailed Description

A dose-escalation part will first determine the maximum tolerated dose (MTD) and/or recomended dose for expansion (RDE) of abiraterone acetate in combination with BEZ235 and abiraterone acetate in combination with BKM120 in CRPC patients with abiraterone acetate failure.

Subsequently, the MTD and/or RDE of each combination will be investigated in two expansion treatment groups of CRPC patients who have failed abiraterone acetate therapy.

• Study Type: Interventional
• Enrollment (Actual): 43
• Phase: Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, BE-B-1200
    • Novartis Investigative Site
  • Wilrijk, Belgium, 2610
    • Novartis Investigative Site
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • Novartis Investigative Site
• France
  • Marseille, France, 13273
    • Novartis Investigative Site
  • Villejuif Cedex, France, 94805
    • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28041
    • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08036
      • Novartis Investigative Site
• United Kingdom
  • Sutton, United Kingdom, SM2 5PT
    • Novartis Investigative Site
• United States
  • California
    • Los Angeles, California, United States, 90048
      • Cedars Sinai Medical Center SC
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center Hackensack Univ

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Adult males ≥ 18 years old
• Eastern Cooperative Oncology Group Performance Status ≤ 2
• Patient must have a castrate level of testosterone (<= 50 ng/dL or 1.7 nmol/L). ( Castrate status must be maintained by continued GnRH analogues unless patient has undergone surgical orchiectomy).
• Histologically or cytologically confirmed diagnosis of advanced or metastatic prostate cancer.
• Advanced or metastatic castration-resistant prostate cancer progression after abiraterone acetate failure
• Patients should have no more than 2 lines of prior chemotherapies including cytotoxic agents
• Discontinuation of all anti-androgen, anti-neoplastic or investigational treatment >= 4 weeks (6 weeks for bicalutamide).

Exclusion Criteria:

• Previous treatment with PI3K pathway inhibitors (e.g. PI3K, AKT, mTOR inhibitor), ketoconazole, CYP17 inhibitors (exception of AA), or enzalutamide.
• Patient has active uncontrolled or symptomatic CNS metastases
• Inadequately controlled hypertension (e.g. systolic blood pressure >=160 mmHg or diastolic blood pressure >=95 mmHg)
• Patient has a QTcF > 480 msec on the screening ECG (using the QTcF formula), has a short/long QT syndrome, or history of QT prolongation/Torsades de Pointes
• Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drugs
• Patient has a medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (e.g. risk of doing harm to self or others)
• Patients who experienced dose reductions and/or treatment interruptions due to abiraterone acetate related toxicities (i.e. serious AEs, AEs, liver toxicities during abiraterone acetate treatment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Dose escalation: BEZ235 + Zytiga®; BEZ235 oral twice daily: 200 mg, 300 mg, and 400 mg dose levels to be tested in the dose escalation part in combination with abiraterone acetate Zytiga® abiraterone acetate oral once daily: 1000 mg taken with low dose prednisone as per the label	Drug: BEZ235; BEZ235 will be supplied as 50mg, 100mg, 200mg, 300mg and 400mg SDS sachets. At each patient's visit, patient will reecive a prescription of an adequate drug supply for self administration at home.
EXPERIMENTAL: Dose escalation: BKM120 + Zytiga®; BKM120 oral once daily: 60 mg, 80 mg and 100 mg dose levels to be tested in the dose escalation part in combination with abiraterone acetate Zytiga® abiraterone acetate oral once daily: 1000 mg taken with low dose prednisone as per the label	Drug: BKM120; BKM120 will be supplied as 10mg and 50mg hard gelatin capsules. At each patient's visit, patient will reecive a prescription of an adequate drug supply for self administration at home.
EXPERIMENTAL: Dose expansion: BEZ235 + Zytiga®; BEZ235 oral twice daily: 200 mg, 300 mg, and 400 mg dose levels to be tested in the dose escalation part in combination with abiraterone acetate Zytiga® abiraterone acetate oral once daily: 1000 mg taken with low dose prednisone as per the label	Drug: BEZ235; BEZ235 will be supplied as 50mg, 100mg, 200mg, 300mg and 400mg SDS sachets. At each patient's visit, patient will reecive a prescription of an adequate drug supply for self administration at home.
EXPERIMENTAL: Dose Expansion: BKM120 + Zytiga®; BKM120 oral once daily: 60 mg, 80 mg and 100 mg dose levels to be tested in the dose escalation part in combination with abiraterone acetate Zytiga® abiraterone acetate oral once daily: 1000 mg taken with low dose prednisone as per the label	Drug: BKM120; BKM120 will be supplied as 10mg and 50mg hard gelatin capsules. At each patient's visit, patient will reecive a prescription of an adequate drug supply for self administration at home.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of dose limiting toxicities (DLTs)	Dose escalation part: Determine MTD and /or RDE of the combinations abiraterone acetate + BEZ235 and abiraterone acetate + BKM120 by assessing the incidence of DLTs in cycle 1	from days 1-35 in BEZ235/abiraterone acetate arm and from days 1-28 in BKM120/abiraterone acetate arm
Prostate specific antigen (PSA) decline ≥ 30%	Dose expansion part: Assess anti-tumor activity of the combinations (abiraterone acetate + BEZ235 and abiraterone acetate + BKM120) in castration-resistant prostate cancer patients with abiraterone acetate failure as on treatment PSA progression according to prostate cancer working group criteria 2 (PCWG2) by assessing PSA decline ≥ 30% at Week 12 or later.	At week 12 or later after treatment discontinuation

Secondary Outcome Measures

Outcome Measure	Time Frame
Number of patients with at least one adverse event	Treatment start until 30 days after the last dose
radiological Progression Free Survival as per RECIST 1.1 and PCWG2	Every 12 weeks until disease progression
radiological Response Rate according to RECIST 1.1	Every 12 weeks until disease progression
Overall Survival	From treatment start until 75% of deaths from any cause have occurred
Number and percentage of patients with laboratory abnormalities	Treatment start until 30 days after the last dose
Changes in ECG (electrocardiogram)	Treatment start until 30 days after the last dose
Changes in vital signs	Treatment start until 30 days after the last dose
Changes in mood scales	Treatment start until 30 days after the last dose

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• Results for CBEZ235D2101 can be found on the Novartis Clinical Trial Results Website

Study record dates

Study Major Dates

• Study Start: September 1, 2012
• Primary Completion (ACTUAL): July 1, 2015
• Study Completion (ACTUAL): July 1, 2015

Study Registration Dates

• First Submitted: June 26, 2012
• First Submitted That Met QC Criteria: July 2, 2012
• First Posted (ESTIMATE): July 6, 2012

Study Record Updates

• Last Update Posted (ACTUAL): December 9, 2020
• Last Update Submitted That Met QC Criteria: December 6, 2020
• Last Verified: September 1, 2015

More Information

Terms related to this study

• Keywords: Castration-resistant prostate cancer, abiraterone acetate, BEZ235, BKM120, dose escalation, abiraterone acetate failure
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms; Antineoplastic Agents; Dactolisib
• Other Study ID Numbers: CBEZ235D2101; 2012-002250-23 (EUDRACT_NUMBER)