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A Multicenter Phase I/II Trial of Abiraterone Acetate + BEZ235 in Metastatic, Castration-Resistant Prostate Cancer

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ClinicalTrials.gov Identifier: NCT01717898
Recruitment Status : Terminated (Dose limiting toxicities on lowest dose level)
First Posted : October 31, 2012
Last Update Posted : July 28, 2017
Novartis Pharmaceuticals
Information provided by (Responsible Party):
Charles Ryan, University of California, San Francisco

Brief Summary:

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

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 6 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Primary Completion Date : September 3, 2013
Study Completion Date : August 29, 2016

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arm Intervention/treatment
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.
Drug: BEZ235
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.
Drug: Prednisone
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

Primary Outcome Measures :
  1. Number of reported Dose Limiting Toxicities when combining BEZ235 with Abiraterone Acetate (Phase I). [ Time Frame: Up to 15 months ]
  2. 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 [ Time Frame: Up to 12 weeks ]
  3. 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). [ Time Frame: Up to 12 weeks ]
  4. Determination of a Maximum Tolerated Dose for BEZ235 when given with Abiraterone Acetate (Phase I). [ Time Frame: Up to 15 months ]

Secondary Outcome Measures :
  1. Trough concentrations of BEZ235 and Abiraterone Acetate plus Prednisone when used in combination (Phase I). [ Time Frame: Up to 15 months ]
  2. Determination of Progression Free Survival (PFS) of the combination of BEZ235 plus Abiraterone Acetate/prednisone as determined by PSAWG2 criteria (Phase II). [ Time Frame: Up to 15 months ]
  3. Determination of the time to PSA progression based on PSAWG2 criteria (Phase II). [ Time Frame: Up to 15 months ]
  4. Determination of the proportion of patients achieving an objective response to BEZ235 plus Abiraterone Acetate/prednisone according to RECIST criteria (Phase II). [ Time Frame: Up to 15 months ]
  5. Number of reported Adverse Events in BEZ235 and Abiraterone Acetate plus Prednisone when used in combination (Phase II). [ Time Frame: Up to 15 months ]

Other Outcome Measures:
  1. 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: Up to 12 weeks ]
  2. 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: Up to 12 weeks ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No

Inclusion Criteria:

Patients eligible for inclusion in this study have to meet all of the following criteria:

  1. Patient has provided a signed study Informed Consent Form prior to any screening procedure.
  2. Patient is ≥ 18 years of age on the day of consenting to the study.
  3. Patients must have histologically confirmed adenocarcinoma of the prostate.
  4. Radiographic evidence of disease (bone scan, CT scan, ultrasound or MRI acceptable) that is amenable to image-guided biopsy must be present.
  5. Patients must have castrate levels of testosterone (< 50 ng/dL) on GnRH analogues or have had prior orchiectomy. GnRH analogues must be continued while on study.
  6. Progressive disease as demonstrated by a rising PSA or radiographic progression per PCWG2 criteria.
  7. Asymptomatic or minimally symptomatic disease: No use of opiate analgesics (EXCLUDING codeine or dextromethorphan) for cancer related pain within 28 days of day 1, cycle 1.
  8. Phase II Cohort 1: No prior Abiraterone Acetate therapy
  9. Phase II Cohort 2: Immediate prior Abiraterone Acetate therapy is required. No intervening therapy is allowed between Abiraterone Acetate therapy and study therapy.
  10. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
  11. Men of reproductive potential who have not had a radical prostatectomy must agree to use an effective contraceptive method. Patients who have had a prostatectomy are sterile and do not need to use contraception.
  12. Patient has adequate bone marrow and organ function as shown by:

    • Absolute neutrophil count (ANC) ≥ 1.0 x 109/L
    • Platelets ≥ 100 x 109/L
    • Hemoglobin (Hgb) ≥ 9.0 g/dL
    • INR ≤ 2
    • Serum creatinine ≤ 1.5 x ULN
    • Total serum bilirubin ≤ 1.5 x ULN (in patients with known Gilbert Syndrome, a total bilirubin ≤ 3.0 x ULN, with direct bilirubin ≤ 1.5 x ULN)
    • AST and ALT ≤ 3 x ULN (or ≤ 5.0 x ULN if hepatic metastases are present)
    • Fasting plasma glucose (FPG) ≤ 140mg/dL [7.8 mmol/L]
    • HgbA1c ≤8% (Patients with diabetes mellitus not actively being treated and patients with an HgbA1c level between 7-8% will be required to have home glucose monitoring three times weekly during the first cycle. Patients may also be referred to a diabetes specialist as indicated.)

Exclusion Criteria:

Patients eligible for this study must not meet any of the following criteria:

  1. Patient has received previous treatment with PI3K and/or mTOR inhibitors.
  2. Phase II Cohort 1: Prior Abiraterone Acetate therapy is an exclusion
  3. Prior therapy with any of the following for >1 month: MDV-3100, Orteronel, ketoconazole or other drugs given with the intention to inhibit CYP 17.
  4. Patient has active uncontrolled or symptomatic CNS metastases. Note: A patient with controlled and asymptomatic CNS metastases may participate in this trial. As such, the patient must have completed any prior treatment for CNS metastases > 90 days (including radiotherapy and/or surgery) prior to start of treatment in this study and should not be receiving chronic corticosteroid therapy for the CNS metastases.
  5. Patient has a concurrent malignancy or has had a malignancy in the last 3 years prior to start of study treatment (with the exception of adequately treated basal or squamous cell carcinoma or cervical carcinoma in situ).
  6. Patient has received wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) ≤ 28 days or limited field radiation for palliation ≤ 14 days prior to starting study drug or has not recovered from side effects of such therapy.
  7. Patient has had major surgery within 28 days prior to starting study drug or has not recovered from major side effects of the surgery.
  8. Patient has active cardiac disease including any of the following:

    • Left Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO)
    • QTcF > 480 msec on screening ECG
    • Unstable angina pectoris
    • Ventricular arrhythmias except for benign premature ventricular contractions
    • Supraventricular and nodal arrythmias requiring a pacemaker or not controlled with medication
    • Conduction abnormality requiring a pacemaker
    • Valvular disease with documented compromise in cardiac function
    • Symptomatic pericarditis
  9. Patient has a history of cardiac dysfunction including any of the following:

    • Myocardial infarction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF function.
    • History of documented congestive heart failure (New York Heart Association functional classification III-IV)
    • Documented cardiomyopathy
  10. Family history of congenital long or short QT, or known history of QT/QTc prolongation or Torsades de Pointes (TdP).
  11. Patient with medically documented history of active major depressive episodes, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation.
  12. Active or uncontrolled infection of hepatitis B or hepatitis C.
  13. Inadequately controlled hypertension (i.e., SBP > 180 mmHg or DBP > 100 mmHg).
  14. Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of BEZ235 (e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea grade ≥ 2, malabsorption syndrome or small bowel resection).
  15. Use of any chemotherapy, investigational agents, immunotherapy, or hormonal therapy other LHRH agonists within 28 days of the start of treatment on protocol. Use of bone targeted agents including bisphosphanates and RANK ligand inhibitors is allowed if on stable dose; Xgeva or Zometa cannot be started within 28 days of initiating study therapy.
  16. Systemic corticosteroids except as part of on label treatment prostate cancer regimens.

    Note: Topical applications (e.g., rash), inhaled sprays (e.g., obstructive airways diseases), eye drops or local injections (e.g., intra-articular) are allowed.

  17. Patient is undergoing active treatment for diabetes mellitus.
  18. Patient is being treated at start of study treatment with any of the following drugs:

    • Drugs known to be moderate and strong inhibitors or inducers of isoenzyme CYP3A4 including herbal medications (see Appendix 1 for a list of prohibited CYP3A4 inhibitors and inducers)
    • Drugs with a known risk to induce Torsades de Pointes (see Appendix 3 for a list of prohibited drugs)
    • Warfarin and coumadin analogues
  19. Patient is consuming Seville oranges, grapefruit, grapefruit hybrids, pomelos and exotic citrus fruits (as well as their juices) during the last 7 days prior to start of treatment. Regular orange juice is permitted.
  20. Immunocompromised patients, including known seropositivity for HIV (testing is not mandatory).
  21. Patient has other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment contraindicate his participation in the clinical study (e.g. uncontrolled diabetes, chronic pancreatitis, active chronic hepatitis etc.).
  22. Patient is not able to understand or to comply with study instructions and requirements or has a history of non-compliance to medical regimen.
  23. Patients in whom, in the opinion of the treating physician, should receive cytotoxic chemotherapy with docetaxel.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

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
Sponsors and Collaborators
Charles Ryan
Novartis Pharmaceuticals
Study Chair: Charles Ryan, MD University of California, San Francisco

Responsible Party: Charles Ryan, Associate Professor of Clinical Medicine & Urology, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT01717898     History of Changes
Other Study ID Numbers: UCSF CC#125510
First Posted: October 31, 2012    Key Record Dates
Last Update Posted: July 28, 2017
Last Verified: July 2017

Keywords provided by Charles Ryan, University of California, San Francisco:
Castrate-resistant prostate cancer

Additional relevant MeSH terms:
Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Genital Diseases, Male
Prostatic Diseases
Abiraterone Acetate
Anti-Inflammatory Agents
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Hormone Antagonists
Cytochrome P-450 Enzyme Inhibitors