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

NCT01717898 | Terminated Phase 1 Results DMC

• 1 other identifier: UCSF CC#125510
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

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.

Conditions

Castrate-resistant Prostate Cancer

Keywords

Castrate-resistant prostate cancer

Outcome Measures

Primary Outcomes (4)

• Number of Reported Dose Limiting Toxicities When Combining BEZ235 With Abiraterone Acetate (Phase I).

  Beginning of study up to 15 months

• Anti-tumor Responses as Defined by a Decline in PSA of > 50%

  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

  From day 1 of therapy initiation up to 12 weeks

• Response Proportion as Defined by a Decline in PSA of > 50%

  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.

  From day 1 of therapy initiation up to 12 weeks

• Maximum Tolerated Dose for BEZ235 + Abiraterone Acetate (Phase I).

  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).

  Beginning of study up to 15 months

Secondary Outcomes (5)

• Trough Concentrations of BEZ235 and Abiraterone Acetate Plus Prednisone When Used in Combination

  Beginning of study up to 15 months

• Progression Free Survival (PFS) in Phase II

  Beginning of Phase II up to 15 months

• Determination of the Time to PSA Progression in Phase II

  Beginning of Phase II up to 15 months

• Objective Response Rate (ORR) in Phase II

  From beginning of Phase II up to 15 months

• Safety of BEZ235 and Abiraterone Acetate Plus Prednisone When Used in Combination

  Beginning of Phase II up to 15 months

Other Outcomes (2)

• 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.

  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.

  post study

Study Arms (1)

Abiraterone/prednisone + BEZ235

EXPERIMENTAL

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; Drug: Prednisone; Drug: Abiraterone acetate

Interventions

BEZ235 DRUG

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.

Abiraterone/prednisone + BEZ235

Prednisone DRUG

10/mg po daily. Prednisone can be modified at the investigator's discretion, but should not be discontinued.

Abiraterone/prednisone + BEZ235

Abiraterone acetate DRUG

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.

Also known as: CB7630

Abiraterone/prednisone + BEZ235

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient has provided a signed study Informed Consent Form prior to any screening procedure.
• Patient is ≥ 18 years of age on the day of consenting to the study.
• Patients must have histologically confirmed adenocarcinoma of the prostate.
• Radiographic evidence of disease (bone scan, CT scan, ultrasound or MRI acceptable) that is amenable to image-guided biopsy must be present.
• 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.
• Progressive disease as demonstrated by a rising PSA or radiographic progression per PCWG2 criteria.
• 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.
• Phase II Cohort 1: No prior Abiraterone Acetate therapy
• Phase II Cohort 2: Immediate prior Abiraterone Acetate therapy is required. No intervening therapy is allowed between Abiraterone Acetate therapy and study therapy.
• Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
• 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.
• 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

You may not qualify if:

• Patients eligible for this study must not meet any of the following criteria:
• Patient has received previous treatment with PI3K and/or mTOR inhibitors.
• 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.
• 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.
• 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).
• 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.
• Patient has had major surgery within 28 days prior to starting study drug or has not recovered from major side effects of the surgery.
• 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

Sponsors & Collaborators

• Charles Ryan: lead
• Novartis Pharmaceuticals: collaborator

Study Sites (1)

University of California, San Francisco

San Francisco, California, 94115, United States

Location

Related Publications (1)

• Wei XX, Hsieh AC, Kim W, Friedlander T, Lin AM, Louttit M, Ryan CJ. A Phase I Study of Abiraterone Acetate Combined with BEZ235, a Dual PI3K/mTOR Inhibitor, in Metastatic Castration Resistant Prostate Cancer. Oncologist. 2017 May;22(5):503-e43. doi: 10.1634/theoncologist.2016-0432. Epub 2017 Mar 17.

  PMID: 28314838 DERIVED

MeSH Terms

Interventions

dactolisib; Prednisone; Abiraterone Acetate

Intervention Hierarchy (Ancestors)

Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Androstenes; Androstanes

Limitations and Caveats

Study got terminated due to safety issues.

Results Point of Contact

• Title: Charles Ryan, MD
• Organization: University of California, San Francisco

clinicaltrials@ucsf.edu

877-827-3222

Study Officials

• Charles Ryan, MD

  University of California, San Francisco

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor of Clinical Medicine & Urology

Study Record Dates

• First Submitted: October 23, 2012
• First Posted: October 31, 2012
• Study Start: January 31, 2013
• Primary Completion: September 3, 2013
• Study Completion: August 29, 2016
• Last Updated: March 27, 2018
• Results First Posted: March 27, 2018

Record last verified: 2018-02

Locations

US (1)