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A Randomized Gene Fusion Stratified Phase 2 Trial of Abiraterone With or Without ABT-888 for Patients With Metastatic Castration-Resistant Prostate Cancer

Phase 2
18 Years
Open (Enrolling)
Hormone-resistant Prostate Cancer, Recurrent Prostate Cancer, Stage IV Prostate Cancer

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Trial Information

A Randomized Gene Fusion Stratified Phase 2 Trial of Abiraterone With or Without ABT-888 for Patients With Metastatic Castration-Resistant Prostate Cancer


I. To evaluate the role of v-ets erythroblastosis virus E26 oncogene (ETS) gene fusion as a
predictive biomarker for response to hormone therapy (abiraterone [abiraterone acetate])
alone or hormone therapy plus poly adenosine diphosphate-ribose polymerase 1 (PARP-1)
targeted therapy (ABT-888 [veliparib]) in patients with metastatic castration resistant
prostate cancer.

II. To evaluate whether the addition of PARP-1 targeted therapy is superior to hormone
therapy alone based on ETS gene fusion status.


I. Rate of prostate-specific antigen (PSA) declines. II. Objective response rate. III.
Progression-free survival. IV. Evaluate the qualitative and quantitative toxicity of
abiraterone acetate with and without ABT-888.


I. To determine the concordance in fusion status among prostate cancer samples from the
primary site, biopsied metastasis, and circulating tumor cells (CTCs).

II. To assess if ETS fusion status in the CTCs is associated with response to therapy.

III. To evaluate the number and ETS fusion status of CTCs at baseline in all patients.

IV. To determine the role of phosphatase and tensin homolog (PTEN) loss as a predictive
biomarker of response to abiraterone, alone or in combination with ABT-888.

V. To determine the role of PARP1 activity as a predictive biomarker of response to
abiraterone, alone or in combination with ABT-888.

VI. To perform next-generation sequencing for discovery of novel gene fusions in prostate
cancers negative for ETS fusions.

VII. To perform germline single nucleotide polymorphism (SNP) analysis of genes involved in
hormone synthesis, transport, binding, metabolism, and degradation for discovery of novel
SNPs predictive of response to abiraterone, alone or in combination with ABT-888.

VIII. To determine if ETS fusion ribonucleic acid (RNA) levels in blood are predictive of
response to abiraterone, alone or in combination with ABT-888.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive abiraterone acetate orally (PO) once daily (QD) and prednisone PO
twice daily (BID) on days 1-28. Courses repeat every 28 days in the absence of disease
progression or unacceptable toxicity.

ARM II: Patients receive veliparib PO BID on days 1-28. Patients also receive abiraterone
acetate PO QD and prednisone PO BID on day 1 (day 8 of course 1).Courses repeat every 28
days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for up to 2

Inclusion Criteria:

- Have a histologic or cytologic diagnosis of prostate cancer

- Have progressive metastatic castration-resistant prostate cancer, on
androgen-deprivation therapy, based on at least one of the following criteria:

- Prostate-specific antigen (PSA) progression defined as 25% increase over
baseline value with an increase in the absolute value of at least 2 ng/mL that
is confirmed by another PSA level with a minimum of a 1-week interval with a
minimum PSA of 2 ng/mL

- Progression of bidimensionally measurable soft tissue (nodal metastasis)
assessed within one month prior to registration by a computed tomography (CT)
scan or magnetic resonance imaging (MRI) of the abdomen and pelvis

- Progression of bone disease (evaluable disease) (new bone lesion[s]) by bone

- Agree to undergo a biopsy of >= 1 metastatic site for gene-fusion status

- Adequate archival metastatic tissue can be used if available in lieu of a
biopsy; patients will only be eligible for protocol therapy if the biopsy has
tumor and the tissue is evaluable for ETS fusion status

- Have testosterone < 50 ng/dL; patients must continue primary androgen-deprivation
with a luteinizing hormone-releasing hormone (LHRH) analogue if they have not
undergone orchiectomy

- Patients with known brain metastases should be excluded from this clinical trial

- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

- White blood cells >= 3,000/uL

- Absolute neutrophil count >= 1,500/uL

- Platelet count >= 100,000/uL

- Creatinine within the institutional limits of normal

- Potassium >= 3.5 mmol/L

- Bilirubin within the institutional limits of normal

- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =<
2 times upper limit of normal

- Serum glutamic pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2
times upper limit of normal

- Must agree to use effective contraception during treatment and for at least 1 week
after the last administration of therapy

- Patients must be able to take oral medication without crushing, dissolving, or
chewing tablets

- Ability to understand and the willingness to sign a written informed-consent document
that is approved by the local institutional review board

- Patients with history of active seizures are not eligible

- Patients with a history of pituitary or adrenal dysfunction, active or symptomatic
viral hepatitis, or chronic liver disease are not eligible

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to ABT-888 or abiraterone

- No uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure (New York Heart Association class III
and IV heart failure), unstable angina pectoris, cardiac arrhythmia, or psychiatric
illness/social situations that would limit compliance with study requirements or
concurrent medications that alter cardiac conduction

- Patients with a "currently active" second malignancy other than non-melanoma skin
cancers are not eligible; patients are not considered to have a "currently active"
malignancy if they have completed all therapy and are now considered without evidence
of disease for 1 year

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible

- Patients must discontinue antiandrogen therapy for at least 4 weeks (e.g., flutamide,
bicalutamide, nilutamide) prior to registration with no evidence of a falling PSA
after washout; patients on steroids are eligible as long as they will be switched to

- Have no prior exposure to cytochrome P450, family 17, subfamily A, polypeptide 1
(CYP-17) or poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors

- Patients with up to 2 prior chemotherapy regimens are eligible

- Patients may have received prior radiation therapy or surgery; however, at least 21
days must have elapsed since completion of radiation therapy or surgery and patient
must have recovered from all side effects at the time of registration

- Patients may not be receiving any other investigational agents; any prior
investigational products must be stopped at least 14 days (2-week washout) prior to

- No patients who have had chemotherapy or antifungal agents (itraconazole,
fluconazole) within 3 weeks prior to entering the study or those who have not
recovered (e.g., back to baseline or grade 1) from adverse events due to agents
administered more than 3 weeks earlier

- Patients may continue on a daily multivitamin, calcium, and vitamin D, but all other
herbal, alternative, and food supplements (i.e., PC-SPES, saw palmetto, St. John
wort, etc.) must be discontinued before registration

- Patients must not be planning to receive any concurrent cytotoxic chemotherapy,
surgery, or radiation therapy during protocol treatment

- Hormonal-acting agents (including diethylstilbestrol [DES], aldosterone, and
spironolactone) are forbidden during the trial and must be stopped prior to
registration; no washout period will be required for any of these agents

- Patients on stable doses of bisphosphonates or denosumab which have been started
prior to registration may continue on this medication, patients who are not on
bisphosphonates or denosumab are eligible as long as they initiate therapy prior to

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Confirmed PSA response rate

Outcome Description:

The corresponding binomial confidence intervals will be reported for each arm. A logistic model including treatment group, fusion status, and prior ketoconazole use will be used to determine the interaction between the rates of PSA response between abiraterone and abiraterone + ABT-888 and ETS fusion status.

Outcome Time Frame:

Up to 2 years

Safety Issue:


Principal Investigator

Maha Hussain

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Chicago Comprehensive Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

March 2012

Completion Date:

Related Keywords:

  • Hormone-resistant Prostate Cancer
  • Recurrent Prostate Cancer
  • Stage IV Prostate Cancer
  • Prostatic Neoplasms



Johns Hopkins University Baltimore, Maryland  21205
University of Washington Medical Center Seattle, Washington  98195-6043
City of Hope Medical Center Duarte, California  91010
University of North Carolina Chapel Hill, North Carolina  27599
Indiana University Medical Center Indianapolis, Indiana  46202
University of Chicago Chicago, Illinois  60637
UC Davis Comprehensive Cancer Center Sacramento, California  95817
M D Anderson Cancer Center Houston, Texas  77030
University of Southern California Los Angeles, California  90033
Evanston CCOP-NorthShore University HealthSystem Evanston, Illinois  60201
University of Michigan University Hospital Ann Arbor, Michigan  48109
UMDNJ - Robert Wood Johnson University Hospital New Brunswick, New Jersey  08903
University of Wisconsin Cancer Center Riverview Wisconsin Rapids, Wisconsin  54494