Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Trial Description

Summary

This randomized phase II trial studies abiraterone acetate and prednisone together with veliparib to see how well it works compared to abiraterone acetate and prednisone alone in treating patients with metastatic hormone-resistant prostate cancer. Androgens can cause the growth of prostate cancer cells. Antiandrogen drugs, such as abiraterone acetate, may lessen the amount of androgens made by the body. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether giving abiraterone acetate together with prednisone and veliparib is more effective than abiraterone acetate and prednisone alone in treating prostate cancer

Further Study Information

PRIMARY OBJECTIVES:

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.

SECONDARY OBJECTIVES:

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.

TERTIARY OBJECTIVES:

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 years.

Eligibility Criteria

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 scan

• 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 prednisone

• 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 registration

• 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 registration

Trial Contact Information

Trial Lead Organizations/Sponsors

National Cancer Institute

Maha Hussain

Principal Investigator

U.S.A.
Illinois
	Chicago
	University of Chicago Cancer Research Center
		Walter M. Stadler	Ph: 773-702-4150
			Email: wstadler@medicine.bsd.uchicago.edu
		Walter M. Stadler	Principal Investigator
	Evanston
	CCOP - Evanston
		Daniel H. Shevrin	Ph: 847-570-2515
			Email: DShevrin@northshore.org
		Daniel H. Shevrin	Principal Investigator
Indiana
	Indianapolis
	Indiana University Melvin and Bren Simon Cancer Center
		Noah M. Hahn	Ph: 317-948-1186
			Email: nhahn@iupui.edu
		Noah M. Hahn	Principal Investigator
Maryland
	Baltimore
	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
		Emmanuel S. Antonarakis	Ph: 410-502-7528
			Email: eantona1@jhmi.edu
		Emmanuel S. Antonarakis	Principal Investigator
Michigan
	Ann Arbor
	University of Michigan Comprehensive Cancer Center
		Maha H. Hussain	Ph: 734-936-8906
			Email: mahahuss@umich.edu
		Maha H. Hussain	Principal Investigator
North Carolina
	Chapel Hill
	Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
		Young E. Whang	Ph: 919-843-9983
			Email: ywhang@med.unc.edu
		Young E. Whang	Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT01576172
Information obtained from ClinicalTrials.gov on February 13, 2013

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