Abiraterone Acetate and Prednisone With or Without Veliparib in Treating Patients With Metastatic Castration-Resistant Prostate Cancer

Phase 2

Completed

Conditions: Recurrent Prostate Carcinoma
Castration-Resistant Prostate Carcinoma
Stage IV Prostate Cancer AJCC v7

Interventions: Drug: Abiraterone Acetate
Other: Laboratory Biomarker Analysis
Drug: Prednisone
Drug: Veliparib

Registration Number: NCT01576172

Lead Sponsor: National Cancer Institute (NCI)

Brief 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 castration-resistant prostate cancer that has spread from the primary site to other places in the body. 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. Giving abiraterone acetate together with prednisone and veliparib may work better than abiraterone acetate and prednisone alone in treating patients with castration-resistant prostate cancer.

Detailed Description: 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, at baseline, 12 weeks, and disease progression (or when off study) is associated with response to therapy.

III. To evaluate if the number of CTCs, as well as the expression levels of androgen receptor, RAD51 recombinase (RAD51), and gamma-H2A histone family, member X (H2aX) foci in the CTCs at baseline, at 12 weeks, and at disease progression in all patients is associated with response to therapy.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 159

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:
- 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 at least 1 metastatic site for gene-fusion status analysis; 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
Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
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 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 450 family 17(CYP-17) (other than ketoconazole) or PARP inhibitors for prostate cancer; patients with prior exposure to ketoconazole are eligible
Patients with up to 2 prior chemotherapy regimens are eligible
Obtained within 14 days prior to registration: White blood cells (WBC) >= 3,000/ul
Obtained within 14 days prior to registration: Absolute neutrophil count (ANC) >= 1,500/ul
Obtained within 14 days prior to registration: Platelet count >= 100,000/ul
Obtained within 14 days prior to registration: Serum creatinine =< 1.5 x the institutional upper limits of normal or corrected creatinine clearance of >= 50 mg/ml/hr/1.73 m^2 body surface area (BSA)
Obtained within 14 days prior to registration: Potassium >= 3.5 mmol/L
Obtained within 14 days prior to registration: Bilirubin within the institutional limits of normal
Obtained within 14 days prior to registration: Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 2 times upper limit of normal
Obtained within 14 days prior to registration: Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2 times upper limit of normal
Measured within 28 days prior to administration of ABT-888: >= 10.0 g/dL hemoglobin (Hb) with no blood transfusion in the past 28 days
Men 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
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
Ability to understand and the willingness to sign a written informed-consent document that is approved by the local institutional review board

Exclusion Criteria

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
Patients who have had chemotherapy, radiotherapy or oral antifungal agents (ketoconazole, 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
- There is a potential drug interaction when abiraterone is concomitantly used with a cytochrome P450 family 2, subfamily D, polypeptide 6 (CYP2D6) substrate narrow therapeutic index (e.g., thioridazine, dextromethorphan), or strong cytochrome P450 family 3, subfamily A, polypeptide 4 [CYP3A4] inhibitors (e.g., atazanavir, erythromycin, indinavir, itraconazole, Ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) or strong inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine); caution should be used when patients are on one of these drugs
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
Patients with known brain metastases should be excluded from this clinical trial
History of allergic reactions attributed to compounds of similar chemical or biologic composition to ABT-888 or abiraterone
Patients may continue on a daily multi-vitamin, calcium and vitamin D, but all other herbal, alternative and food supplements (i.e. PC-Spes, saw palmetto, St John's 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 megestrol acetate for hot flashes are allowed to continue therapy
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
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 with treatment-related acute myeloid leukemia (AML) (t-AML)/myelodysplastic syndrome (MDS) or with features suggestive of AML/MDS. Prior allogeneic bone marrow transplant or double umbilical cord blood transplantation

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm II (abiraterone acetate, prednisone, and veliparib)	Laboratory Biomarker Analysis	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.
Arm I (abiraterone acetate and prednisone)	Laboratory Biomarker Analysis	Patients receive abiraterone acetate PO QD and prednisone PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Arm I (abiraterone acetate and prednisone)	Abiraterone Acetate	Patients receive abiraterone acetate PO QD and prednisone PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Arm I (abiraterone acetate and prednisone)	Prednisone	Patients receive abiraterone acetate PO QD and prednisone PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Arm II (abiraterone acetate, prednisone, and veliparib)	Abiraterone Acetate	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.
Arm II (abiraterone acetate, prednisone, and veliparib)	Prednisone	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.
Arm II (abiraterone acetate, prednisone, and veliparib)	Veliparib	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.

Primary Outcome Measures

Name	Time	Method
Confirmed Prostate-specific Antigen (PSA) Response Rate	Up to 3 years	50% or greater decline in PSA from baseline.

Secondary Outcome Measures

Name	Time	Method
Rates of PSA Decline	12 weeks	Change in PSA from baseline to 12 weeks
Objective Response Rates in Patients With Measurable Disease.	Up to 3 years	Overall response per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT or MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Progression-free Survival (PFS)	Up to 42 months	Time from randomization to disease progression or death.
Grade 4 or 5 Adverse Events	30 days after completion of study treatment	Grade 4 or greater toxicity graded by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 at least possibly related to treatment.

Trial Locations

Locations (14): University of Chicago Comprehensive Cancer Center
🇺🇸
Chicago, Illinois, United States
City of Hope South Pasadena
🇺🇸
South Pasadena, California, United States
NorthShore University HealthSystem-Evanston Hospital
🇺🇸
Evanston, Illinois, United States
Johns Hopkins University/Sidney Kimmel Cancer Center
🇺🇸
Baltimore, Maryland, United States
Rutgers Cancer Institute of New Jersey
🇺🇸
New Brunswick, New Jersey, United States
M D Anderson Cancer Center
🇺🇸
Houston, Texas, United States
University of Washington Medical Center
🇺🇸
Seattle, Washington, United States
University of Wisconsin Women's Health Center
🇺🇸
Madison, Wisconsin, United States
University of Wisconsin Hospital and Clinics
🇺🇸
Madison, Wisconsin, United States
City of Hope Comprehensive Cancer Center
🇺🇸
Duarte, California, United States
USC / Norris Comprehensive Cancer Center
🇺🇸
Los Angeles, California, United States
Indiana University/Melvin and Bren Simon Cancer Center
🇺🇸
Indianapolis, Indiana, United States
University of Michigan Comprehensive Cancer Center
🇺🇸
Ann Arbor, Michigan, United States
UNC Lineberger Comprehensive Cancer Center
🇺🇸
Chapel Hill, North Carolina, United States