Skip to main content

Enzalutamide with or without Galunisertib in Treating Patients with Metastatic Castrate Resistant Prostate Cancer

Trial Status: Active

This randomized phase II trial studies how well giving enzalutamide with or without galunisertib works in treating patients with prostate cancer that has spread to other places in the body (metastatic) and keeps growing even when the amount of testosterone in the body is reduced to very low levels (castrate-resistant). Enzalutamide may help slow or stop the growth of prostate cancer cells by blocking testosterone production in the body. Some tumors need growth factors, which are made by the body's white blood cells, to keep growing. Galunisertib may interfere with growth factors and help cause tumor cells to die. It is not yet known whether enzalutamide works better alone or with galunisertib in treating patients with castrate resistant prostate cancer.

Inclusion Criteria

  • Have metastatic castration-resistant prostate cancer, are chemo-naïve for mCRPC (however, six cycles of docetaxel are allowed in hormone-sensitive disease), and have progressed on abiraterone treatment (patients may have had prior therapy including sipuleucel-T, radium-223, abiraterone, ketoconazole, and/or Tak-700); progression on abiraterone is defined as * Radiologic progression by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and Prostate Cancer Working Group (PCWG)2 criteria, or * PSA progression on abiraterone: ** For responders to abiraterone: 25% or greater increase and an absolute increase of 2 ng/mL or more from the nadir, confirmed by a second value obtained 2 or more weeks later ** For non-responders to abiraterone: 25% increase above baseline with an increase in absolute value of 2 ng/mL or more after 12 weeks of treatment
  • Have a pathological diagnosis of prostate carcinoma
  • Patients may be receiving continuous hormonal ablation with surgical or medical castration with baseline testosterone < 50ng/dL
  • Patient may be receiving bone targeted agents
  • Must have had prior abiraterone treatment
  • Have evaluable disease by RECIST 1.1 and PCWG2 criteria
  • Patient’s acceptance to have a tumor biopsy of an accessible lesion at baseline and on treatment if the lesion can be biopsied with acceptable clinical risk (as judged by the investigator)
  • Have Eastern Cooperative Oncology Group (ECOG) performance status 0-2
  • Have estimated life expectancy > 3 months
  • Be able to take oral medication
  • Absolute neutrophil count >= 1500/mm^3
  • Platelets >= 100,000/mm^3
  • Hemoglobin >= 9 g/dL
  • Total bilirubin =< 1.5 upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT) serum glutamate pyruvate transaminase (SGPT) =< 2.5 x ULN (< 5 x ULN if with known liver metastases provided bilirubin is normal)
  • Creatinine =< 2.0 x ULN (for patients with > 1.5 x ULN, calculated or measured creatinine clearance must be = 40 mL/minute [Cockcroft-Gault]).
  • Men of reproductive potential and those who are surgically sterilized (i.e., postvasectomy) must agree to practice effective barrier contraception that has an expected failure rate of < 1% during and for 6 months after discontinuation of study treatment * If condoms are used as a barrier contraceptive, a spermicidal agent should be added to ensure that pregnancy does not occur
  • Have the ability to understand, and have given written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care

Exclusion Criteria

  • Have had known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for CNS involvement for at least one week prior to trial treatment; patients with primary brain tumors are not eligible; however, as patients are completing abiraterone therapy, they will be allowed to continue up to 10 mg/day of prednisone
  • Have had prior chemotherapy for metastatic disease in castration-resistant prostate cancer (prior chemotherapy for hormone-sensitive disease, more than six months prior to registration, is acceptable)
  • Have had had surgery within four weeks of dosing of investigational agent, excluding minor procedures (dental work, skin biopsy, etc.), celiac plexus block, and biliary stent placement
  • Have had palliative radiation or biological cancer therapy within 2 weeks prior to the first dose of study drug
  • Have had second-line hormonal therapy (abiraterone, ketoconazole, and/or Tak-700, etc.) within two weeks prior to the first dose of study drug; patients require a two-week wash out; patients may continue standard supportive dosing of prednisone and hydrocortisone for abiraterone and ketoconazole, respectively, as needed
  • Have received other investigational drugs within 14 days prior to enrollment
  • Is expected to require any other form of systemic or localized antineoplastic therapy while on study
  • Have received systemic corticosteroids (used in the management of cancer or non-cancer-related illnesses) within one week prior to first dose; Note: systemic steroid therapy is allowed for subjects on replacement therapy as long as prednisone =< 10 mg or its steroid equivalent, and those patients should continue at the same dose through the trial
  • Have had prior enzalutamide, ARN-509, or galeterone therapy
  • Are taking strong or moderate cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) or cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) inducers, or CYP3A4, cytochrome P450, family 2, subfamily C, polypeptide 9 (CYP2C9) and cytochrome P450, family 2, subfamily C, polypeptide 19 (CYP2C19) substrates with a narrow therapeutic index; patients may switch to an alternative any time prior to day 1 of trial drug administration
  • Have moderate or severe cardiovascular disease: * Has the presence of cardiac disease, including a myocardial infarction within six months prior to study entry, unstable angina pectoris, New York Heart Association class III/IV congestive heart failure, or uncontrolled hypertension * Has documented clinically significant electrocardiography (ECG) abnormalities (not responding to medical treatments) or not clinically stable for at least 6 months * Has major abnormalities documented by echocardiogram (ECHO) with Doppler (for example, moderate or severe heart valve function defect) that is not stable for at least 6 months; Note: left ventricular [LV] ejection fraction < 50% is allowed only if clinically stable for at least 6 months (evaluation based on the institutional lower limit of normal) * Has predisposing conditions that are consistent with development of aneurysms of the ascending aorta or aortic stress (for example, family history of aneurysms, Marfan-Syndrome, bicuspid aortic valve, evidence of damage to the large vessels of the heart documented by computed tomography [CT] scan/magnetic resonance imaging [MRI] with contrast)
  • Have a history of a seizure
  • Have uncontrolled intercurrent illness, including but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Have a history of any autoimmune disease; patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn’s Disease, are excluded from this study, as are patients with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, or autoimmune vasculitis [e.g., Wegener’s Granulomatosis]); CNS or motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre Syndrome and Myasthenia Gravis, multiple sclerosis); patients with thyroid disease will be allowed; autoimmune diagnoses not listed here must be approved by the protocol chair
  • Have a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies), hepatitis B, or hepatitis C infection

District of Columbia

Sibley Memorial Hospital
Status: ACTIVE
Contact: Channing J. Paller


Northwestern University
Status: ACTIVE
Contact: Maha H. A. Hussain
Phone: 312-695-6180
Rush University Medical Center
Status: ACTIVE
Contact: Timothy M. Kuzel
University of Chicago Comprehensive Cancer Center
Status: ACTIVE
Contact: Russell Zelig Szmulewitz
Phone: 773-926-0708
NorthShore University HealthSystem
Status: ACTIVE
Contact: Daniel H. Shevrin


Johns Hopkins University / Sidney Kimmel Cancer Center
Status: ACTIVE
Contact: Channing J. Paller
Phone: 410-955-8239


I. To compare radiographic progression-free survival (rPFS) in chemotherapy-naive, post-abiraterone-treated metastatic castration-resistant prostate cancer (mCRPC) patients treated with enzalutamide and galunisertib (LY2157299) versus enzalutamide alone.


I. To compare the prostate-specific antigen (PSA) response rate and of chemotherapy-naive, post-abiraterone mCRPC patients treated with a combination of enzalutamide and LY2157299 versus (vs.) enzalutamide alone.

II. To summarize and compare overall survival in chemotherapy-naive, post-abiraterone mCRPC patients treated with a combination of enzalutamide and LY2157299 vs. enzalutamide alone.

III. To assess safety and tolerability the combination of enzalutamide and LY2157299 as measured by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 criteria.

IV. To assess the pharmacokinetics of LY2157299 in the presence of enzalutamide during the safety run-in phase.


I. To measure correlates that may, individually or as a group, be predictive of response or lack of response to the combination of enzalutamide and LY2157299: androgen receptor splice variant 7 (AR-V7) splice variant status, C-reactive protein (CRP), transforming growth factor beta (TGF-beta), and SMAD family member 2 (SMAD2).

II. To quantify and compare the function of the peripheral cluster of differentiation (CD)8+ and CD4+ cells from patients in each of the two treatment groups.

III. To evaluate and compare the serum cytokine profile from patients in each of the two treatment groups (including but not limited to interleukin [IL]-1, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-13, tumor necrosis factor alpha [TNF-alpha], and interferon gamma [IFN-gamma]).

IV. To evaluate and compare the generation of novel antibody specificities to prostate-associated antigens in the serum of patients in each group, after the receipt of protocol therapy.

V. To evaluate markers of epithelial to mesenchymal transition in tumor biopsies pre- and post-therapy: E-cadherin (CDH1), N-cadherin (CDH2), TGF-beta1, vimentin (VIM), zinc finger E-box binding homeobox 1 (ZEB1), and SMAD2.

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

ARM 1: Patients receive enzalutamide orally (PO) once daily (QD) on days 1-28. Patients receive galunisertib PO twice daily (BID) on days 1-14. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM 2: Patients receive enzalutamide PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 6 months for 2 years.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Johns Hopkins University / Sidney Kimmel Cancer Center

Principal Investigator
Channing J. Paller

  • Primary ID J1557
  • Secondary IDs NCI-2015-00854, CRMS-61500, IRB00065746
  • ID NCT02452008