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4P-12-1 A Randomized Phase II Trial of Dasatinib plus Abiraterone Compared to Abiraterone Alone for Metastatic, Castration-Resistant Prostate Cancer Prior to Chemotherapy

Description

PRIMARY OBJECTIVES: I. To compare the progression-free survival of men with metastatic castration-resistant prostate cancer treated with abiraterone (abiraterone acetate) plus dasatinib to that of men treated with abiraterone alone. SECONDARY OBJECTIVES: I. To describe the toxicity profile of the combination, as well as the rate of prostate-specific antigen (PSA) response, objective responses, and changes in circulating tumor cell (CTC) numbers. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM A: Patients receive abiraterone acetate 1000 mg orally (PO) once daily (QD) and prednisone 5 mg PO twice daily (BID) on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. ARM B: Patients receive abiraterone acetate and prednisone as patients in arm A. Patients also receive dasatinib 100 mg PO QD on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up periodically.

Phase

Phase 2 - takes the treatment one step further, assessing the activity of a particular therapy in a disease, often building upon leads from the Phase I trial. While patients are generally required to be previously untreated, participation in a Phase II trial doesn't usually preclude the patient from getting the standard treatment after they've received the investigational agent. At best they are allowed to get a new drug they wouldn't be able to get otherwise that may turn out to be better for their disease.

Inclusion and Exclusion Criteria

  • Metastatic, castration-resistant prostate cancer
  • Defined as evaluable radiographic disease with rising PSA x 2 (at least 1 week apart) or radiographic progression (new soft tissue/bone lesions or enlarging soft tissue lesions) despite medical or surgical castration
  • No limit on prior hormonal therapies (i.e. anti-androgens, ketoconazole) except that subject must not have received abiraterone previously
  • No limit on prior biologic therapies (i.e. immune therapy, antiangiogenic, targeted) except that patient should not have received dasatinib or other v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian) (src)-targeted therapy
  • No prior chemotherapy for metastatic disease * Subjects who have received chemotherapy in the neoadjuvant or adjuvant setting will be eligible provided chemotherapy was completed > 6 months prior to enrollment
  • Eastern Cooperative Oncology Group (ECOG) 0-2
  • Total bilirubin =< 1.5 times the institutional upper limit of normal (ULN) except for Gilbert's syndrome
  • Hepatic enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT] ) =< 2.5 times the institutional ULN
  • Serum sodium (Na), potassium (K+), magnesium (Mg+), phosphate and calcium (Ca+) > lower limit of normal (LLN)
  • Serum creatinine =< 1.5 time the institutional ULN
  • Hemoglobin (Hb) >= 9
  • Platelets >= 100,000
  • Absolute neutrophil count (ANC) >= 1000
  • Ability to take oral medication (study medications must be swallowed whole)
  • Men with fathering potential must agree to use contraception throughout study treatment; acceptable methods include: condoms, sponge, intrauterine device (IUD), oral contraceptives
  • Concomitant medications * Patient agrees to discontinue St. Johns wort while receiving dasatinib therapy (discontinue St. Johns wort at least 5 days before starting dasatinib)

  • Known hepatitis B or C or human immunodeficiency virus (HIV), regardless of viral load * Testing for the purposes of enrollment is not mandatory, however a documented history of these infections will be exclusionary due to concerns for drug-drug interactions with antivirals and potential for increased risk of liver toxicity
  • Radiation for palliation of bony metastases within the preceding 2 weeks
  • Prior chemotherapy for metastatic castration-resistant prostate cancer (CRPC) * Immune therapy with sipuleucel-T is allowed, provided the last infusion was >= 28 days prior to study therapy and there has been at least one documented PSA value rising after completion of sipuleucel-T therapy or progression of disease on imaging after sipuleucel-T
  • Malignancy (aside from prostate cancer) which required radiotherapy or systemic treatment within the past 5 years
  • Superficial bladder cancer treated with intravesical therapy and currently in remission will not be an exclusion
  • Skin cancers will not be an exclusion, except for melanoma with a thickness > 1 mm
  • Concurrent medical condition which may increase the risk of toxicity, including:
  • Pleural or pericardial effusion of any grade at the time of study entry
  • Cardiac symptoms; any of the following should be considered for exclusion: ** Uncontrolled angina, congestive heart failure or myocardial infarction (MI) within (6 months)
  • Diagnosed congenital long QT syndrome
  • Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes) ** Prolonged QTc/f interval on pre-entry electrocardiogram (> 450 msec)
  • Hypokalemia or hypomagnesemia if it cannot be corrected prior to abiraterone administration
  • History of significant bleeding disorder unrelated to cancer, including:
  • Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease)
  • Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies)
  • Ongoing or recent (=< 3 months) significant gastrointestinal bleeding
  • Prohibited treatments and/or therapies
  • Should not be on any additional anti-cancer therapy except for luteinizing hormone-releasing hormone (LHRH) agonist/antagonist; specifically excluded medications include ketoconazole, estrogens, and anti-androgens
  • Category I drugs that are generally accepted to have a risk of causing Torsades de pointes including: (Patients must discontinue drug 7 days prior to starting dasatinib)
  • Quinidine, procainamide, disopyramide
  • Amiodarone, sotalol, ibutilide, dofetilide
  • Erythromycin, clarithromycin
  • Chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide
  • Cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine
  • Prisoners or subjects who are involuntarily incarcerated
  • Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness

Sites

  • California

    • USC Norris Comprehensive Cancer Center, Los Angeles, California, 90033
    • USC Norris Comprehensive Cancer Center, Los Angeles, California, 90033
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