TKI258 in Castrate Resistant Prostate Cancer
Condition: Prostate Cancer
MeSH terms: Prostatic Neoplasms
Intervention: TK1258
Intervention description: 4 capsules (100 mg/capsules) of TKI 258 by mouth once daily (total of 400 mg of TKI258 per day).
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 46.0
Sex: Male
Healthy volunteers: No
Keywords: Prostate Cancer; Advanced Prostate Cancer; Castrate Resistant Prostate Cancer; Prostate Specific Antigen; PSA; Castration-Resistant Prostate Cancer Patients; TK1258; CHIR-258

Summary:

      The goal of this clinical research study is to learn if a decrease in the levels of prostate
      specific antigen (PSA) may be linked with the status of prostate cancer that has spread to
      the bones. Researchers also want to learn how changes in your blood PSA level might affect
      the rebuilding of healthy bones while you are being treated with TKI258 for prostate cancer.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Histologically proven adenocarcinoma of the prostate with evidence for skeletal
             metastases on bone scan and/or CT scan.

          2. Eastern Cooperative Oncology Group (ECOG) performance status </= 2. (Karnofsky
             Performance Status >/= 50%)

          3. Serum testosterone levels </= 50ng/ml

          4. Ongoing gonadal androgen deprivation therapy with luteinizing hormone-releasing
             hormone (LHRH) analogues or orchiectomy. Patients, who have not had an orchiectomy,
             must be maintained on standard dosing of LHRH analogue therapy at appropriate
             frequency for the duration of the study.

          5. Progression of disease despite androgen ablation (either documented osseous or soft
             tissue metastatic disease progression or by PSA criteria progression). a)Definition of
             Progressive disease by PSA evidence: a PSA level of at least 5 ng/ml which has risen
             on at least 2 successive occasions, at least 2 weeks apart. The participant will need
             a baseline test and a test to show that the PSA has increased.

          6. Discontinue diethylstilbestrol (DES) for >/= 4 weeks and antiandrogens >/= 6 weeks
             prior to study drug.

          7. Discontinue any steroids prescribed to specifically treat prostate cancer (for e.g as
             a secondary hormonal manipulation or for cord compression) >/= 4 weeks prior to study
             drug. Steroids chronically prescribed for a non-cancer-related illness (e.g. asthma or
             COPD) that is well controlled with medical management are permissible to an equivalent
             of < 10 mg Prednisone daily.

          8. Antiandrogen Withdrawal: Patients who are receiving an antiandrogen as part of primary
             androgen ablation must demonstrate disease progression following discontinuation of
             antiandrogen. Disease progression after antiandrogen withdrawal is defined as 2
             consecutive rising PSA values, obtained at least 2 weeks apart, or documented osseous
             or soft tissue progression.

          9. For patients receiving flutamide, at least one of the PSA values must be obtained 4
             weeks or more after flutamide discontinuation.

         10. For patients receiving bicalutamide or nilutamide, at least one of the PSA values must
             be obtained 6 weeks or more after antiandrogen discontinuation

         11. Laboratory Requirements: 1) Adequate adrenal function (absence of symptoms or
             electrolyte imbalances that indicate adrenal insufficiency); 2) White blood cell count
             (WBC) count >/= 3,000/microl; 3) Absolute Neutrophil Count (ANC) >/= 1,500/microl; 4)
             Hemoglobin >/= 8.0 g/dL independent of transfusion; 5) Platelet count >/=
             75,000/microL; 6) Serum albumin >/= 3.0 g/dL; 7) Serum creatinine < 1.5 x ULN or a
             calculated creatinine clearance > 60 mL/min (as calculated by Cockcroft-Gault method)
             8) Serum potassium >/= 3.5 mmol/L

         12. No evidence of chronic or acute DIC (Disseminated Intravascular Coagulation) or
             bleeding tendency and no angina at rest.

         13. Patient must be willing and able to comply with protocol requirements. All patients
             must sign an informed consent indicating that they are aware of the investigational
             nature of this study. Patients must also have signed an authorization for the release
             of their protected health information.

        Exclusion Criteria:

          1. Histologic variants other than adenocarcinoma in the primary tumor

          2. Abnormal liver functions consisting of any of the following: a) Serum bilirubin >/=
             1.5 * upper limit of normal (ULN) b) AST and ALT > 2.5 * ULN

          3. Therapy with other hormonal therapy, including any dose of Ketoconazole, finasteride
             (Proscar), dutasteride (Avodart) any herbal product known to decrease PSA levels (eg,
             Saw Palmetto and PC-SPES) within 4 weeks of study drug.

          4. Requirement for corticosteroids greater than the equivalent of 7.5 mg of prednisone
             daily.

          5. Therapy with samarium or strontium within 8 weeks prior to first dose of study drug.

          6. Active infection or concomitant illness that is not controlled with medical
             management.

          7. Prior radiation therapy completed < 4 weeks or single fraction of palliative
             radiotherapy within 14 days prior to first dose of study drug.

          8. Any currently active second malignancy, other than non-melanoma skin cancer. Patients
             are not considered to have a currently active malignancy, if they have completed
             therapy and are considered by their physician to be at least less than 30% risk of
             relapse over next 3 months.

          9. Active psychiatric illnesses/social situations that would limit compliance with
             protocol requirements.

         10. Active or uncontrolled autoimmune disease that may require corticosteroid therapy
             during study

         11. Severely compromised immunological state, including being positive for the human
             immunodeficiency virus (HIV)

         12. Acute or chronic hepatitis B or C

         13. Chemotherapy and other investigational therapies (targeted or immunotherapy) will
             require a 4-week washout period before treatment initiation

         14. Initiation of bisphosphonate therapy within 4 weeks prior to first dose of study drug.
             Patients on stable doses of bisphosphonates that show subsequent tumor progression may
             continue on this medication; however, patients are not allowed to initiate
             bisphosphonate therapy during the study.

         15. Impaired cardiac function or clinically significant cardiac diseases, including any of
             the following: a.) History or presence of serious uncontrolled ventricular arrhythmias
             or presence of atrial fibrillation; b.) Clinically significant resting bradycardia (<
             50 beats per minute); c.) Left ventricular ejection fraction (LVEF) assessed by 2-D
             echocardiogram (ECHO) < 50% or lower limit of normal (whichever is higher) or multiple
             gated acquisition scan (MUGA) < 45% or lower limit of normal (whichever is higher);

         16. (# 13 Conti'd) Any of the following within 6 months prior to study entry: myocardial
             infarction (MI), severe/unstable angina, Coronary Artery Bypass Graft (CABG),
             Congestive Heart Failure (CHF), Cerebrovascular Accident (CVA), Transient Ischemic
             Attack (TIA), Pulmonary Embolism (PE); e.) Uncontrolled hypertension defined by an
             SBP>150 and/or a DBP>100 mm Hg with or without anti-hypertensive medication; f.)
             Previous pericarditis; clinically significant pleural effusion in the previous 12
             months or current ascites requiring 2 or more interventions per month.

         17. History of pituitary or adrenal dysfunction

         18. History of gastrointestinal disorders (medical disorders or extensive surgery) which
             may interfere with the absorption of the study drug.

         19. Prior therapy with TKI258

         20. Any acute toxicities due to prior chemotherapy and/or radiotherapy that have not
             resolved to a National Cancer Institute Common Terminology Criteria for Adverse Events
             (NCI CTCAE) (version 3.0) grade of </= 1. Chemotherapy induced alopecia and grade 2
             neuropathy is allowed.

         21. Condition or situation which, in the investigator's opinion, may put the patient at
             significant risk, may confound the study results, or may interfere significantly with
             the patient's participation in the study.

         22. Men whose partner is a woman of child-bearing potential, (i.e. biologically able to
             conceive), and who is not employing two forms of highly effective contraception.
             Highly effective contraception (e.g. male condom with spermicide, diaphragm with
             spermicide, intra-uterine device) must be used by both sexes during the study and must
             be continued for 8 weeks after the end of study treatment. Oral, implantable, or
             injectable contraceptives may be affected by cytochrome P450 interactions, and are
             therefore not considered effective for this study. Women of child-bearing potential is
             defined as sexually mature women who have not undergone a hysterectomy or who have not
             been naturally postmenopausal for at least 12 consecutive months (e.g., who has had
             menses any time in the preceding 12 consecutive months).