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Dovitinib(TKI258) in Patients With Castration-resistant Prostate Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01741116
Recruitment Status : Unknown
Verified November 2012 by Kyong-Hwa, Park, Korean Cancer Study Group.
Recruitment status was:  Recruiting
First Posted : December 4, 2012
Last Update Posted : December 4, 2012
Information provided by (Responsible Party):
Kyong-Hwa, Park, Korean Cancer Study Group

Brief Summary:
The aim of this study is to evaluate efficacy and safety of Dovitinib(TKI258) in patients with castration resistant prostate cancer after failure of docetaxel-based chemotherapy. Further correlative study for metabolic response using PET image and change in serum fibroblast growth factor 23(FGF23) will be conducted.

Condition or disease Intervention/treatment Phase
Hormone Refractory Prostate Cancer Drug: TKI258 Phase 2

Detailed Description:

Growth factor signals are important in carcinogenesis and progression of prostate cancer, and fibroblast growth factors (FGF) have important roles in this regard. FGF ligands (FGF1, -2, -6, -8, and -17) and FGF receptors (FGFR1 and FGFR4) have all shown to be significantly overexpressed in prostate cancer1-5. And, the recent studies have demonstrated that the critical roles of the FGF family members are mediated by the signaling between epithelial and stromal compartments, thus, promoting epithelial-mesenchymal transition (EMT)6,7. Moreover, a recent study has shown that FGF-2 is a mediator of second wave angiogenesis and tumor progression in men during the formation of castration-resistant tumors. Therefore, inhibition of signaling via FGF axis might be a viable strategy for the treatment of castration-resistant prostate cancer.

TKI258, an oral multitargeted receptor tyrosine kinase (RTK) inhibitor is known to potently inhibit the class III, IV, and V RTKs, showing biochemical 50 percent inhibitory concentration(IC50) values <20 nmol/L for VEGFRs (VEGFR-1, VEGFR-2, and VEGFR-3); the platelet-derived growth factor receptor-β (PDGFR-β); fibroblast growth factor receptors 1, 2, and 3 (FGFR-1,2,3); fetal liver tyrosine kinase receptor 3 (FLT-3); and KIT Ret, tyrosine kinase A (TrkA), and csf-1 RTKs. Due to the unique inhibitory activity on FGF pathways, TKI258 has shown significant activity in a variety of tumor xenograft models in athymic mice, including acute myeloid leukemia, multiple myeloma, and colon- and prostate-derived models9.

Castration-resistant prostate cancers (CRPC) are one of the challenges in oncology practice. Although there have been advances in chemotherapy10, new hormonal agents11, and immunotherapeutics12, patients in this subgroup still have limited life expectancy. Therefore, there is an urgent need to identify therapeutic targets and clinical development of target agents for the treatment of CRPC. For this end, sorafenib has been tested in multiple phase II studies earlier13-17; however, the clinical efficacy was very limited. The low efficacy of sorafenib might be partly explained by the lower potency in inhibition of RTKs. Considering nanomolar concentration range of IC50 for TKI258 compared with micromolar concentration for other multi-TKIs, the efficacy of TKI258 should be evaluated in CRPC patients.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 44 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of TKI258 in Patients With Castration-resistant Prostate Cancer
Study Start Date : November 2012
Estimated Primary Completion Date : October 2014
Estimated Study Completion Date : June 2016

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Prostate Cancer

Arm Intervention/treatment
Experimental: TKI258, inhibitor of RTKs

Intervention: TKI258

Investigational drug, TKI258, will be administered to all of the patients after enrollments. Treatment will initially be administered as 28-day cycles as follows:

- Daily 500mg of TKI258 will be self-administered orally by the patient for 5 days, followed by 2 days of treatment off.

Drug: TKI258
Investigational treatment refers to TKI258 in this study Until Progression, unacceptable toxicity, withdrawal
Other Name: Dovitinib

Primary Outcome Measures :
  1. 16 week progression free survival rate [ Time Frame: Week 16 ]
    disease progression defined as either the appearance of new lesions or unidimensional tumor measurements increasing >20% or symptomatic progression

Secondary Outcome Measures :
  1. Overall response rate [ Time Frame: up to 24 months ]
    Overall response rate per Response Evaluation Criteria in Solid Tumors(RECIST)1.0 and Prostate-specific antigen(PSA), overall survival time, toxicity, and biological effect of TKI258 in patients via correlative study using serum and PET-CT image

Other Outcome Measures:
  1. Overall survival [ Time Frame: up to 36 months ]

    Overall survival is defined as the time from date of randomization to date of death due to any cause. If the patient is not known to have died, survival will be censored at the date of the last contact. Overall survival will be analyzed at the final analysis cut-off date.

    The Kaplan-Meier product-limit method will be used to describe the overall survival for the study drug (median, 95% confidence intervals, and plots).

  2. Serum FGF23 [ Time Frame: 2 months after chemotherapy ]

    The objective of the exploratory biomarker is to identify a biomarker 'profile' of a patient population most likely to benefit from treatment with TKI258.

    Since this clinical trial was not designed to address specific biomarkers-related hypotheses, the analysis of this data should be viewed as exploratory and hypotheses generating.

  3. PET-CT [ Time Frame: 2 months after chemotherapy ]
    The objective of the exploratory biomarker is to identify a biomarker 'profile' of a patient population most likely to benefit from treatment with TKI258.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Patients with histologically confirmed progressive metastatic androgen-independent adenocarcinoma of the prostate with radiographic evidence of disease.
  • No more than two previous cytotoxic chemotherapy
  • Castration level of testosterone (< 50 ng/dl) achieved by orchiectomy or gonadotropin-releasing hormone(GnRH) agonist
  • Eastern Cooperative Oncology Group(ECOG) performance status 0 - 2
  • Finished any study drug or chemotherapy earlier than 4 weeks before the first administration of the study drug.
  • Age ≥ 20 years old
  • Patients must have the following laboratory values:

    • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
    • Platelets ≥ 75 x 109/L
    • Hemoglobin (Hgb) > 8 g/dL
    • Serum total bilirubin: ≤ 1.5 x ULN
    • alanine transaminase(ALT) and aspartate aminotransferase(AST) ≤ 2.0 x upper limit of normal(ULN) with or without liver metastases
    • Serum creatinine ≤ 1.5 x ULN or serum creatinine >1.5 - 3 x ULN or 1.5 x ULN<serum creatinine < 3 x ULN, if calculated creatinine clearance (CrCl) is ≥ 30 mL/min using the Cockcroft-Gault equation, see formula below:

CrCl = [140-age (years)] x weight (kg) / [72 x serum Cr (mg/dL)] (if patient is female multiply the above by 0.85)

  • Patients who give a written informed consent obtained according to local guidelines

Exclusion Criteria:

Patients eligible for this study must not meet any of the following criteria

  • Patients with known brain metastases or who have signs/symptoms attributable to brain metastases and have not been assessed with radiologic imaging to rule out the presence of brain metastases
  • Patients with another primary malignancy within 3 years prior to starting study drug, with the exception of adequately treated in-situ carcinoma of the uterine cervix, basal or squamous cell carcinoma or non-melanomatous skin cancer

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01741116

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Contact: Kyong Hwa Park, MD, phD +82-2-920-5983 ext 5980

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Korea, Republic of
Korean Cancer Study Group Recruiting
Seoul, Chongro-ku, Korea, Republic of, 110999
Contact: So-Yeon Kang    82-2-3276-3511   
Korea University Anam Hospital Recruiting
Seoul, Seongbuk-gu, Inchon-ro, Korea, Republic of, 136-705
Contact: Kyong Hwa Park, MD, phD    +82-2-920-5983 ext 5980   
Sponsors and Collaborators
Korean Cancer Study Group
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Principal Investigator: Kyong Hwa Park, MD, phD Korea University
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Responsible Party: Kyong-Hwa, Park, Korean Cancer Study Group Identifier: NCT01741116    
Other Study ID Numbers: KCSG-GU11-05
GU11-05 ( Other Identifier: KCSG )
First Posted: December 4, 2012    Key Record Dates
Last Update Posted: December 4, 2012
Last Verified: November 2012
Keywords provided by Kyong-Hwa, Park, Korean Cancer Study Group:
castration-resistant prostate cancer
Additional relevant MeSH terms:
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Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Prostatic Diseases