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Trial of Dasatinib (Sprycel®) in Subjects With Hormone-refractory Prostate Cancer

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ClinicalTrials.gov Identifier: NCT00570700
Recruitment Status : Completed
First Posted : December 11, 2007
Results First Posted : May 25, 2018
Last Update Posted : May 25, 2018
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Chao Family Comprehensive Cancer Center, University of California, Irvine

Brief Summary:

The purpose of this research study is to find out if a new anti-cancer drug, dasatinib (Sprycel®), previously approved for treatment of some forms of leukemia, will be safe and helpful in treating patients with hormone-refractory prostate cancer.

This is a research study because the study drug, dasatinib (Sprycel®), has not been evaluated for safety or effectiveness in patients with hormone-refractory prostate cancer. The drug is approved by the Food and Drug Administration for treatment of some forms of leukemia; thus, dasatinib (Sprycel®) is not an investigational drug. It has been given safely to hundreds of patients already. However its safety and usefulness in this study population (prostate cancer) is unknown.

Subjects who agree to participate will take 150mg (3 pills) of dasatinib (Sprycel®) daily by mouth for as long as the drug benefits them. During this time, the subject will periodically return to the office for blood/urine tests, X-rays, imaging scans, and/or to complete questionnaires.


Condition or disease Intervention/treatment Phase
Hormone-refractory Prostate Cancer Adenocarcinoma of the Prostate Hormone-resistant Prostate Cancer Prostate Cancer Recurrent Prostate Cancer Drug: Dasatinib Phase 2

Detailed Description:

Metastatic prostate adenocarcinoma is initially dependent on exogenous androgens for survival and growth; hence, androgen blockade is a key initial intervention for these patients. Whether by orchiectomy or by biochemical blockade, androgen deprivation produces objective regression of prostate cancer in >90% of patients for an average of 1.5-2yrs. Afterwards, however, the remaining prostate cancer cells become independent of exogenous androgen and resume their growth. At this stage the disease is referred to as hormone-refractory prostate cancer (HRPC).

Treatment for HRPC remains unsatisfactory. Only two interventions have been proven through randomized, prospective studies to confer a survival advantage. Docetaxel administered along with prednisone or estramsutine increases overall survival by approximately 3 months, compared with patients treated with mitoxantrone (1,2). In addition, a cell-based vaccine (APC8015) has recently been shown to confer a similar survival advantage for patients with HRPC (3). In 127 patients with HRPC randomized to receive the APC8015 vaccine or unactivated autologous peripheral blood mononuclear cells, there was a 4.5-month increase in median overall survival for the treated cohort (p = 0.01). Thus additional therapeutic tools are needed.

Although the mechanisms whereby androgen-independence develops are not yet fully clarified (7), it is known that malignant progression of prostate cancer involves upregulation of autocrine growth factors and their receptors (8). The process of autocrine reprogramming facilitates autonomous growth and metastasis of the tumor cells. For this reason many of the major novel therapeutic approaches for prostate cancer, currently in clinical trials, are directed against growth factor signaling pathways involving tyrosine kinase receptors and their downstream signaling messengers. Among these, recent evidence suggests a centrol role for the non-receptor tyrosine kinase c-src, in the development, growth, and metastasis of many human cancers (9,10), including prostate carcinomas. Several SFKs are present in prostate cancer cells, including c-src, yes, lck, and lyn (11). SFKs are thought to mediate the signaling pathways of several growth factors and stressors, such as lysophosphatidic acid, bombesin, androgens, and hypoxia (12-15). In prostate cancer cells that are androgen-independent, activation of SFKs is constitutive, rather than ligand-regulated (16). SFKs in turn regulate such diverse prostate cell pathways as VEGF production (15), and FAK signaling (17). Among the response phenotypes mediated by SFKs include cell spreading and attachment, migration and invasion. Genetic and pharmacologic inhibitors of SFKs have been tested on prostate cancer cell lines. Thus two pyrrolopyrimidine c-src inhibitors were shown to inhibit production of the protease MMP-9, as well as the functional ability of the cells to invade Matrigel (18). These phenotypes occurred at inhibitor concentrations that did not significantly affect cell proliferation. In contrast a peptide inhibitor of the lyn kinase inhibited the proliferation of prostate cancer cell lines in culture, and reduced the growth of DU145 xenografts in nude mice (19). Thus a spectrum of responses have been seen in prostate cancer cells or tumors treated with SFK inhibitors, including inhibition of growth.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 38 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: BMS CA180-097: A Phase II Trial of Dasatinib (Sprycel®) in Subjects With Hormone-refractory Prostate Cancer, Previously Treated With Chemotherapy
Study Start Date : July 2007
Actual Primary Completion Date : February 2012
Actual Study Completion Date : February 2012

Resource links provided by the National Library of Medicine

Drug Information available for: Dasatinib

Arm Intervention/treatment
Experimental: Dasatinib
Patients receive oral dasatinib once daily in the absence of disease progression or unacceptable toxicity.
Drug: Dasatinib
150mg (3 pills) orally daily for as long as the drug benefits
Other Names:
  • Sprycel®
  • BMS-354825




Primary Outcome Measures :
  1. Number of Subjects With Disease Control (DC) (Based on PSA, Bone Scan, FACT-P, RECIST) [ Time Frame: From day 56 (8 weeks) and every 8 weeks thereafter until the date of first documented progression or date of death from any cause, whichever came first, assessed until death, the patient withdraws consent, or the study ends, up to 2 years ]

    A "positive effect" will be defined as a complete response, partial response, or stable disease. "Lack of positive effect" will be defined as progressive disease. Subjects with a mixed response should be continued on therapy until they either fulfill the criteria for positive effect or lack of positive effect, with evaluation every 56 days.

    The disease control (DC) rate was evaluated as a composite endpoint of the treatment effect on four parameters: 1) Prostate-specific antigen (PSA), 2) measurable disease (if present) by RECIST criteria, 3) bone scan, and 4) quality-of-life as measured by the FACT-P questionnaire.



Secondary Outcome Measures :
  1. Time to Prostate-specific Antigen (PSA) Progression [ Time Frame: From initial date of treatment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years ]
    Time to PSA progression, defined as the interval from the first day of dasatinib treatment until either (1) there has been a 50% increase in PSA above the treatment nadir, with a minimum of 5ng/mL, or (2) a 25% increase in PSA level above pretreatment levels, with a minimum of 5ng/mL. All PSA-based assessments require a confirmatory level no more than 1 month later.

  2. Number of Subjects With Dasatinib Toxicity Using Common Terminology Criteria (CTC) (v. 3.0) [ Time Frame: From initial date of treatment through study completion, up to 2 years ]
    Due to relatively poor drug tolerance and relatively rapid PSA increases in most patients it was not feasible to continue patients on treatment until there was radiographic evidence of disease progression.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Must have biopsy-proven adenocarcinoma of the prostate
  • Must have hormone-refractory prostate cancer, defined as an increasing PSA by >= 3 ng/ml from androgen-blockade nadir, or new measurable or evaluable lesion on imaging studies, after treatment with orchiectomy, luteinizing hormone-releasing hormone (LHRH) agonist, antiandrogen or diethylstilbestrol (DES)
  • Subjects must have received at least one cycle of single-agent or combination chemotherapy for hormone refractory prostate cancer (HRPC), last administered at least 4 weeks prior to the start of dasatinib
  • Subjects may not have received more than one type (single agent or combination) of chemotherapy regimen; subjects may include (but are not limited to) the following: HRPC subjects who were treated with palliative chemotherapy and either failed to respond, or responded for a period of time but now have worsening disease (i.e. relapsed/refractory to chemotherapy); HRPC subjects who were treated with palliative chemotherapy but stopped treatment because of toxicity (i.e. intolerant of chemotherapy); HRPC subjects who have been treated with palliative chemotherapy with response, whose chemotherapy has been interrupted, and who now have evidence of progressive disease (i.e. potentially chemotherapy responsive but subject does not desire to restart cytotoxic drugs)
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
  • Life expectancy of at least 8 weeks, based on clinical judgment of the treating physician
  • Adequate hematologic, renal and liver function as evidenced by the following (subjects may have lower hematologic parameters if the cytopenias are thought by the treating physician to be secondary to marrow involvement by prostate cancer):
  • white blood cell count (WBC) > 2.0 bil/L; grade 0-1
  • absolute neutrophil count (ANC) > 1.0 bil/L; grade 0-1
  • Platelets > 100 bil/L; grade 0-1
  • Hemoglobin > 8.0gm/dL
  • Creatinine < 1.5x upper limit of normal (ULN)
  • Prothrombin time (PT), Partial Thromboplastin Time (PTT) < 1.2 x ULN; grade 0-1
  • Total bilirubin < 2x ULN
  • aspartate aminotransferase (AST), alanine aminotransferase (ALT) < 2.5x ULN
  • Na, K, Mg, P, Ca >= lower limit of normal
  • Elevated PSA level (at least 3 ng/mL), or measurable prostate cancer by CT or MRI scans (PSA level must have shown two consecutive increases [at >= 14 day intervals] since the previous nadir)
  • Ability to take oral medication (dasatinib must be swallowed whole)
  • Subjects of reproductive potential must agree to use an adequate method of contraception throughout treatment and for at least 4 weeks after study drug is stopped
  • Signed informed consent documents including Health Insurance Portability and Accountability Act (HIPAA) according to institutional guidelines
  • Concomitant Medications: Patient agrees to discontinue St. Johns Wort while receiving dasatinib therapy (in addition Patient agrees that IV bisphosphonates will be withheld for the first 8 weeks of dasatinib therapy due to risk of hypocalcemia)

Exclusion Criteria:

  • Subjects should have had no chemotherapy within 4 weeks of the start of treatment with dasatinib
  • Prior localized radiotherapy for metastatic disease is permitted, provided the treatment volume is less than25% of potential marrow space (the radiotherapy must have been completed 6 weeks prior to enrollment)
  • Systemic radiotherapy with samarium-153 must have been completed at least 2 months prior to enrollment (subjects may not have received prior strontium-89 [Metastron] therapy)
  • At least 6 weeks have elapsed from the last dose of cytotoxic or targeted therapeutics to the time of prescreening; if the subject has received a combination regimen of standard chemotherapy plus an investigational agent, a 6 week washout period is required
  • Subjects may not have received treatment with any kinase inhibitor
  • At least 2 months must have elapsed from time of dosing with vaccines to the time of prescreening
  • No malignancy, other than prostate cancer, that required radiotherapy or systemic treatment within the past 5 years
  • Subjects may not have any of the following: Clinical evidence of uncontrolled heart failure, myocardial infarction, or angina within the previous 6 months; prolonged QT interval Fridericia's (QTcF) > 450msec; history of unstable ventricular arrhythmias (ventricular tachycardia, ventricular fibrillation, or torsades de pointes); concomitant use of drugs known to cause torsades de pointes [quinidine, procainamide, disopyramide, amiodarone, sotalol, ibutilide, dofetilide, erythromycins, clarithromycin, chlorpromazine, haloperidol, mesoridazine,thioridazine, pimozide, cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine] (these agents must have been discontinued at least 7 days prior to starting dasatinib); subjects with hypokalemia or hypomagnesemia are excluded if the electrolyte anomaly cannot be corrected
  • Subjects may not be enrolled with any of the following: History of a significant bleeding disorder unrelated to cancer, including diagnosed congenital bleeding disorders (e.g., von Willebrand's disease), and diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies); GI bleeding from any cause within 3 months; Concomitant use of anticoagulants, except for low-dose warfarin (for prophylaxis to prevent catheter thrombosis) or heparin flushes (for IV lines), is prohibited (Note that chronic use of aspirin is prohibited)
  • Subjects must meet the following restrictions: Subjects may not have a concurrent medical condition which may increase the risk of toxicity, including pleural or pericardial effusion of any grade, or uncontrolled hypertension; Concomitant use of H2 blockers or proton pump inhibitors with dasatinib is not recommended (The use of antacids should be considered in place of H2 blockers or proton pump inhibitors in patients receiving dasatinib therapy); Patient must discontinue St. Johns Wort while receiving dasatinib therapy; Subjects must not use intravenous bisphosphonates during the first 8 weeks of dasatinib therapy due to risk of hypocalcemia; Subjects may not be receiving any restricted cytochrome P450 3A4 (CYP3A4) inhibitors (If the investigator feels that any of these agents should be given as uniquely useful for a clear diagnosis, the situation should be discussed with the Principal Investigator, and a clear monitoring program should be planned)
  • Subjects may not have evidence of untreated intracranial metastases, or untreated prostate cancer producing spinal cord compression

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 ClinicalTrials.gov identifier (NCT number): NCT00570700


Locations
United States, California
City of Hope National Medical Center
Duarte, California, United States, 91010
Loma Linda University Cancer Center
Loma Linda, California, United States, 92354
Chao Family Comprehensive Cancer Center
Orange, California, United States, 92868
St. Joseph Hospital
Orange, California, United States, 92868
United States, Pennsylvania
University of Pittsburgh
Pittsburgh, Pennsylvania, United States, 15232
United States, South Carolina
Medical University of South Carolina, and Hollings Cancer Network
Charleston, South Carolina, United States, 29425
Sponsors and Collaborators
University of California, Irvine
Bristol-Myers Squibb
Investigators
Principal Investigator: Michael B Lilly, MD, FACP Chao Family Comprehensive Cancer Center

Publications of Results:
Responsible Party: Chao Family Comprehensive Cancer Center, Cancer Center, University of California, Irvine
ClinicalTrials.gov Identifier: NCT00570700     History of Changes
Other Study ID Numbers: UCI 06-60
2007-5564 ( Other Identifier: University of California, Irvine )
BMS CA180-097 ( Other Identifier: Bristol-Myers Squibb )
NCI-2010-00336 ( Other Identifier: NCI Clinical Trials Reporting Program (CTRP) )
First Posted: December 11, 2007    Key Record Dates
Results First Posted: May 25, 2018
Last Update Posted: May 25, 2018
Last Verified: May 2018

Keywords provided by Chao Family Comprehensive Cancer Center, University of California, Irvine:
prostate

Additional relevant MeSH terms:
Prostatic Neoplasms
Adenocarcinoma
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Genital Diseases, Male
Prostatic Diseases
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Hormones
Dasatinib
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action