Clinical trial NCT00303251: Safety of TKI258 in Advanced/Metastatic Melanoma Subjects
Official title: A Phase I/II Dose Escalating Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of TKI258 (CHIR-258) in Patients With Locally Advanced or Metastatic Melanoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Melanoma
Keywords: Locally Advanced or Metastatic Melanoma
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2006-03-16
Enrollment: 47
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study is an open-label, dose-escalating study to delineate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of TKI258. Pharmacokinetics and pharmacodynamics will be performed on all subjects. The eligible subject population consists of subjects who have been diagnosed with locally advanced or metastatic melanoma that is refractory to standard therapy or for which no curative standard therapy exists.


Eligibility criteria: Inclusion Criteria:

* Confirmed diagnosis of locally advanced or metastatic melanoma (American Joint Committee on Cancer \[AJCC\] stage IIIB, IIIC or IV) that is refractory to standard therapy or for which no curative standard therapy exists.
* Measurable disease
* Must be eighteen years of age or older
* Must meet baseline laboratory requirements
* ECOG performance status 0 or 1
* Adults of reproductive potential must agree to use effective contraception or be sterile

Exclusion Criteria:

* Concurrent therapy with any other investigational agent
* Uncontrolled central nervous system metastases
* Impaired cardiac function or clinically significant cardiac disease
* Received

  * chemotherapy, targeted therapy or monoclonal antibody therapy ≤4 weeks
  * biological therapy or immunotherapy (therapeutic or diagnostic) ≤2 weeks
  * an investigational agent (therapeutic or diagnostic) ≤4 weeks prior to starting study drug or has not recovered from side effects of such therapy
* Received any hematopoietic colony-stimulating factor (e.g., G-CSF, GM-CSF) ≤ 2 weeks prior to starting study drug. Erythropoietin is allowed.
* Has undergone major surgery ≤ 2 weeks prior to starting study drug or has not recovered from side effects of such surgery.
* Malabsorption syndrome or uncontrolled gastrointestinal symptoms such as nausea, diarrhea, vomiting
* Pregnant or breast feeding women
* History of another primary malignancy that is currently clinically significant or currently requires active intervention.
* Chronic anticoagulation therapy with full strength aspirin, Coumadin, or heparin.
* History of thromboembolic or cerebrovascular events within the last 12 months.
* History of rectal bleeding, bloody vomit, or spitting up blood within the last 3 months.
* Known diagnosis of HIV infection (HIV testing is not mandatory)
* Use of ketoconazole, erythromycin, carbamazepine, phenobarbital, phenytoin, rifampin, St. John's wort and quinidine is prohibited.
* Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study-drug administration or may interfere with the interpretation of study results and, in the judgment of the investigator, make the patient inappropriate for this study

Primary outcomes:
measure: Dose Expansion: Determine the maximum tolerated dose based on dose limiting toxicity of TKI258
timeFrame: end of dose escalation
measure: Dose Expansion: Determine the plasma and whole blood pharmacokinetics of orally administered TKI258
timeFrame: PK run-in days 1 & 2, cycle 1 days 1, 8, 15, 16, 28, cycle 2 day 15, cycle 2+ day 28
measure: Dose Escalation: Assess tumor response according to RECIST as measured by response rate and lack of early progressive disease (<=2 months)
timeFrame: every 8 weeks
Secondary outcomes:
measure: Assess the safety profile of TKI258 in this patient population
timeFrame: PK run in day 1 & 2, cycle 1 day 8, 15, 28, cycle 2+ day 15 & 28, end of study
measure: Assess the effect of TKI258 on biomarkers in the blood
timeFrame: PK run day 1 & 2, cycle 1 day 2, 15, 28, cycle 2+ day 28, end of study
measure: Assess biomarker changes in tumor/nevi biopsies and archival tumor tissues where accessible, pre- and post-treatment
timeFrame: baseline, cycle 1 day 15, end of study
measure: Assess changes in tumor glucose metabolism/cell viability between pre- and post-treatment using [18F]-FDG-PET
timeFrame: baseline, cycle 1 day 15, cycle 2 day 28
measure: Assess anti-angiogenic effects of TKI258 using DCE-MRI pre- and post-treatment
timeFrame: baseline, cycle 1 day 2 and cycle 2 day 28
Other outcomes:
Locations:
city: Louisville
country: United States
facility: James Graham Brown Cancer Center
state: Kentucky
city: Pittsburgh
country: United States
facility: University of Pittsburgh Cancer Institute
state: Pennsylvania
city: Houston
country: United States
facility: MD Anderson Cancer
state: Texas
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Wang X, Kay A, Anak O, Angevin E, Escudier B, Zhou W, Feng Y, Dugan M, Schran H. Population pharmacokinetic/pharmacodynamic modeling to assist dosing schedule selection for dovitinib. J Clin Pharmacol. 2013 Jan;53(1):14-20. doi: 10.1177/0091270011433330. Epub 2013 Jan 24.
citation: Kim KB, Chesney J, Robinson D, Gardner H, Shi MM, Kirkwood JM. Phase I/II and pharmacodynamic study of dovitinib (TKI258), an inhibitor of fibroblast growth factor receptors and VEGF receptors, in patients with advanced melanoma. Clin Cancer Res. 2011 Dec 1;17(23):7451-61. doi: 10.1158/1078-0432.CCR-11-1747. Epub 2011 Oct 5.