Clinical trial NCT00715182: A Phase I/II Study to Assess the Safety and Efficacy of TKI258 for the Treatment of Refractory Advanced/Metastatic Renal Cell Cancer
Official title: A Phase I/II Multi-center, Open Label Study of TKI258 Administered Orally on an Intermittent Schedule in Adult Patients With Advanced or Metastatic Renal Cell Cancer (RCC)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Advanced/ Metastatic Renal Cell Cancer
Keywords: Renal Cell Cancer
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2008-07-15
Enrollment: 87
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 is a phase I/II open-label study to delineate the safety, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of TKI258. The eligible subject population consists of subjects who have been diagnosed with advanced or metastatic renal cell cancer that is refractory to standard therapy or for which no curative standard therapy exists.


Eligibility criteria: Inclusion Criteria:

* For phase I, confirmed advanced/ metastatic renal cell carcinoma for which no other therapeutic options exist.
* For phase II, must have been previously treated with VEGF receptor tyrosine kinase inhibitor (sunitinib and/or sorafenib).
* For phase II, must have at least one measurable lesion at baseline.
* For both phase I \& II, measurable histologically or cytology confirmed progressive metastatic renal cell carcinoma with predominant clear cell histology (\>50%).
* At least 4 weeks must have elapsed since any prior anti-cancer therapy (6 weeks for nitrosoureas or mitomycin C).
* Must have recovered from adverse events (to grade 1 or less toxicity according to CTCAE 3.0) due to agents administered more than 28 days earlier.
* Must be eighteen years of age or older
* ECOG performance status 0 or 1.
* Must meet baseline laboratory requirement
* Life expectancy greater than or equal to 12 weeks.
* Signed and witnessed informed consent prior to any screening procedures.

Exclusion Criteria:

* Concurrent therapy with any other investigational agent within 28 days prior to baseline.
* Pregnant or breast feeding women.
* Clinically significant cardiac disease (New York Heart Association, Class III or IV) or impaired cardiac function or clinically significant cardiac diseases.
* Uncontrolled infection.
* Diabetes mellitus with signs of clinically significant peripheral vascular disease.
* Previous pericarditis; clinically significant pleural effusion in the previous 12 months or current ascites requiring two or more interventions/month.
* Known pre-existing clinically significant disorder of the hypothalamic-pituitary axis, adrenal or thyroid glands.
* Prior acute or chronic pancreatitis of any etiology.
* Acute and chronic liver disease and all chronic liver impairment.
* Malabsorption syndrome or uncontrolled gastrointestinal symptoms (such as nausea, diarrhea and vomiting) with toxicity greater than NCI CTCAE grade 2.
* Other severe, acutem or chronic medical or psychiatric condition or laboratory abnormality that may interfere with the interpretation of study results and, in the judgement of the investigator, would make the subject inappropriate for this study.
* Treatment with any of the medications that have a potential risk of prolonging the QT interval or inducing Torsades de Points and the treatment cannot be discontinued or switched to a different medication prior to starting study drug.
* Use of ketoconazole, erythromycin, carbamazapine, phenobarbital, rifampin, phenytoin and quinidine 2 weeks prior to baseline.
* Major surgery within 28 days prior to starting study drug or who have not recovered from side effects of such therapy.
* Known diagnosis of HIV infection (HIV testing is not mandatory).
* History of another clinically significant primary malignancy that requires active intervention.
* Patients with brain metastases as assessed by radiologic imaging.
* Alcohol or substance abuse disorder.

Primary outcomes:
measure: Phase I: To determine the MTD of TKI258, administered orally on a 5 days on/2 days off schedule to adult patients with advanced or metastatic RCC whose diseases have progressed despite standard therapy or for whom no standard anticancer therapy exists.
timeFrame: at end of phase I
measure: Phase II: To determine anti-tumor activity of TKI258 in advanced or metastatic RCC patients with predominant clear cell histology that have been previously treated with VEGF receptor tyrosine kinase inhibitor (sunitinib and/or sorafenib).
timeFrame: at end of phase II
Secondary outcomes:
measure: To assess the safety profile of TKI258
timeFrame: cycle 1: day 1,8,15,26; cycle 2: day 15, 28; cycle 3+: day 28 & at end of study
measure: To assess the effect of TKI258 on plasma biomarkers, pre- and post-treatment
timeFrame: cycle 1: day 1,15,26; cycle 2: 15 & 28; every other cycles: day 28 & at end of study
measure: To explore the pharmacokinetic and pharmacodynamic relationship
timeFrame: end of study
measure: To characterize the single and multiple-dose PK profiles of oral TKI258
timeFrame: cycle 1: day 1, 8, 15 &26; cycle 2 & 3: day 15 & 28
measure: Progression free survival and over all survival
timeFrame: end of study
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: Novartis Investigative Site
state: California
city: Durham
country: United States
facility: Novartis Investigative Site
state: North Carolina
city: Seattle
country: United States
facility: Novartis Investigative Site
state: Washington
city: Bordeaux Cedex
country: France
facility: Novartis Investigative Site
city: Villejuif Cedex
country: France
facility: Novartis Investigative Site
city: Hannover
country: Germany
facility: Novartis Investigative Site
city: München
country: Germany
facility: Novartis Investigative Site
city: Rotterdam
country: Netherlands
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
state: Taiwan, ROC
city: Taichung
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: