advanced or metastatic renal cell carcinoma MedDRA version: 9.1 Level: LLT Classification code 10050513 Term: Metastatic renal cell carcinoma
Conditions
Interventions
Product Name: TKI258
Product Code: TKI258
Pharmaceutical Form: Capsule, hard
CAS Number: 692737-80-7
Current Sponsor code: TKI258
Concentration unit: mg milligram(s)
Concentration type: equal
Concent
Sponsors
Novartis Pharma Services AG
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Inclusion criteria -- Dose escalation part only • Patients with advanced or metastatic renal cancer for whom no other therapeutic options exist (measurable lesion by RECIST is not required). Dose expansion part only -- • Patients that must have been previously treated with sunitinib and/or sorafenib. • Patients with at least one measurable lesion at baseline as per the RECIST criteria, either on physical exam or as determined by Computer Tomography (CT) Scan or Magnetic Resonance Imaging (MRI). Dose escalation and dose expansion parts -- • Prior therapy with any prior anti-cancer agent (i.e. IL-2, Interferon, bevacizumab, etc.) is permitted as long as it is administered 28 days (6 weeks for nitrosoureas or mitomycin C) prior to first administration of TKI258 (cycle 1 day 1). Patients 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 (with the exception of the GI toxicities mentioned in the exclusion criteria). The only exception is made for palliative radiotherapy for painful bone metastases. • Patients with measurable histologically or cytology confirmed progressive metastatic renal cell carcinoma with predominant clear cell histology (>50%). • Age at least 18 years. • ECOG performance status 0 or 1. • Required baseline laboratory data includes: • Absolute neutrophil count (ANC) greater than or equal to 1,500/mm3 [SI units 1.5 x 109/L] • Platelets greater than or equal to 75,000/mm3 [SI units 75 x 109/L] • Hemoglobin greater than or equal to 8.0 gm/dL [SI units 80 gm/L] • Serum creatinine less than or equal to 1.5 x upper limit of normal (ULN) • Bilirubin less than or equal to 1.5 x ULN • AST (SGOT) and ALT (SGPT) less than or equal to 2.5 x ULN, except for subjects with tumor involvement of the liver who must have AST and ALT less than or equal to 5 x ULN • Amylase, Lipase less than or equal to ULN • Electrolyte levels should be within normal limits (If =65 years) yes F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: • Concurrent therapy with any other investigational agent at least 28 days prior to baseline. • Women of child-bearing potential who are pregnant or breast feeding or adults of reproductive potential not employing an effective method of birth control. Barrier contraceptives must be used throughout the trial in both sexes. 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, defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (i.e. who has had menses any time in the preceding 12 consecutive months), must have a negative serum pregnancy test less than or equal to 72 hours prior to starting TKI258. • Clinically significant cardiac disease (New York Heart Association, Class III or IV) or impaired cardiac function or clinically significant cardiac diseases, including any one of the following: • LVEF 100 bpm). Patients with stable atrial fibrillation are eligible, provided they do not meet any of the other cardiac exclusion criteria • Clinically significant resting bradycardia ( 480 msec on screening ECG • Right bundle branch block + left anterior hemiblock (bifasicular block) • Angina pectoris less than or equal to 3 months prior to starting study drug • Acute Myocardial Infarction less than or equal to 3 months prior to starting study drug • Other clinically significant heart disease (e.g., CHF, uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen) • Uncontrolled infection. • Diabetes mellitus (insulin dependent or independent disease, requiring chronic medication) 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 (in both the dose escalation and dose expansion). • 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 toxicities (nausea, diarrhea, vomiting) with toxicity greater than NCI CTCAE grade 2. • 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, 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,
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Dose escalation part • To determine the maximum tolerated dose (MTD) based on the incidence of the dose limiting toxicities (DLT) of TKI258, administered orally on a 5 days on/2 days off schedule to adult patients with advanced or metastatic renal cell cancer (RCC) whose diseases have progressed despite standard therapy or for whom no standard anticancer therapy exists. Dose expansion part • To determine the preliminary anti-tumor activity of TKI258 in patients that must have been previously treated with sunitinib and/or sorafenib and have measurable histologically or cytology confirmed progressive advanced or metastatic renal cell carcinoma with predominant clear cell histology (>50%) according to the RECIST criteria.;Secondary Objective: Secondary objectives (both escalation and expansion parts) • To assess the safety profile of TKI258 administered orally on a 5 days on/2 days off schedule in this patient population. • To characterize the single and multiple-dose pharmacokinetic (PK) profiles of oral TKI258 on a 5 days on/2 days off dosing schedule. • To assess the effect of TKI258 on plasma biomarkers pre- and post-treatment: • To evaluate concentrations of circulating growth factors, soluble receptors (e.g. bFGF, VEGF, PlGF, sVEGFR1 and 2). • To assess the relationship between dose and exposure of TKI258. • To explore the relationship between PK and biomarker responses (PD) of TKI258.;Primary end point(s): Primary endpoints • Dose escalation part: incidence rate of DLT. • Dose expansion part: frequency of clinical responder (R) and stable disease (SD). Patients will be categorized into one of 3 distinct categories: clinical responders (CR and/or PR) at any time point prior the analysis [R], patients with stable disease for at least 8 weeks excluding clinical responders [SD] and all other patients (No Clinical Benefit [NCB]). | — |
Countries
France, Germany, Netherlands
Outcome results
None listed