E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
advanced or metastatic renal cell carcinoma |
|
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10050513 |
E.1.2 | Term | Metastatic renal cell carcinoma |
|
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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. |
|
E.2.2 | Secondary objectives of the trial |
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. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 < LLN should be corrected with supplement prior to dosing) • Urine dipstick reading: Negative for proteinuria or, if documentation of +1 results for protein on dipstick reading, then total urinary protein less than or equal to 500 mg and measured creatinine clearance greater than or equal to 50 mL/min/1.73m2 from a 24-hour urine collection • Life expectancy greater than or equal to 12 weeks. • Signed and witnessed informed consent form obtained prior to any screening procedures. |
|
E.4 | Principal 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 < 45% as determined by MUGA scan or echocardiogram • Complete left bundle branch block • Obligate use of a cardiac pacemaker • Congenital long QT syndrome • History or presence of ventricular tachyarrhythmia • Presence of unstable atrial fibrillation (ventricular response > 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 (< 50 bpm) • Hypertension of Grade 2 or above • QTc > 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, and quinidine 2 weeks prior baseline. • Major surgery less than or equal to 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 primary malignancy that is currently clinically significant or currently requires active intervention. • Known symptomatic cerebral metastases. • Alcohol or substance abuse disorder. |
|
E.5 End points |
E.5.1 | 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]). |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
|
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 4 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
| |
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 2 |