| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| advanced or metastatic renal cell carcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 13.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10050513 |
| E.1.2 | Term | Metastatic renal cell carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Dose escalation phase (Phase I)
• To determine the MTD based on the incidence of the DLT 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.
Dose expansion phase (Phase II)
• To assess anti-tumor activity of TKI258 in patients who have been previously treated with VEGF receptor tyrosine kinase inhibitor (sunitinib and/or sorafenib) mTOR inhibitor and have measurable histologically or cytologically confirmed progressive advanced or metastatic RCC with predominant clear cell histology (>50%) based on the proportion of patients experiencing clinical response (CR and PR) and no clinical benefit at 8 weeks post-treatment |
|
| 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 |
Dose escalation phase only
• Patients with advanced or metastatic RCC for whom no other
therapeutic options exist (measurable lesion by RECIST is not required).
Dose expansion phase only
• Patients that must have been previously treated with VEGF receptor
tyrosine kinase inhibitor (sunitinib and/or sorafenib) and an mTOR
inhibitor. However, patients previously treated with other therapies
(e.g. IL-2, IF-α) are also allowed to be enrolled and treated to determine
the effect of TKI258 in patients who had not been treated with VEGF
receptor tyrosine kinase inhibitor and mTOR therapy.
• Patients of Asian ethnicity: who failed standard treatment or for whom
no standard treatment exists.
• 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 phases
In order to determine and confirm the eligibility of a patient, after all
screening procedures are completed, a checklist of key eligibility criteria
must be completed manually by the investigator or designee prior to
administering the first dose. After all eligibility criteria have been
checked and it is confirmed that the patient is eligible for the trial, then
the patient can be enrolled.
Prior therapy with any prior anti-cancer agent (i.e. IL-2, Interferon, etc.)
is permitted as long as it is administered 14 days (6 weeks for
nitrosoureas or mitomycin C, and 4 weeks for any investigational agents
and bevacizumab) prior to first administration of TKI258 (cycle 1 day 1).
The only exception is made for palliative radiotherapy for symptomatic
bone metastases. Patients must have recovered from adverse events (to
grade 1 or less toxicity according to CTCAE 3.0) due to the prior anticancer
agents (with the exception of the GI toxicities mentioned in the
exclusion criteria).
• Patients with measurable histologically or cytologically confirmed
progressive metastatic RCC 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) >= 1,500/mm3 [SI units 1.5 x
10^9/L]
• Platelets >= 75,000/mm3 [SI units 75 x 109/L]
• Hemoglobin >= 8.0 gm/dL [SI units 80 gm/L]
• Serum creatinine <= 1.5 x upper limit of normal (ULN)
• Bilirubin <=1.5 x ULN
• AST (SGOT) and ALT (SGPT)<= 2.5 x ULN (with or without liver
metastases)
• Electrolyte levels:
• Potassium <LLN – 3.0mmol/L or >ULN – 5.5mmol/L
• Sodium <LLN – 130mmol/L or >ULN – 150mmol/L
• Urine dipstick reading: Negative for proteinuria or, if documentation of
<= +2 results for protein on dipstick reading, then total urinary protein
≤ 500 mg and measured creatinine clearance ≥ 50 mL/min from a 24-
hour urine collection
• Life expectancy >= 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 within 28
days prior to baseline.
• Women of child-bearing potential,who are biologically able to
conceive, not employing two forms of highly effective contraception.
Highly effective contraception (e.g. male condom with spermicide,
diaphragm with spermicide, intra-uterine device) must be used by both
sexes during the study and must be continued for 8 weeks after the end
of study treatment. 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 ≤ 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 assessed by 2-echocardiogram (ECHO) <50% or lower limit of
normal (which ever is higher) or multiple gated acquisition scan (MUGA)
<45% or lower limit of normal (which ever is higher)
• 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)
• Uncontrolled hypertension (systolic blood pressure ≥ 150 mmHg
and/or diastolic blood pressure ≥ 100 mmHg, with or without antihypertensive
medication).
• QTc > 480 msec on screening ECG
• Right bundle branch block + left anterior hemiblock (bifasicular block)
• Angina pectoris ≤ 3 months prior to starting study drug
• Acute Myocardial Infarction ≤ 3 months prior to starting study drug
• Other clinically significant heart disease (e.g., CHF, 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 hypothalamicpituitary
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 ≤ 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.
• Patients with brain metastases as assessed by radiologic imaging (e.g.
CT, MRI)
• 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.5.1.1 | Timepoint(s) of evaluation of this end point |
Dose escalation phase: continuously
Dose expansion phase: 8 weeks post treatment |
|
| E.5.2 | Secondary end point(s) |
• Frequency, and severity of Adverse Events (AE) of oral TKI258.
• Progression free survival (PFS), Overall survival (OS). Standard
survival analysis using the Kaplan-Meier approach will be performed.
• PK: plasma concentration of TKI258, and PK parameters (e.g. Cmax,
Tmax, AUC0-24,
AUC0-t) .
• PD: changes between pre- and post-treatment target and downstream
signaling components. Circulating growth factors (including but not
limited to VEGF, bFGF, PLGF), and soluble receptors (including but not
limited to sVEGFR1 and 2) will be evaluated as core PD biomarkers.
Plasma FGF23 may be explored as a potential PD biomarker of FGFR
inhibition.
• PK/PD relationship.
• Best overall tumor response (CR, PR, SD and PD) data during dose
escalation will be reported by descriptive statistics by dose cohort. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Various timepoints for according protocol |
|
| 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 | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| 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 | 5 |
| 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 | No |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
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