To evaluate the effects of mild, moderate or severe hepatic impairment versus normal hepatic function on the pharmacokinetics of TKI258 in patients with advanced solid tumor
ID
Source
Brief title
Condition
- Hepatic and hepatobiliary disorders
- Miscellaneous and site unspecified neoplasms benign
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Pharmacokinetic parameters of TKI258 including AUCinf following a single dose
and Cmax, Tmax, and AUClast following a single dose and at the steady state
Secondary outcome
Incidence of dose limiting toxicity (DLT) and other adverse events (AEs),
serious adverse events (SAE), and laboratory results (hematology, blood
chemistry) as assessed by the Common Terminology Criteria for Adverse Events
(CTCAE) v4.03
PK parameters and hepatic functional abnormalities (i.e. bilirubin, ALT/AST,
and Child-Pugh classification)
Best overall response (RECIST 1.1)
Background summary
TKI258 is a new investigational drug available as an oral formulation. In
clinical studies, TKI258 has been investigated as a single agent in sefveral
solid tumor studies. As of September 10, 2010, a total of 420 patients have
received TKI258 treatment.
Hepatic impairment is one of the common co-morbidities in cancer patients.
Patients with hepatic impairment are at a higher risk to have a decreased
ability to eliminate TKI258. Decreased drug clearance as a result of impaired
organ function may lead to an increased systemic exposure and possibly
toxicity.
Study objective
To evaluate the effects of mild, moderate or severe hepatic impairment versus
normal hepatic function on the pharmacokinetics of TKI258 in patients with
advanced solid tumor
Study design
Treatment period consists of a single-dose PK period and multiple dosing period
on a 5 days on / 2 days off dosing schedule.
The purpose of this single-dose PK analysis is to obtain pharmacokinetics (PK)
for a single dose of TKI258. A 2-day rest period was selected, based on the 28
hour half-life of a single dose of TKI258.
The multiple dosing period with TKI258 (on a 5 days on/2 days off dosing
regimen) will start on Day 4 of Week 1 (Figure 6-1) and continue until disease
progression, unacceptable toxicity, death or discontinuation from the study
treatment for any other reason
Approximately 18-48 patients are expected to be enrolled in the study.
Individual patients will be allocated to one of the three treatments groups
based on their total bilirubin and ALT/AST levels on Day 1 (pre-dose). The
enrollment to the individual treatment groups are in parallel, with at least 6
evaluable patients per treatment group. The mild hepatic impairment group may
require 6-12 evaluable patients, whereas, moderate hepatic impairment group
6-18 evaluable patients. To the extent possible, the enrollment of the control
group (Treatment Group 1, normal hepatic function) should be similar to the
enrollment to Treatment Groups 2 (mild hepatic impairment) and 3 (moderate
hepatic impairment in HCC patients only) with respect to age (±10 years) and
body weight (±10 Kg). Therefore, enrollment in Treatment Group 1 will remain
open until the enrollment in the two impairment groups (mild and moderate) is
complete and a sufficient number of matching controls has been achieved for
comparison, with a minimum of 6 evaluable patients in this treatment group.
For Treatment Groups 2 and 3, patient enrollment will be done in a staggered
fashion, one patient in every two weeks, which allows ongoing monitoring of
safety data collected from the first two weeks before the next patient is
treated. After the first 3 evaluable patients complete a 4-week treatment and
study assessment as per protocol, the sponsor and investigators will review
safety and PK data from the current treatment dose level and determine the next
dose level for further evaluation.
Patients with severe hepatic impairment will start once an acceptable dose has
been identified in the previous groups.
Intervention
Patients will receive, depending on the treatment group they are allocated to,
400 or 500 mg TKI258 orally administrated according a scheme of 5 days
treatment, 2 days rest. During the trial, based on interim analysis of safety
and pharmacokinetics, the dosing can be adjusted in favour of the patient.
Depending on the tolerance of the other group, patients in the severe hepatic
impairment group will start on 100 of 200 mg TKI258
Study burden and risks
Adverse events of TKI258 as known to date from animal experiments and previous
clinical trials. The main adverse events are
Diarrhea, Nausea, Vomiting, Fatigue, Decreased appetite , Headache, Dyspnea,
Constipation, Dysgeusia , Abdominal pain, Rash, Hypertension , Weight
decreased, Cough, Anemia, Dry skin, Edema peripheral, Dizziness, Dry mouth,
Pyrexia, Stomatitis, Myalgia
Besides these the discomforts and risks during blood drawing: pain, fainting,
bruising
More frequent visits to the hospital, more test than usual like blooddraws, ECG
and ECHO
Raapopseweg 1
Arnhem 6824 DP
NL
Raapopseweg 1
Arnhem 6824 DP
NL
Listed location countries
Age
Inclusion criteria
1. Patients with histologically or cytologically confirmed solid tumor, excluding breast cancer and lymphoma, that is either refractory to the standard therapy or has no available therapies. HCC patients with a diagnosis of advanced HCC according to the AASLD guidelines (Bruix and Sherman 2010)
2. Male or female patients * 18 years old
3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2
4. Patients must meet the following criteria for laboratory values:
a. Absolute neutrophile count (ANC) * 1.5 x 109/L
b. Platelets * 75 x 109/L
c. Hemoglobin * 9 g/dL
d. Total bilirubin and ALT/AST levels as described in Table 5-1
e. Serum creatinine * 1.5 x ULN
f. Urine dipstick reading: Negative for proteinuria or, if documentation of +1 results for protein on dipstick reading, then total urinary protein * 500 mg and measured creatinine clearance * 50 mL/min/1.73m3 from a 24 hour urine collection
5. Patients must have measurable and/or non-measurable lesion(s) as assessed by Computer Tomography (CT) Scan or Magnetic Resonance Imaging (MRI) per RECIST 1.1
6. Patients who give a written informed consent obtained according to local guidelines
Exclusion criteria
1. Patients with known brain metastases or who have signs/symptoms attributable to brain metastases and have not been assessed by radiologic imaging (e.g. CT or MRI scan) to rule out the presence of metastases.
2. Patients who have received the last administration of chemotherapy or immunotherapy or hormone therapy the timeframe defined below after the end of the last treatment Cycle (prior to starting study drug), or who have not recovered from the side effects of such therapy:
a. Last administration of chemotherapy/immunotherapy/hormone therapy in a daily schedule * 7 days prior to starting study treatment
b. Last administration of chemotherapy/immunotherapy/hormone therapy in a weekly schedule * 2 weeks prior to starting study treatment
c. Last administration of chemotherapy/immunotherapy/hormone therapy in a 2-weekly schedule * 3 weeks prior to starting study treatment
d. Last administration of chemotherapy/immunotherapy/hormone therapy in a 3-weekly schedule * 4 weeks prior to starting study treatment
e. Last administration of chemotherapy/ immunotherapy/hormone therapy in a 4-weekly schedule * 5 weeks prior to starting study treatment
f. Last administration of nitrosourea, mitomycin-C * 6 weeks prior to starting study treatment
3. Patients who received small molecule targeted agents * 2 weeks prior to starting study treatment
4. Patients who have received radiotherapy * 4 weeks prior to starting the study treatment or who have not recovered from radiotherapy-related toxicities. Palliative radiotherapy for bone lesions * 2 weeks prior to starting study treatment is allowed
5. Patients who have undergone major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) * 4 weeks prior to starting study treatment or who have not recovered from side effects of such therapy
6. Patients with another primary malignancy within 3 years prior to starting study drug, with the exception of adequately treated in-situ carcinoma of the uterine cervix, basal or squamous cell carcinoma or non-melanomatous skin cancer
7. Impaired cardiac function or clinically significant cardiac diseases, including any of the following:
a. History or presence of serious uncontrolled ventricular arrhythmias
b. Clinically significant resting bradycardia (< 50 beats/minute)
c. LVEF assessed by 2-D 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)
d. Any of the following within 6 months prior to study entry: myocardial infarction (MI), severe/unstable angina, coronary artery bypass graft (CABG), congestive heart failure (CHF), cerebrovascular accident (CVA), transient ischemic attack (TIA)
e. Uncontrolled hypertension defined by a systolic blood pressure (SBP) * 160 mm Hg and/or diastolic blood pressure (DBP) * 100 mm Hg, with or without anti-hypertensive medication
8. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of TKI258 (e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
9. Known history of human immunodeficiency virus (HIV) seropositivity (HIV testing is not mandatory)
10. Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. active or uncontrolled infection, with the exception of Hepatitis B or Hepatitis C in patients who have Hepatocellular Carcinoma (HCC), uncontrolled diabetes) that could cause unacceptable safety risks or compromise compliance with the protocol
11. Patients with known active bleeding (including bleeding from GI ulcers or esophageal varices) within 8 weeks (2 months) prior to baseline/screening visit or who have signs/symptoms attributable to portal hypertension and have not been assessed with upper GI endoscopy to rule out high-risk of GI bleeding
12. Patients with a history of pulmonary embolism (PE), or untreated deep venous thrombosis (DVT) within the past 6 months
13. Evidence of biliary sepsis in patients with biliary obstruction
14. Clinically significant third space fluid accumulation (i.e., ascites requiring tapping (despite use of diuretics) or pleural effusion that either requires tapping or is associated with shortness of breath)
15. HCC patients who have received liver transplant or who are listed for high urgent transplantationawaiting for immediate transplant
16. Patients who are currently receiving full dose anticoagulation treatment with therapeutic doses of warfarin or anti-platelet therapy (e.g., Plavix® [clopidogrel bisulfate]). However, treatment with low doses of warfarin (e.g., < 2 mg/day) or locally accepted low doses of acetylsalicyclic acid (up to 81 mg 100 mg daily) to prevent cardiovascular events or strokes is allowed.
17. Patients with known active alcohol abuse
18. Pregnant or breast-feeding women
19. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using two forms of highly effective contraception during dosing and 30 days after the end of study treatment. Highly effective contraception methods include:
* Total abstinence, or
* Male or female sterilization or
* Combination of the following
a. Placement of an interuterine device (IUD) or intrauterine system (IUS)
b. Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository
* Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.
* Use of oral, injected or implanted hormonal methods of contraception may be affected by cytochrome P450 interactions, and are therefore NOT considered effective for this study.
25. Patients with concurrent portal vein tumor thrombus, inferior vena cava tumor
thrombus, or vascular invasion.
26. Patients who developed liver toxicities attributed to VEGF inhibitors or other treatments
used during prior anti-cancer therapy.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2011-000103-41-NL |
| ClinicalTrials.gov | NCT01443481 |
| CCMO | NL37661.068.11 |