Primary• To determine the safety profile of oral topotecan in subjects with cancer andmildly moderately or severely impaired renal function (Groups C, D and E) compared to subjects with cancerwhose renal function is normal and who have received…
ID
Source
Brief title
Condition
- Other condition
- Miscellaneous and site unspecified neoplasms benign
- Renal disorders (excl nephropathies)
Synonym
Health condition
elke uitgebreide solide tumor
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• Adverse events (AEs) and changes in laboratory values.
Secondary outcome
• Maximum plasma concentration (Cmax) and area under the concentration-time
curve (AUC) of oral topotecan (total topotecan and topotecan lactone).
• Apparent oral clearance (CL/F), time of maximum plasma concentration (tmax),
apparent oral volume of distribution (Vd/F), half-life (t*), fraction excreted
(Fe), and renal clearance (CLr).
Background summary
Topotecan is predominantly excreted by the kidneys. A previous intravenous (IV)
study including eight subjects with creatinine clearance (CrCl) 20-40 mL/min
(SK&F-104864/097) demonstrated marked reduction in plasma clearance of
Topotecan and total topotecan. Higher plasma concentrations of total topotecan
were observed in the subjects with moderate renal impairment. The current
labelling for IV Topotecan recommends a 50% decrease in the dose for subjects
presenting with moderate renal impairment. It is unknown whether the dosage
adjustments for IV topotecan directly apply to oral administration as the
pharmacokinetics (PK) of oral versus IV topotecan are significantly different
with respect to bioavailability, Cmax and tmax. The impact of renal disease on
these parameters may be different for oral versus IV topotecan and warrants
specific investigation. In addition, evidence suggests that cisplatin has a
direct toxic effect on the proximal tubule [Townsend, 2001] that could change
tubular secretion of topotecan and increase exposure to topotecan lactone (the
active species) without markedly affecting creatinine clearance. As a result,
prior platinum-based chemotherapy may affect the PK and tolerability of oral
topotecan; hence, the impact of prior platinum chemotherapy on oral topotecan
also warrants further investigation.
The current study will determine the effect of renal impairment and prior
platinum-based chemotherapy on the safety and PK of oral topotecan and identify
the appropriate dose adjustments for subjects with mild, moderate or severe
renal impairment and prior platinum-based chemotherapy (either less than three
courses, or three or more courses, of cisplatin or carboplatin, but not
oxaliplatin).
Study objective
Primary
• To determine the safety profile of oral topotecan in subjects with cancer and
mildly moderately or severely impaired renal function (Groups C, D and E)
compared to subjects with cancer
whose renal function is normal and who have received limited prior
platinum-based chemotherapy (Group A).
Secondary
• To determine the safety profile of oral topotecan in subjects with cancer and
normal renal function who have received prior platinum-based chemotherapy
(Group B) compared to subjects with cancer and normal renal function who have
received limited prior platinum-based chemotherapy (Group A).
• To evaluate the pharmacokinetics of oral topotecan (topotecan lactone and
total
topotecan) on this schedule in the designated subject populations (renally
impaired and control groups with limited prior platinum-based chemotherapy).
• To explore the correlation between changes in topotecan pharmacokinetic
parameters and clinical measures of renal impairment.
Study design
This will be a multi-center, Phase I, multiple-dose, open-label, safety and PK
study of oral topotecan in subjects with advanced solid tumors who have limited
treatment options. Subjects will be grouped by level of renal function (normal
or mild, moderate or severe impairment) and prior platinum-based chemotherapy
(P-B CT) into five study groups, as follows:
Group Parameters
A subjects with normal renal function with limited P-B CT
B subjects with normal renal function with P-B CT
C subjects with mild renal impairment
D subjects with moderate renal impairment
E subjects with severe renal impairment
Subjects may remain on study until occurrence of unacceptable toxicities,
disease progression, withdrawal of consent, investigator discretion, or a
treatment delay for more than two months.
During course 1, all doses of topotecan must be oral. During subsequent
courses, all dose of topotecan within the course must be in one form, either
oral or IV. Patients with severe renal impairment who remains on study beyond
Course 1 will be required to continue treatment with oral topotecan since an
appropriate dose adjustment for IV topotecan in subjects with severe renal
impairment has not been defined.
The 5 groups of cancer patients have to follow courses of 21 days during a
period of 12 months or until desease progression. So, there will be a maximum
of 17 courses. At the first day, the patient will take oral topotecan during
his stay in the hospital. The investigator dispenses to the patient oral
topotecan for the next 4 days. During the subsequent 16 days of the course, no
specific investigational medication will be administered.
During course 1, all doses of topotecan must be oral.
During subsequent courses, all dose of topotecan within the course must be in
one form, either oral or IV. Patients with severe renal impairment who remains
on study beyond course 1 will be required to continue treatment with oral
topotecan since an appropriate dose adjustment for IV topotecan in subjects
with severe renal impairment has not been defined.
The maximum dose of oral topotecan is 2,3 mg/m²/day for the first 3 groups,
this is for patients with a normal or slightly worse renal function. For
patients with a moderate renal impairement (group 4) the maximum dose is 1,2
mg/m²/day. For patients with severe renal impairement (group 5) the maximum
dose is 0,6 mg/m²/day. For all groups the dose may be adapted according
appearance of haematological toxicities (the neutrophil count, the platelet
count) and the number of non-haematological AE's (CTCAE criteria).
Intervention
The patient can follow a maximum of 17 courses. Each course last 21 days. The
patient will be hospitalised for 24 hours during the first day of the first
course in order to be able to take the necessary blood and urine samples for PK
measurements. The other tests and samples on D8 and D15 of the first course and
within 5 days of D1 of the following courses can be done in teh hospital or by
the general physician of the patient.
Table 6 PK (Blood) Sampling Schedule: Day 1, Course 1 (pg 31) (5 ml)
Sample
Number Sample Times
1) Pre-dose; within 30 minutes prior to dosing topotecan
2) 15 min after dosing topotecan
3) 30 min after dosing topotecan
4) 1 hr after dosing topotecan
5) 1.5 hrs after dosing topotecan
6) 2 hrs after dosing topotecan
7) 3 hrs after dosing topotecan
8) 4 hrs after dosing topotecan
9) 6 hrs after dosing topotecan
10) 8 hrs after dosing topotecan
11) between 10 and 12 hrs after dosing topotecan
12) 24 hrs after dosing topotecan
Table 7 PK (Urine) Sampling Schedule: Day 1, Course 1 (pg 32)
Sample
Number Sample Times
1) Pre-dose; 1 hour prior to dosing topotecan
2) between dosing and 6 hrs after dosing topotecan
3) between 6 and 12 hrs after dosing topotecan
4) between 12 and 18 hrs after dosing topotecan
5) between 18 and 24 hrs after dosing topotecan
Study burden and risks
For cancer patients with advanced solid tumors an with renal empairement there
exists not many alternatives for the treatment of their tumor(s). Oral
topotecan offers maybe a solution.
A summary of the extent of burden for participation to this trial is provided
in the flow-chart (time and event schedule) on pages 56 en 57.
1250 S. College Ville Road
P.A. 19426
US
1250 S. College Ville Road
P.A. 19426
US
Listed location countries
Age
Inclusion criteria
1. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
2. Age 18 years or older.
3. A performance status score of 0, 1, or 2 on the Eastern Cooperative Oncology Group (ECOG) Scale.
4. Histologically- or cytologically-confirmed advanced solid tumours.
5. Failed conventional therapy for their tumor type; or subjects who have a tumor type for which no standard effective therapy exists; or subjects for whom single-agent topotecan therapy is suitable.
6. Completion of a 24-hour urine collection within 14 days prior to the first dose to calculate the creatinine clearance value and determine the renal impairment category.
7. Documentation of a stable renal function for at least 14 days prior to first scheduled dose using the Cockcroft-Gault formula, and at least 2 serum creatinine values separated by a minimum of 7 days. Stable renal function is defined as:
a. < or = 25% change of CrCl<40 mL/min
b. < or = 10 mL/min change for CrCl > or = 40mL/min
NOTE: Documentation of stable renal function will NOT be required if the 24-hour urine collection to determine the renal impairment category is completed within 7 days prior to the first dose.
Exclusion criteria
1. Currently undergoing dialysis.
2. Pregant or lactating
3. Women of childbearing potential who refuse to either abstain from secual intercourse or practice adequate contraception defined as:
a. complete abstinence from sexual intercourse for 14 days before exposure to study drug, continuing throughout the clinical trial, and for a period of at least 14 days after the last dose of study drug;
b. oral contraceptives or intrauterine device [IUD] initiated at least 3 months prior to start of the study medication;
c. double barrier such as diaphragm plus spermicide;
d. vasectomized partner who is sterile prior to the female subject*s entry and is the sole sexual partner of that female.
Childbearing potential is defined as women who are not surgically sterilized (i.e., have not had a hysterectomy, bilateral oophorectomy [ovariectomy], or bilateral
tubal ligation) or post-menopausal (i.e., documented absence of menses for one year prior to entry into the study).
4. Male subjects with female partners of childbearing potential who have not had a prior vasectomy or if both the male subject and the female partner refuse to:
use adequate contraception (as described above) beginning 14 days before exposure to study drug, continuing throughout the clinical trial, and for a period of 3 months after the last dose of study drug.
5. Uncontrolled emesis, regardless of etiology.
6. Bilirubin > 1.5 X ULN.
7. SGOT/AST, SGPT/ALT and alkaline phosphatase > 2 times the upper limit of normal (ULN) if liver metastases cannot be visualized by abdominal computed tomography (CT) or magnetic resonance imaging (MRI). If liver metastases are present, subjects with <5 times ULN are eligible to participate, following discussion with and approval from a GSK Medical Monitor.
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 | EUCTR2007-002488-28-NL |
| ClinicalTrials.gov | NCT00483860 |
| CCMO | NL18333.031.07 |