Based on the above, we propose to perform a prospective pharmacokinetic cross-over trial to test the hypothesis that splitting pazopanib intake moment will increase Cmin and AUC0-24h. In addition, we will show that this is a feasible, safe and cost-…
ID
Source
Brief title
Condition
- Renal and urinary tract neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary outcome will be the increase in Cmin and AUC when comparing
pazopanib 800mg QD and 400mg BID.
Secondary outcome
To compare the incidence and severity of adverse events between the two dosing
schedules, according to CTC-AE v4.03.
Background summary
Pazopanib exposure has been linked to clinical efficacy in multiple studies. A
large retrospective analysis by Suttle et al showed an increase in progression
free survival and tumor shrinkage in patients with a Cmin * 20 mg/L.
A prospective clinical trial in cancer patients has shown that increasing
pazopanib dose, based on measured Cmin levels, was feasible, safe and leads to
an increase in pharmacokinetic exposure (Verheijen et al).
Pazopanib pharmacokinetics have been shown to be non-linear and recent efforts
using a population pharmacokinetic two-compartmental model based on multiple
clinical trials (n=96) support this (Yu et al) The model suggests that
pazopanib bioavailability is non-linear and simulations comparing the exposure
of 800mg QD versus 400mg BID were made. These results indicate a relevant
increase in pazopanib Cmin and AUC0-24h of 75% and 59% respectively.
Splitting pazopanib intake in this way would offer a cost-neutral option to
optimize pazopanib treatment for patients with low pharmacokinetic exposure.
This is relevant for a significant subset of patients as based on our own
clinical experience and published data. 20 - 56.7% of patients do not reach the
threshold of Cmin * 20 mg/L using the current fixed dose of 800mg QD (Suttle et
al, Verheijen et al).
Study objective
Based on the above, we propose to perform a prospective pharmacokinetic
cross-over trial to test the hypothesis that splitting pazopanib intake moment
will increase Cmin and AUC0-24h. In addition, we will show that this is a
feasible, safe and cost-neutral strategy to optimize pazopanib therapy in
patients with low pharmacokinetic exposure.
Study design
Prospective pharmacokinetic cross-over trial comparing pazopanib 800mg QD and
400mg BID.
Intervention
Patients will receive pazopanib 400mg BID for a period of one week (instead of
800mg QD).
Study burden and risks
Pazopanib will be used in patients for whom it is considered standard of care.
Importantly, patients will receive the approved dose of 800 mg a day throughout
this study, only the intake moments will be split during a one week period.
Theoretically, a possible risk of additional toxicity exists, as we expect an
increase in exposure by splitting intake moments of pazopanib. However, this
risk is minimized by:
- The short duration of the intervention (only seven days);
- The exclusion of patients with a high Cmin at screening.
Patients will undergo two days of intensive pharmacokinetic sampling (24 hours)
requiring two overnight stays at the hospital (day 1 and day 8).
The total amount of blood required for pharmacokinetic sampling is estimated to
remain below 100 mL for the entire study
Plesmanlaan 121
Amsterdam 1066 CX
NL
Plesmanlaan 121
Amsterdam 1066 CX
NL
Listed location countries
Age
Inclusion criteria
1. Histological or cytological proof of cancer for which pazopanib is considered standard care;
2. Patients should have received pazopanib 800 mg QD as routine care for at least 3 weeks before day 1 of the trial;
3. Age * 18 years;
4. Able and willing to give written informed consent;
5. WHO performance status of 0, 1 or 2;
6. Adequate organ function per judgement of the treating physician;
7. Able and willing to undergo blood sampling for PK analysis.
Exclusion criteria
1. Concomitant use of medication(s) which could influence the pharmacokinetics of pazopanib within 14 days or five half-lives of the drug (whichever is shorter) before start of the study, consisting of (but not limited to) gastric acid suppressing agents, CYP3A4-inhibitors/inductors, PgP and/or BCRP modulators. In particular, proton pump inhibitors (such as omeprazole and pantoprazole) are to be avoided;
2. Woman who are pregnant or breast feeding;
3. Patients with known alcoholism, drug addiction and/or psychiatric of physiological condition which in the opinion of the investigator would impair study compliance;
4. Pazopanib related side effects that would require a dose reduction per judgement of the treating physician;
5. Legal incapacity;
6. (Calculated) pazopanib Cmin > 33 mg/L at screening visit.
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 | EUCTR2016-005252-21-NL |
| CCMO | NL60393.031.17 |