The overall main objective is to develop a safe and effective individualized dosing regimen for pemetrexed.
ID
Source
Brief title
Condition
- Respiratory and mediastinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
IMPROVE-I
The fraction of patients safely reaching the target dose in combination with
folinic acid or folinic acid and G-CSF, with the target dose being the dose
most likely to result in an AUC of 164 mg*h/L.
IMPROVE-II
The fraction (percentage) of patients with attainment of therapeutic exposure
defined as an AUC of 164 mg*h/l ±25%, with pemetrexed dosing based on renal
function versus BSA-based dosing. AUC will be calculated based on the dose and
the estimated pemetrexed clearance.
IMPROVE-III
The predictive performance of microdosing for pemetrexed clearance at
therapeutic doses by assessing accuracy (MPE) and precision (NRMSE) in
reference to full dose pharmacokinetics.
Secondary outcome
IMPROVE-I
•The AUC of pemetrexed reached at each dose level.
•Population pharmacokinetics in patients with renal impairment
•Comparative performance of different renal function markers to predict
pemetrexed pharmacokinetics by assessing which algorithm provides best model
fit and best reduction in clearance variability. Algorithms to be assessed:
•Safety of pemetrexed dosing in patients with a creatinine clearance <45ml/min.
IMPROVE-II
•Population pharmacokinetics in patients with adequate renal function
•Comparative performance of different renal function markers to predict
pemetrexed pharmacokinetics by assessing which algorithm provides best model
fit and best reduction in clearance variability.
•Safety of pemetrexed dosing based on renal function in patients with a
creatinine clearance >45ml/min versus dosing based on BSA.
•Quality of life measured with the EORTC QLQ-C30/L13 questionnaire before start
of chemotherapy and three months after start of chemotherapy
•Cost-effectiveness of renal-based dosing versus BSA-based dosing by using an
in silico evaluation of neutropenic response and related costs
IMPROVE-III
No secondary endpoints are studied in IMPROVE-III
Background summary
Pemetrexed is a multi-targeted folate antagonist, which is primarily indicated
for the treatment of advanced non-small cell lung cancer (NSCLC) and
mesothelioma. Dosing of cytotoxic agents like pemetrexed requires balancing the
dual risk of sub-therapy and toxicity. Administration of pemetrexed to patients
with a creatinine clearance <45 ml/min is currently not advised. Pemetrexed is
dosed based on body surface area (BSA), while renal function and dose are the
sole determinants for systemic exposure. This causes 3 major issues:
1. In patients with renal dysfunction, BSA-based dosing may lead to
haematological toxicity
2. Patients have to discontinue treatment due to declining renal function, and
are withheld effective treatment
3. Even in patients with adequate renal function (GFR >45 ml/min) treatment may
be improved by individualized dosing based on renal function, resulting in less
toxicity. Also, BSA-based dosing may lead to ineffective therapy in patients
with above average renal function.
We aim to address these problems.
Study objective
The overall main objective is to develop a safe and effective individualized
dosing regimen for pemetrexed.
Study design
IMPROVE-I is a single arm dose finding study to assess the feasibility of renal
function-based dosing of pemetrexed in combination with folinic acid or folinic
acid and pegfilgrastim in renally impaired patients
IMPROVE-II is an open label, double arm, randomized study to compare renal
function-based dosing of pemetrexed versus BSA-based dosing on attainment of
therapeutic exposure.
IMPROVE-III is an explorative microdosing study to assess the extrapolability
of microdose pharmacokinetics to the pharmacokinetics of a therapeutic dose.
Intervention
IMPROVE-I:patients will be treated with pemetrexed dose based on renal
function. As a safety measure, the first dose will be calculated based on 10%
exposure. If this is tolreated well,intra-patient dose escalation will be
performed to 33, 66 and 100% respectively. Adiitionally, prophylactic treatment
with folinic acid will be administered to prevent toxicity, on day 2-15 of the
treatment cycle. If neccesary, pefgilgrastim can be used to treat neutropenia.
IMPROVE-II: patients will be randomized in a 1:1 ratio to Arm A (BSA-based
dosing according drug label) or to Arm B (renal function based dosing). The
renal function-based dose will be calculated to reach the target AUC.
Pharmacokinetic assessment after administration will be performed after the
first pemetrexed dose in both arms.
IMPROVE-III: patients will be administered a microdose with subsequent
pharmacokinetic assessment.
Study burden and risks
We consider the extra burden from participating in the planned studies limited.
The extra interventions compared to routine care, consist of sampling extra
blood. The pharmacokinetic assessments require placement of one additional
intravenous venflon. To ensure minimal impact of study participation on daily
life, we will use a limited sampling strategy. Patients may benefit from
participating in IMPROVE I and -II, as they will be treated with a potentially
safe and effective drug that is dosed individually, which prevents toxic
exposure.
Geert Grooteplein-Zuid 10
Nijmegen 6525 GA
NL
Geert Grooteplein-Zuid 10
Nijmegen 6525 GA
NL
Listed location countries
Age
Inclusion criteria
IMPROVE-I,
1. >=18 years old
2. Eligible for treatment with pemetrexed-based chemotherapy based on indication
3A. For the first three patients (cohort 1): estimated creatinine clearance of
30-45 mL/min
3B. For every next patient (cohort 2): estimated creatinine clearance <45ml/min
4. ECOG performance score of 0-2
5. Subject is able and willing to sign the Informed Consent Form
IMPROVE-II
1. >=18 years old
2. Eligible for treatment with pemetrexed-based chemotherapy
3. Creatinine clearance >45ml/min
4. ECOG performance score of 0-2
5. Subject is able and willing to sign the Informed Consent Form,
IMPROVE-III
1. >=18 years old
2. Planned for treatment with pemetrexed-based chemotherapy
3. ECOG performance score of 0-2
4. Subject is able and willing to sign the Informed Consent Form
Exclusion criteria
IMPROVE-I, -II and -III
1. Conditions that affect haemostasis in a way that blood drawing is
complicated (to be assessed by physician)
2. Contraindications for treatment with pemetrexed in line with the SmPC
(except for creatinine clearance <45 ml/min in IMPROVE-I)
a.Hypersensitivity to the active substance or to any of the excipients
b.Pregnancy or lactation
c. Concomitant yellow fever vaccine
3. The presence of clinically relevant pharmacokinetic interactions, according
to the current SmPC
4. Obesity (defined as a body mass index (BMI) >40 kg/m2)
5. Limb amputation
6. Use of trimethoprim and/or cimetidine
additional for IMPROVE-I:
7. Baseline absolute neutrophil count <1.5*109/L
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 | EUCTR2018-001291-38-NL |
| Other | IMPROVE |
| CCMO | NL65481.091.18 |