This study has been transitioned to CTIS with ID 2023-506886-76-00 check the CTIS register for the current data. The primary objective will be a prolonged mPFS for the TDM-guided dosing cohort versus the standard fixed dosing cohort in the group of…
ID
Source
Brief title
Condition
- Respiratory and mediastinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The main endpoint will an increase in progression free survival (PFS according
to RECIST v1.1) in the subgroups of patients with an alectinib Cmin treshhold
<435 ng/mL in the TDM-guided dosing cohort versus the same subgroup in the
fixed dosing cohort
Secondary outcome
The secondary objectives are:
1. Feasibility and safety of TDM. This will be measured as percentage of
successful TDM measures, in which successful is defined as target attainment
with manageable toxicity.
2. Physician adherence to TDM advice. This will be measured as the percentage
of dose recommendations that are implemented by the treating physicians.
3. Overall response rates (ORR). ORR will be defined as partial response or
complete response (according to RECIST v1.1) percentage of the total treated
population.
4. Median overall survival (mOS). OS will be defined as the time from
randomization to death from any cause in the total population. Patients who do
not die or are lost to follow-up will be censored at their last available date.
5. Intracranial PFS. The intracranial PFS will be measured as time from start
of treatment to progressive disease in the brain, or death from any cause.
Patients who did not die or progress, or lost to follow-up, will be censored at
their last available date.
6. Patient adherence. This will be estimated by pill counts of returned
medication as well as a patient diary on drug intake.
7. Toxicity related to the plasma concentration and dose increases. This will
be defined as AE*s in the subgroups with Cmin < 435 ng/mL and all Cmin >= 435
ng/mL, and in patients who did and who did not receive a PK-guided dose
increase.
8. Quality of life (QoL). This will be determined using the EORTC QLQ_LC13 as
addition to the QLQ-C30 questionnaire, and the EQ-5D-5L questionnaire.
9. Cost-effectiveness. This will be determined by the incremental
cost-effectiveness ratio based on costs and quality adjusted life-years (QALYs)
10. Alectinib-M4 concentrations. These will be measured in the alectinib plasma
samples.
Background summary
Currently, over 40% of all recently approved oncolytics are oral agents.
Compared with the more traditional intravenous therapies, these oral agents are
less invasive and more patient friendly. On the other hand, due to home
administration, patient*s adherence could be compromised.2 Secondly, the oral
administration route makes these agents more prone to drug-drug and drug-food
interactions, both resulting in suboptimal drug exposure, with rates varying
between only 30% and 70% of desired drug exposure targets. Notably, overdosing
causes unnecessary and preventable side effects, while underdosing results in
reduced effects and tumour growth.
In lung cancer patients treatment with EGFR-TKI has been shown to be influenced
by e.g. body weight and renal impairment. Adapting the EGFR-TKI dose could help
in preventing major side effects and improve outcome of the treatment. For
ALK-TKI this has not been studied largely yet.
Despite the relative short treatment period of on average a year, and the
severity of the disease, still 20% of lung cancer patients have suboptimal
adherence.5 This may partly help to explain why survival of patients with
metastatic non-small cell lung carcinoma (NSCLC) in real-world daily practice
is nearly one quarter shorter than for patients included in clinical trials.
Adherence is the single most modifiable risk factor that comprises treatment
outcomes but is difficult to measure and no studies so far have employed
objective methods. Objective, long-term adherence data can support patients*
self-management in the outpatient setting, allows enhanced physician clinical
decision making and informs therapeutic drug monitoring (TDM) targets (dose
increase or decrease).
Alectinib is used in first and second line settings in ALK positive advanced
lung cancer as standard of care. Groenland et al. found in an exposure-response
analysis of alectinib a median alectinib Cmin of 517 ng/mL (range: 141-1944
ng/mL), with an interindividual variability of 57%. In total, 37% of the
patients had a median Cmin< 435 ng/mL. The median PFS was 12.8 months vs. not
estimated (95%CI: 19.8 months - not estimated) for patients with Cmin below or
above 435 ng/mL, respectively (p=0.04, log-rank) (Figure 1). Multivariable
analysis corrected for WHO performance status and prior treatment with
ALK-inhibitor(s) resulted in hazard ratio of 4.29 (95%CI: 1.33-13.90, p=0.015)
in favour of patients with higher drug exposure.8
Therefore, patients should have an alectinib Cmin >= 435 ng/mL, which could be
established by therapeutic drug monitoring (i.e. adjusting the dose based on
measured drug concentrations). Taken together, we hypothesize that the PFS will
increase by more than 10 months comparing therapeutic drug monitoring (TDM) and
increasing the dose of alectinib if the Cmin threshold of 435 ng/mL is not
reached and with fixed alectinib dosing
Study objective
This study has been transitioned to CTIS with ID 2023-506886-76-00 check the CTIS register for the current data.
The primary objective will be a prolonged mPFS for the TDM-guided dosing
cohort versus the standard fixed dosing cohort in the group of patients with an
alectinib Cmin below the threshold of< 435 ng/mL.
The secondary objectives are functioning and safety of TDM, overall response
rates (ORR), median overall survival (mOS), intracranial PFS, physician
adherence and toxicity (also in relationship to alectinib plasma concentrations
and dose increases), quality of life, cost-effectiveness en alectinib
M4-concentrations.
Study design
A phase IV randomized controlled trial between TDM guided dosing (Arm A) and
standard dose (Arm B) alectinib will be conducted
Intervention
One group (Arm A) will receive standard dose alectinib (600mg BID) and the
other group will receive alectinib adapted based on TDM (Arm B; dose
adaptations based on drug exposure in case of limited toxicity)
Study burden and risks
In both treatment groups, plasma samples will be drawn at different time points
(every 8 weeks during the first year of treatment and every 8 weeks from the
second year of treatment onwards). This blood draw is in combination with
standard blood draws for monitoring organ function (eg liver and renal tests).
For the intervention group, TDM results will be available directly (within 1-2
weeks) and used to adapt the alectinib dose. We expect that this intervention
will result in prolonged mPFS. For the fixed dosing group, the samples will be
analysed at the end of the study.
Hanzeplein 1
Groningen 9713 GZ
NL
Hanzeplein 1
Groningen 9713 GZ
NL
Listed location countries
Age
Inclusion criteria
1. Patients with locally advanced or metastatic NSCLC (stage IIIB to stage IV
by AJCC 8th)
2. Male or female >=18 years old
3. ECOG Performance Status of 0*4
4. Histologically or cytology confirmed NSCLC
5. Documented ALK rearrangement based on an EMA approved test
6. Patients can either be chemotherapy-naïve or have received one line of
platinum-based chemotherapy
7. Patients with brain or leptomeningeal metastases are allowed on study if
the lesions are asymptomatic without neurological signs and clinically stable
for at least 2 weeks without steroid treatment. Patients who do not meet these
criteria are not eligible for the study. However, they can be re-screened after
completing WBRT or gamma -knife treatment. They must have completed any
corticosteroid therapy >=2 weeks prior to the first dose of study treatment.
8. Measurable disease (by RECIST criteria version 1.1) prior to the first dose
of study treatment
9. Signed written Institutional Review Board (IRB)/Ethical Committee (EC)
approved informed consent form, prior to performing any study-related
procedures
Exclusion criteria
1. Any significant concomitant disease determined by the investigator to be
potentially aggravated by the investigational drug
2. Consumption of agents which modulate CYP3A4 or agents with potential QT
prolonging effects within 14 days prior to admission and during the study (see
concomitant medication restrictions)
3. Any clinically significant concomitant disease or condition that could
interfere with, or for which the treatment might interfere with, the conduct of
the study, or absorption of oral medications, or that would, in the opinion of
the Principal Investigator, pose an unacceptable risk to the subject in this
study.
4. Any psychological, familial, sociological or geographical condition
potentially hampering compliance with the study protocol requirements and/or
follow-up procedures; those conditions should be discussed with the patient
before trial entry.
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 |
|---|---|
| EU-CTR | CTIS2023-506886-76-00 |
| EudraCT | EUCTR2020-001737-NL |
| CCMO | NL77596.042.21 |
| Other | NL9441 |