Primary objectives• To identify the percentage of patients in which a drug resistant clone can be detected with ctDNA before the emergence of radiological progression.• To determine the success rate of crizotinib and osimertinib combination…
ID
Source
Brief title
Condition
- Respiratory and mediastinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The number of patients with a resistant clone detected before radiological
progression will be calculated as a percentage of total number of patients.
The success rate of crizotinib treatment to eliminate resistance due to MET
amplification will be calculated as the percentage of patients with
disappearance of MET amplification in a subsequent ctDNA sample (not
necessarily the first ctDNA following MET directed treatment) of the total
number of patients with MET amplification detected in the ctDNA.
Secondary outcome
The Lag time between ctDNA based detection of a resistant clone and
radiological progression will be calculated as a median with 95% confidence
interval. This parameter will be calculated for all resistance mechanisms
combined, as well as for the individual resistance mechanisms.
The time to re-appearance of the MET amplification clone after successful
elimination after crizotinib treatment will be calculated as a median with 95%
confidence interval.
Background summary
The current strategy is to test for treatment resistance at the time of
radiological progression and design subsequent treatment based on the mechanism
of resistance. However, upon disease progression patients tend to deteriorate
quickly and 30% - 40% of patients will not be in the clinical condition to
receive next line treatment. Therefore, there is a potential for early
resistance identification and directing treatment against it in order to
improve patient outcome.
Next Generation Sequence (NGS) technology rapidly evolves and it is now
feasible to use circulating tumor DNA (ctDNA) as a BioSource for comprehensive
analysis of the molecular make up of tumors. ctDNA based techniques are able to
detect the emergence of drug resistance mechanisms with high sensitivity and
prior to radiological progression.
Study objective
Primary objectives
• To identify the percentage of patients in which a drug resistant clone can be
detected with ctDNA before the emergence of radiological progression.
• To determine the success rate of crizotinib and osimertinib combination
treatment to eliminate MET amplification, defined by disappearance of the MET
amplification clone in a subsequent ctDNA sample.
Secondary objectives
• Lag time between ctDNA based detection of a resistant clone and radiological
progression.
• Correlation of ctDNA results with that of the tumor biopsy upon radiological
progression.
• The time to disappearance of the MET amplification clone after crizotinib
initiation as detected by ctDNA.
• The time to re-appearance of MET amplification as detected by ctDNA or tumor
biopsy in case of radiological progression after successful elimination with
crizotinib treatment.
Study design
Patients with EGFR mutation positive NSCLC who are eligible for osimertinib
treatment will be treated with osimertinib. At baseline and every eight weeks
during treatment blood will be drawn to analyse ctDNA with Avenio ctDNA
(Expanded panel) to detect all known EGFR TKI resistance mechanisms. Patients
will also be monitored with CT every eight weeks.
With the exception of MET amplification, detection of resistant clones by ctDNA
will be followed over time until radiological progression. Upon radiological
progression, a tumor biopsy will be performed according to routine clinical
care for EGFR mutation positive patients, and a comparable Avenio FFPE panel
will be analysed on the tissue sample for comparison. Tissue and ctDNA based
resistance profiling will be compared.
When MET amplification is detected by ctDNA at any time, the patient will be
treated with crizotinib 250 mg bi-daily in combination with osimertinib 80 mg
once daily for as long as MET amplification can be detected with (8-weekly
assessment of) ctDNA. Crizotinib treatment will be discontinued when MET
amplification becomes undetectable with the Avenio ctDNA panel, while
continuing osimertinib treatment.
Intervention
All subjects will receive continuous daily treatment with osimertinib 80mg
once daily.
Study burden and risks
The disadvantage of participating in this study is that more blood will be
taken than normal.
Plesmanlaan 121
Amsterdam 1066CX
NL
Plesmanlaan 121
Amsterdam 1066CX
NL
Listed location countries
Age
Inclusion criteria
1. Histologically confirmed metastatic NSCLC, characterized by a sensitizing
exon 19 deletion or exon 21 L858R EGFR mutation., 2. WHO performance status
0-2., 3. Eligible for osimertinib treatment according to the label and
according to the treating physician., 4. Patients must be >=18 years of age.
Exclusion criteria
1. Patients with symptomatic central nervous system metastases who are
neurologically unstable. Unstable brain metastases except for those who have
completed definitive therapy and have had a stable neurological status for 2
weeks after completion of definitive therapy. Patients may be on
corticosteroids to control brain metastases if they have been on a stable dose
for 2 weeks prior to the start of study treatment and are clinically
asymptomatic.
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 | EUCTR2018-004798-29-NL |
| CCMO | NL67847.031.18 |