Primary objectives: 1) Phase Ib: To estimate the MTD or RP2D of INC280 in combination with gefitinib in NSCLC patients who have c-MET dysregulation. 2) Phase II: To estimate overall clinical activity of INC280 in combination with gefitinib in NSCLC…
ID
Source
Brief title
Condition
- Respiratory and mediastinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Dose-escalation: DLTs in 1st cycle.
Expansion: AEs.
Secondary outcome
Tumor response assessment as per RECIST v1.1. PK. Biomarkers in tumor tissue.
Background summary
c-MET amplification is a frequent molecular event that had been identified as a
cause for acquired resistance to gefitinib and other epidermal growth factor
receptor inhibitors (EGFRi) in EGFR mutated non small cell lung cancer (NSCLC).
Nevertheless, patients may continue to derive benefit from EGFRi after disease
progression through continuing inhibition of the EGFR pathway as reflected in
the National Comprehensive Cancer Network (NCCN) Guidelines. In order to
inhibit both aberrant pathways that drive EGFRi-resistant EGFR mutated NSCLC in
the subset of cases with c-MET dysregulation, INC280 requires combination with
the continued EGFRi treatment.
INC280 in a new anti-cancer drug in development and possesses potent inhibitory
activity against the c-MET kinase.
Gefitinib (Iressa) is a potent and selective inhibitor of the EGFR tyrosine
kinase, registered for the treatment of metastatic NSCLC..
Consequently, the purpose of this study will be to first investigate the safety
and tolerability of INC280 in combination with gefitinib in a phase IB dose
escalation part of the study at a constant dose of gefitinib as per its
prescribing information with increasing dose levels of INC280. Once the
MTD/RP2D (recommended phase II dose) for the combination is established, this
study will move on to a phase II part in order to investigate the clinical
activity of the INC280/gefitinib combination in patients who progressed on
gefitinib or erlotinib treatment. The phase II study is designed to be
hypothesis generating for the design of a potential pivotal trial in this
patient population.
Study objective
Primary objectives: 1) Phase Ib: To estimate the MTD or RP2D of INC280 in
combination with gefitinib in NSCLC patients who have c-MET dysregulation. 2)
Phase II: To estimate overall clinical activity of INC280 in combination with
gefitinib in NSCLC patients with c-MET dysregulation.
Secondary objectives: 1) To determine safety and tolerability of INC280 in
combination with gefitinib. 2) To estimate time dependent clinical activity of
INC280 in combination with gefitinib. 3) To assess the pharmacodynamic effect
of INC280 in combination with gefitinib. 4) To characterize the PK profile of
INC280 and gefitinib in NSCLC patient population and to assess potential drug
interaction between INC280 and gefitinib.
Study design
Open-label phase IB /II dose escalation and dose expansion study. Approximately
258 patients. Minimal 18 patients in the escaltion. 40 patients in the capsule
cohort and 200 patients in the tablet cohort.
Screening for EGFR mutation and c-MET pathway dysregulation.
Determination of the MTD/RP2D of INC280 in combination with gefitinib 250 mg
QD. At least 18 patients. Cycles of 4 weeks. Dose-escalation decision after 1
cycle.
After the MTD/RP2D been determined, patients will be enrolled to be treated
with this dose.
Treatment until progression or unacceptable toxicity.
Intervention
Treatment with INC280 and gefltinib.
Study burden and risks
Risk: Adverse events of study medication.
Burden:
Cycles of 4 weeks.
Prescreening: tumor sample (either archival or fresh) for C-MET and EGFR status.
Screening visit, 4 visits during cycle 1 and 2. Thereafter 1 visit per cycle.
Duration 1,5-2 h. 1 visit with duration of 6-8 h (PK samples). 2 end of
treatment/study visits. Follow-up for survival (every 3 months).
Blood tests 10-20 ml/occasion.
Screening: Physical examination, blood tests, pregnancy test, ECG, tumor
measurements, tumor biopsy.
Cycle 1: 4 times physical examination, 4 times blood tests, 3 times ECG, 1
tumor biopsy.
Cycle 2: 4 times physical examination, 4 times blood tests
Following courses: 1 physical examination, 1 blood draw, tumor measurements
every 8 weeks.
End of treatment visit: Physical examination, blood tests, pregnancy test, ECG,
tumor measurements (unless performed <30 days).
Pregnancy test every cycle.
Raapopseweg 1
Arnhem 6824 DP
NL
Raapopseweg 1
Arnhem 6824 DP
NL
Listed location countries
Age
Inclusion criteria
* * 18 years of age.
* Confirmed c-MET pathway dysregulation (see protocol page 35-36 for details).
* EGFR mutated NSCLC patient who have developed acquired resistance to EGFR inhibitor treatment (see protocol page 35 for details).
* Must have discontinued any previous anti-cancer and investigational therapy (excluding gefitinib or erlotinib) for at least 28 days before study treatment administration.
* No more than 2 lines of chemotherapy and one line of gefitinib or erlotinib treatment.
* Must have discontinued any previous anti-cancer antibody treatment for at least 4 weeks before study treatment administration.
* Measurable disease as determined by RECIST version 1.1.
* ECOG performance status *2.
Exclusion criteria
* Previous treatment with a c-MET inhibitor or HGF-targeting therapy.
* Previous radiation therapy completed less than 4 weeks prior to dosing.
* History of cystic fibrosis.
* History of acute or chronic pancreatitis, surgery of pancreas or any risk factors that may increase the risk of pancreatitis.
* Pregnancy, breast feeding.
* Women of child-bearing potential not willing to use highly effective contraception.
* Sexually active males must use a condom during intercourse and should not father a child in the study period.
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 |
|---|---|
| Other | Clinicaltrials.gov; NCT01610336 |
| EudraCT | EUCTR2011-002569-39-NL |
| CCMO | NL50563.042.14 |