A phase Ib/II, open-label, multicenter trial with oral cMET inhibitor INC280 alone and in combination with erlotinib versus platinum/pemetrexed in adult patients with EGFR mutated, cMET-amplified, locally advanced/metastatic non-small cell lung cancer (NSCLC) with acquired resistance to prior EGFR tyrosine kinase inhibitor (EGFR TKI)

INC280 is a highly potent and selective cMET inhibitor in biochemical and
cellular assays and capable of blocking cMET activation.
Erlotinib is an approved EGFR tyrosine kinase inhibitor (TKI).
Currently approved EGFR TKIs are effective in activated EGFR mutant non-small
cell lung cancer (NSCLC), however nearly all patients develop resistance, and
platinum-based chemotherapy is considered standard of care after failure of
first line EGFR TKI.
An important mechanism of acquired resistance to EGFR TKIs in NSCLC is cMET
amplification that accounts for approximately 15-20% of cases and is mutually
exclusive with the EGFRT790M mutation.
Overall, preclinical and clinical data suggests that INC280 in combination with
an EGFR TKI may have a favorable benefit-risk ratio for the treatment of
cMET-amplified, EGFR mutated and known to be associated with EGFR TKI drug
sensitivity (L858R and/or ex19del), EGFRT790M negative, locally advanced or
metastatic NSCLC with acquired resistance to prior EGFR TKI. This study aims to
further explore the benefit-risk ratio of the combination of INC280 tablet
formulation with erlotinib in this patient population.
This study has two parts:
* a dose escalation part (part 1, phase Ib) in order to determine the maximum
tolerated dose (MTD) or recommended phase II dose (RP2D) of the combination of
INC280 and (fixed-dose) erlotinib.
* A dose expansion part (part 2, phase 2) in order to assess safety and
efficacy of this part 1 dose in comparison with INC280 alone and standard
chemotherapy of platinum plus pemetrexed.
The Netherlands will only participate in part 2. This ABR-form will therefore
only address part 2.

Primary phase 1: To determine MTD and/or RP2D of INC280 in
combination with erlotinib

Primary phase 2:
To compare the antitumor activity of INC280 alone, and INC280 in combination
with erlotinib, vs platinum with pemetrexed, as measured by Progression Free
Survival (PFS) per investigator*s assessment
Secondary:
Duration of response (DOR), overall response rate (ORR), disease control rate
(DCR), overall survival (OS), safety and tolerability, PK profiles.

Multicenter phase I/II open-label study. Prescreening for CMET amplification
and EGFRT790M mutation.

Phase I: INC280 tablets until MTD or RP2D BID plus erlotinib 150 mg QD.
Continuous dosing.
Treatment period until disease progression or unacceptable side effects.
Follow-up for survival (and if relevant for disease progression).
Approx. 15 patients.

Phase II: Randomization (1:1:1) to treatment with
* INC280 tablets 400 mg BID. Continuous dosing.
* INC280 tablets MTD or RP2D BID plus erlotinib 150 mg QD. Continuous dosing.
* Pemetrexed 500 mg/m2 plus (investigator*s choice) cisplatin 75 mg/m2 or
carboplatin AUC 5 or 6. On day 1 of up to 6 cycles.
Cycles of 3 weeks.
Treatment period until disease progression or unacceptable side effects.
Follow-up for survival (and if relevant for disease progression).
Approx. 120 patients.

Phase I: INC280 plus erlotinib or chemotherapy

Phase II: Treatment with INC280 alone, INC280 plus erlotinib or chemotherapy
with platinum and pemetrexed.

Risk: Adverse effects of INC280, INC280 plus erlotinib or standard chemotherapy.
Burden: Cycles of 3 weeks. Cycle 1-2: 3 visits, cycle 3 onwards 1 visit.
Duration mostly 1-4 hours. Day 1 and 15 of cycle 1 take 8 hour with an
additional visit 24 hour later (only phase 1)
Up to 6 cycles with i.v. chemotherapy in one of the arms. However chemotherapy
is currently the standard treatment (only in phase 2)
Physical examination: Once per cycle.
Blood tests (5-25 ml/occasion): Once per cycle (cycle 1 twice). PK on 3
occasions (2 samples in 2 h twice, one sample once). Day 1 and 15 of cycle 1
have 7 samples with an additional sample 24 hour later (only phase 1)

Pregnancy test (if relevant): at screening and end of treatment (blood
mandatory) plus once per cycle (urine or blood).
Urine test once.
ECG: 5 visits in total.
CT-/MRI-scan: every 6 weeks.
Optional tumor biopsies: 2.
Optional storage and use of the remaining blood and tissue for future research.