Clinical trial NCT03333343: Study of EGF816 in Combination With Selected Targeted Agents in EGFR-mutant NSCLC
Official title: A Phase Ib, Open Label, Multi-center Study to Characterize the Safety, Tolerability and Preliminary Efficacy of EGF816 in Combination With Selected Targeted Agents in EGFR Mutant NSCLC
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: EGFR-mutant Non-small Cell Lung Cancer
Keywords: EGFR-mutant NSCLC
EGF816
LXH254
INC280
ribociclib
trametinib
gefitinib
EGFR T790M
BRAF mutation
BRAF fusion
BRAF rearrangement
MET amplification
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2017-11-06
Enrollment: 105
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The study purpose is to evaluate the safety, tolerability, and preliminary efficacy of the addition of INC280, trametinib, ribociclib, gefitinib, or LXH254 to EGF816 in adult patients with advanced Epidermal growth factor receptor- mutant (EGFR-mutant) non-small cell lung cancer (NSCLC).

Detailed description: This is a Phase Ib, open label, non-randomized dose escalation study of EGF816 in combination with ribociclib, trametinib, or LXH254, followed by dose expansion of EGF816 in combination with ribociclib, trametinib, LXH254, INC280, or gefitinib in adult patients with advanced EGFR-mutant NSCLC.

During the dose escalation part, patients were assigned to the addition of trametinib, ribociclib, or LXH254 to EGF816.

Following determination of the recommended dose for the combination of EGF816 + trametinib, EGF816 + ribociclib, and EGF816 + LXH254, patients could be enrolled to the dose expansion arms of each of these combinations. Patients could also be assigned to EGF816 + INC280. The planned arm EGF816 + gefitinib in dose expansion was not opened for enrollment.

Eligibility criteria: Inclusion Criteria:

* Patients must have histologically or cytologically confirmed locally advanced (stage IIIB) or metastatic (stage IV) EGFR mutant (ex19del, L858R) NSCLC.
* Requirements of EGFR mutation status and prior lines of treatment:
* Treatment naive patients, who have locally advanced or metastatic NSCLC with EGFR sensitizing mutation (e.g., L858R and/or ex19del), have not received any systemic antineoplastic therapy for advanced NSCLC and are eligible to receive EGFR TKI treatment. Patients with EGFR exon 20 insertion/duplication are not eligible. Note: patients who have received only one cycle of chemotherapy in the advanced setting are allowed.
* Patients who have locally advanced or metastatic NSCLC with EGFR sensitizing mutation AND an acquired T790M mutation (e.g., L858R and/or ex19del, T790M+) following progression on prior treatment with a 1st-generation EGFR TKI or 2nd-generation EGFR TKI. These patients may not have received more than 4 prior lines of antineoplastic therapy in the advanced setting, including EGFR TKI, and may not have received any agent targeting EGFR T790M mutation (i.e., 3rd-generation EGFR TKI).
* Patients who have locally advanced or metastatic NSCLC with EGFR sensitizing mutation and a "de novo" T790M mutation (i.e., no prior treatment with any agent known to inhibit EGFR including EGFR TKI). These patients may not have received more than 3 prior lines of antineoplastic therapy in the advanced setting, and may not have received any prior 3rd generation EGFR TKI.
* Patients must have a site of disease amenable to biopsy, and be a candidate for tumor biopsy according to the treating institution's guidelines. Patients must be willing to undergo a new tumor biopsy during therapy on this study, and at screening if an archival tumor sample obtained since the diagnosis of advanced disease (1L patients) or since last treatment failure (2L+ patients) is not available.

Exclusion Criteria:

* Patients with a history or presence of interstitial lung disease or interstitial pneumonitis, including clinically significant radiation pneumonitis.
* Patients with unstable brain metastases.
* Patients with a history of another malignancy.
* Patients with a known history of human immunodeficiency virus (HIV) seropositivity.
* Patients with clinically significant, uncontrolled heart disease.
* Patients participating in additional parallel investigational drug or medical device studies.
* Prior therapies:
* Patients who have been treated with EGFR TKI in the adjuvant setting within 6 months, unless acquired EGFR T790M is present in a tumor or blood sample obtained since the discontinuation of the EGFR TKI.
* Patients who have been treated with prior EGFR TKI targeting T790M (3rd generation).
* Patients who have been treated with systemic anti-neoplastic therapy within:

  * 2 weeks for fluoropyrimidine monotherapy
  * 6 weeks for nitrosoureas and mitomycin
  * 4 weeks or ≤ 5 half-lives (whichever is shorter) for biological therapy (including monoclonal antibodies) and continuous or intermittent small molecule therapeutics or any other investigational agent

Primary outcomes:
measure: Number of patients with adverse events and serious adverse events
timeFrame: Every day until study end, approximately 4 years
measure: Number of participants with DLTs in the first cycle of combination (Dose escalation only)
timeFrame: 28 days
measure: Number of participants with dose interruptions and reductions
timeFrame: From first dose until study ends, approximately 4 years
measure: Dose intensity of study drugs
timeFrame: From first dose until study ends, approximately 4 years
measure: ORR2
timeFrame: Every 8-12 weeks until study ends, approximately 4 years
Secondary outcomes:
measure: ORR
timeFrame: Every 8-12 weeks until study ends, approximately 4 years
measure: PFS
timeFrame: Every 8-12 weeks until study ends, approximately 4 years
measure: DCR
timeFrame: Every 8-12 weeks until study ends, approximately 4 years
measure: DOR
timeFrame: Every 8-12 weeks until study ends, approximately 4 years
measure: Time to response
timeFrame: Every 8-12 weeks until study ends, approximately 4 years
measure: Area under the plasma concentration-time curve (AUC) of study drugs
timeFrame: From pre-dose up to 8 hours post-dose on Day 15 of Cycle 1. One cycle=28 days.
measure: Maximum observed plasma concentration (Cmax) of study drugs
timeFrame: From pre-dose up to 8 hours post-dose on Day 15 of Cycle 1. One cycle=28 days.
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Koeln
country: Germany
facility: Novartis Investigative Site
city: Hong Kong
country: Hong Kong
facility: Novartis Investigative Site
city: Ancona
country: Italy
facility: Novartis Investigative Site
state: AN
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Rozzano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Tainan
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis
name: Novartis Pharmaceuticals
role: STUDY_CHAIR
References: