Study of EGF816 in Combination With Selected Targeted Agents in EGFR-mutant NSCLC

Study Overview
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Brief Summary
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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 EGFR-mutant NSCLC.

Detailed Description
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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 will be 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 may be enrolled to the dose expansion arms of each of these combinations. Patients may also be assigned to EGF816 + INC280 or EGF816 + gefitinib in dose expansion. Efficacy assessments will be performed at baseline and every 2 cycles during treatment.

Official Title
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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

Conditions
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EGFR-mutant Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: EGF816
* Drug: trametinib
* Drug: ribociclib
* Drug: LXH254
* Drug: INC280
* Drug: gefitinib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>EGF816+ trametinib in escalation phase | Drug: EGF816<br>* Study Drug<br>Drug: trametinib<br>* Study Drug<br>|
| Experimental: Arm 2<br>EGF816 + ribociclib in escalation phase | Drug: EGF816<br>* Study Drug<br>Drug: ribociclib<br>* Study Drug<br>|
| Experimental: Arm 3<br>EGF816 + LXH254 in escalation phase | Drug: EGF816<br>* Study Drug<br>Drug: LXH254<br>* Study Drug<br>|
| Experimental: Arm A<br>EGF816 + INC280 in expansion phase (patients with no known resistance mechanism) | Drug: EGF816<br>* Study Drug<br>Drug: INC280<br>* Study Drug<br>|
| Experimental: Arm B<br>EGF816 + trametinib in expansion phase | Drug: EGF816<br>* Study Drug<br>Drug: trametinib<br>* Study Drug<br>|
| Experimental: Arm C<br>EGF816 + ribociclib in expansion phase | Drug: EGF816<br>* Study Drug<br>Drug: ribociclib<br>* Study Drug<br>|
| Experimental: Arm D<br>EGF816 + LXH254 in expansion phase (patients with no known resistance mechanism) | Drug: EGF816<br>* Study Drug<br>Drug: LXH254<br>* Study Drug<br>|
| Experimental: Arm E<br>EGF816 + LXH254 in expansion phase (patients with known resistance mechanism) | Drug: EGF816<br>* Study Drug<br>Drug: LXH254<br>* Study Drug<br>|
| Experimental: Arm F<br>EGF816 + gefitinib in expansion phase | Drug: EGF816<br>* Study Drug<br>Drug: gefitinib<br>* Study Drug<br>|
| Experimental: Arm G<br>EGF816 + INC280 in expansion phase (patients with known resistance mechanism) | Drug: EGF816<br>* Study Drug<br>Drug: INC280<br>* Study Drug<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with adverse events and serious adverse events | Assess safety and tolerability including incidence of dose limiting toxicities, adverse events, and serious adverse events. | Every day until study end, approximately 4 years | 
| ORR2 | Modified objective response rate (ORR2) per RECIST v1.1 (taking as baseline the most recent assessment prior to initiating combination) | Every 8-12 weeks until study ends, approximately 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR | Overall response rate (ORR) per RECIST v1.1 | Every 8-12 weeks until study ends, approximately 4 years | 
| PFS | Time from the date of first dose of study treatment to the date of first documented disease progression (per RECIST v1.1) or death due to any cause | Every 8-12 weeks until study ends, approximately 4 years | 
| DCR | Proportion of patients with best overall response of CR, PR, or SD | Every 8-12 weeks until study ends, approximately 4 years | 
| DOR | Time from first documented response (PR or CR) to the date of first documented disease progression or death due to any cause | Every 8-12 weeks until study ends, approximately 4 years | 
| Time to response |  | Every 8-12 weeks until study ends, approximately 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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EGFR-mutant NSCLC, EGF816, LXH254, INC280, ribociclib, trametinib, gefitinib, EGFR T790M, BRAF mutation, BRAF fusion, BRAF rearrangement, MET amplification