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

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT03333343

Collaborator

(none)

105

Enrollment

Locations

Arms

67.4

Anticipated Duration (Months)

9.5

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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 EGFR-mutant NSCLC.

Condition or Disease	Intervention/Treatment	Phase
EGFR-mutant Non-small Cell Lung Cancer	Drug: EGF816 Drug: trametinib Drug: ribociclib Drug: LXH254 Drug: INC280 Drug: gefitinib	Phase 1

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 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.

Study Design

Study Type:

Interventional

Actual Enrollment :

105 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Jan 29, 2018

Anticipated Primary Completion Date :

Sep 8, 2023

Anticipated Study Completion Date :

Sep 10, 2023

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Toronto	Ontario	Canada	M5G 2M9
2	Novartis Investigative Site	Essen		Germany	45147
3	Novartis Investigative Site	Koeln		Germany	50937
4	Novartis Investigative Site	Shatin, New Territories		Hong Kong
5	Novartis Investigative Site	Ancona	AN	Italy	60126
6	Novartis Investigative Site	Milano	MI	Italy	20162
7	Novartis Investigative Site	Rozzano	MI	Italy	20089
8	Novartis Investigative Site	Singapore		Singapore	119228
9	Novartis Investigative Site	Singapore		Singapore	169610
10	Novartis Investigative Site	Tainan		Taiwan	70403
11	Novartis Investigative Site	Taipei		Taiwan	10002