A Study of ASP2215 in Combination With Erlotinib in Subjects With Epidermal Growth Factor Receptor (EGFR) Activating Mutation-Positive (EGFRm+) Advanced Non-Small-Cell Lung Cancer (NSCLC) Who Have Acquired Resistance to an EGFR Tyrosine Kinase Inhibitor (TKI)

Study Overview
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Brief Summary
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The purpose of the Phase 1b part of the study was to evaluate the safety and tolerability of ASP2215 in combination with erlotinib and determine the recommended phase 2 dose (RP2D) of ASP2215. The purpose of the Phase 2 part of the study was to evaluate the objective response rate (ORR) of the RP2D of ASP2215 in combination with erlotinib.

Detailed Description
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No patients were enrolled in the Phase 2 part of the study. Phase 2 endpoints were not analyzed.

Official Title
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A Phase 1b/2 Study of ASP2215 in Combination With Erlotinib in Subjects With EGFR Activating Mutation-Positive (EGFRm+) Advanced NSCLC Who Have Acquired Resistance to an EGFR Tyrosine Kinase Inhibitor (TKI)

Conditions
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Non-Small-Cell Lung Cancer

Intervention / Treatment
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* Drug: Gilteritinib
* Drug: Erlotinib


Participation Criteria
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Eligibility Criteria
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IInclusion Criteria: Participant had histologically or cytologically confirmed metastatic or locally advanced, unresectable non-small-cell lung cancer (NSCLC). Participant had a documented exon 19 deletion or exon 21 L858R EGFR activating mutation. Participant had received prior treatment with any EGFR tyrosine kinase inhibitor Participant had Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to 2 at screening. Participant had adequate organ function. Female participant must either: Be of nonchildbearing potential: Or, if of childbearing potential, Agree not to try to become pregnant during the study and for 45 days after the final study drug administration And had a negative serum pregnancy test at screening And, if heterosexually active, agreed to consistently use 2 forms of highly effective birth control Male participant and their female spouse/partners who were of childbearing potential must be using highly effective contraception consisting of 2 forms of birth control Phase 1b Participants only: Participant was not expected to show a therapeutic response to existing available treatment. Intervening anticancer treatment subsequent to the EGFR TKI was allowed (but not required). Additional inclusion criteria for phase 2 Participants only: Participant had a NSCLC tissue sample obtained after participant developed resistance to EGFR TKI therapy that was available for central testing. Participant's baseline tumor specimen (obtained after participant developed resistance to EGFR TKI therapy) is T790M negative. Participant received an EGFR TKI for at least 6 months and progressed on this therapy within the past 28 days. Participant had not had any intervening anticancer treatment subsequent to the EGFR TKI with the exception of radiotherapy which was allowed if it occurred at least 14 days prior to the first dose of study drug. Participant had at least 1 measureable lesion (not including any lesion that was irradiated) based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Exclusion Criteria: Participant had an ongoing toxicity greater than or equal to grade 3 (NCI CTCAE version 4.03) attributable to prior NSCLC treatment at the time of screening. Participant received any agent with antitumor activity (other than an EGFR inhibitor, including a T790M inhibitor) including chemotherapy, radiotherapy, immunotherapy, within 14 days prior to the first dose of study drug (palliative radiotherapy is allowed). Participant received ASP2215 previously. Participant received blood transfusions or hematopoietic growth factor therapy within 14 days prior to the first dose of study drug. Participant had a major surgical procedure (other than study-related biopsy) within 14 days prior to the first dose of study drug, or a major surgical procedure was planned to occur during the study. Participant had active hepatitis B or C or other active hepatic disorder. Participant t was known to have human immunodeficiency virus (HIV) infection. Participant had symptomatic central nervous system (CNS) metastasis. Participants with asymptomatic, untreated CNS metastases were allowed. Participants with previously treated and currently asymptomatic CNS metastases were eligible provided they met the following: Any whole brain radiotherapy (WBRT) was completed at least 2 weeks prior to the first dose of study drug. Any stereotactic radiosurgery (SRS) was completed at least 1 week prior to the first dose of study drug. Participant did not require steroids or did not require escalating doses of steroids for at least 2 weeks prior to the first dose of study drug. Participant had evidence of active infection requiring systemic therapy within 14 days prior to the first dose of study drug. Participant had uncontrolled hypertension. Participant had severe or uncontrolled systemic diseases or active bleeding diatheses. Participant had history of drug-induced interstitial lung disease or any evidence of active interstitial lung disease. Participant had ongoing cardiac arrhythmia (including atrial fibrillation) that was grade ≥ 2. Participant currently had Class 3 or 4 New York Heart Association congestive heart failure. Participant had history of severe/unstable angina, myocardial infarction or cerebrovascular accident within 6 months prior to the first dose of study drug. Participant had history of gastrointestinal ulcer within 28 days prior to the first dose of study drug. Participant had a history of gastrointestinal bleeding within 90 days prior to the first dose of study drug. Participant had concurrent corneal disorder or any ophthalmologic condition which makes the participant unsuitable for study participation . Participant had any condition which made the participant unsuitable for study participation. Participant had hypokalemia or hypomagnesemia at screening. Participant had QTcF interval > 450 ms on 12-lead ECG at screening. Participant was known to have long QT syndrome. Participant was taking medication known to prolong the QT interval.

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: Gilteritinib 120mg + Erlotinib 150mg<br>Gilteritinib was administered in combination with erlotinib orally once daily. | Drug: Gilteritinib<br>* oral<br>Drug: Erlotinib<br>* oral<br>* Other names: Tarceva;|
| Experimental: Gilteritinib 80mg+ Erlotinib 150mg<br>Gilteritinib was administered in combination with erlotinib orally once daily. | Drug: Gilteritinib<br>* oral<br>Drug: Erlotinib<br>* oral<br>* Other names: Tarceva;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose Limiting Toxicities (DLTs) |  | Cycle 1 and Cycle ≥2 (up to 141 days) | 
| Number of Participants With Adverse Events | Treatment-emergent adverse events (TEAE) was defined as an adverse event (AE) that started after administration of the study drugs and occurred within 30 days of the last dose of the study drugs. If a participant experienced an event both during the preinvestigational period and during the investigational period, the event was considered a TEAE only if it worsened in severity. | From first dose of study drug up to 30 days after the last dose of study (maximum study drug exposure 114 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Concentration-time Curve at 24 Hours (AUC24) for Gilteritinib |  | 0, 0.5, 1, 2, 4, 6, 24 hours post-dose on Days 1 and 28 of cycle 1 | 
| Maximum Concentration (Cmax) for Gilteritinib |  | 0, 0.5, 1, 2, 4, 6, 24 hours post-dose on Days 1 and 28 of cycle 1 | 
| Time After Dosing When Cmax Occurs (Tmax) for Gilteritinib |  | 0, 0.5, 1, 2, 4, 6, 24 hours post-dose on Days 1 and 28 of cycle 1 | 
| Concentration Immediately Prior to Dosing at Multiple Dosing (Ctrough) of Gilteritinib | All participants in Gilteritinib 120 mg + Erlotinib 150 mg group discontinued before cycle 3. | Predose on Day 1, 3, 8, 15, 22, 28 of cycle 1, Day 1 of cycle 3 and Day 1 of cycle 4 | 
| AUC24 of Erlotinib |  | 0, 0.5, 1, 2, 4, 6, 24 hours post-dose on Day 28 of cycle 1 | 
| Cmax of Erlotinib |  | 0, 0.5, 1, 2, 4, 6, 24 hours post-dose on Day 28 of cycle 1 | 
| Tmax of Erlotinib |  | 0, 0.5, 1, 2, 4, 6, 24 hours post-dose on Day 28 of cycle 1 | 
| Ctrough of Erlotinib |  | Day 8, 15, 22, 28 of cycle 1 | 
| Objective Response Rate (ORR) in Phase 1b | ORR was defined as Objective Response Rate (ORR) was the proportion of patients whose best overall response was complete response (CR) or partial response (PR) per RECIST version 1.1. Only patients with measurable disease at baseline were to be included in the analysis of ORR. | End of treatment (approximately 4 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Erlotinib, ASP2215, NSCLC, Gilteritinib, Non-Small-Cell Lung Cancer