Phase 1/2 Study of the Safety and Efficacy of Rociletinib in Combination With Trametinib in Patients With mEGFR-positive Advanced or Metastatic Non-small Cell Lung Cancer

Phase 1

Terminated

Brief Summary: The purpose of this study is to evaluate the safety and anti-tumor effect of rociletinib when administered in combination with trametinib.

Detailed Description: This is a Phase 1/2, open-label, non randomized, multicenter study evaluating the safety and efficacy of rociletinib administered in combination with trametinib.

This study will be conducted in 2 phases:

Phase 1: This will be the dose escalation phase of the study. Phase 1 will determine the MAD or MTD and RP2D of the combination of rociletinib and trametinib, and evaluate its safety and tolerability and PK profile in EGFRm NSCLC patients who have failed at least one prior EGFR TKI.

Phase 2: This will be the dose expansion phase. Phase 2 will evaluate the preliminary efficacy and pharmacodynamics of the combination of rociletinib and trametinib at the RP2D in two subsets of EGFRm NSCLC patients.

Recruitment & Eligibility

Inclusion Criteria

Written informed consent on an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved ICF before any study-specific evaluation
Histologically or cytologically confirmed metastatic or unresectable locally advanced NSCLC with EGFR activating mutation (excluding exon 20 insertion); measurable disease per RECIST 1.1
Prior treatment with an EGFR TKI; in Phase 2, prior treatment with a T790M-directed EGFR TKI for patients in Group B. Previous chemotherapy is allowed; in Phase 2, immediate prior therapy must be EGFR TKI
Patient willingness to undergo tumor biopsy at baseline and on treatment (optional for Phase 1; mandatory for Phase 2)
Eastern Cooperative Oncology Group (ECOG) performance status 0-1; life expectancy at least 3 months
Adequate hematological and biological function; LVEF ≥50%

Exclusion Criteria

Documented evidence in tumor of exon 20 insertion, small cell transformation, or MET amplification
Leptomeningeal carcinomatosis or other untreated or symptomatic CNS metastases (asymptomatic CNS metastases allowed if clinically stable without requirement for steroids within 2 weeks)
Known preexisting interstitial lung disease or pneumonitis
Concurrent use of QT-prolonging medication
Uncontrolled diabetes (HA1C > 10%) despite optional therapy
Cardiac abnormalities:
- Clinically significant abnormal 12-lead ECG, QT interval corrected using Fridericia's method (QTcF) >450 ms
- Inability to measure QT interval on ECG
- Personal or family history of long QT syndrome
- Implantable pacemaker or implantable cardioverter defibrillator
- Resting bradycardia < 55 beats/min
Inability to swallow oral study treatment or any gastrointestinal disease or condition that would preclude adequate absorption of study treatment
Presence of serious or unstable concomitant systemic disorder incompatible with the clinical study (eg, substance abuse; uncontrolled intercurrent illness including active infection; arterial thrombosis; unstable respiratory, hepatic, renal or cardiac disease; and other active malignancy)
Pregnant or breastfeeding females and male or female patients who refuse to use adequate contraception during the study and for 16 weeks after the last dose of study treatment
Any contraindication, allergy, or hypersensitivity to rociletinib, trametinib, or excipients

Arm && Interventions

Group	Intervention	Description
Rociletinib and Trametinib	Rociletinib	-
Rociletinib and Trametinib	Trametinib	-

Primary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR)	Every 6 weeks until disease progression, up to approximately 24 months	ORR according to RECIST Version 1.1 as determined by Investigator assessment
AUC of rociletinib and trametinib at steady state	Cycle 2 Day 1 to Day 2
Cmin of rociletinib and trametinib at steady state	Cycle 2 Day 1 to Day 2
t1/2 of rociletinib at steady state	Cycle 2 Day 1 to Day 2
Incidence of treatment-emergent adverse events	Continuously, up to approximately 24 months	Treatment emergent adverse events (AEs), laboratory abnormalities and ECG abnormalities in EGFR-mutant NSCLC patients given oral rociletinib in combination with oral trametinib; defining in Phase 1 the recommended combination dose for further evaluation in Phase 2
Cmax of rociletinib and trametinib at steady state	Cycle 2 Day 1 to Day 2
Tmax of rociletinib and trametinib at steady state	Cycle 2 Day 1 to Day 2

Secondary Outcome Measures

Name	Time	Method
Disease Control Rate (DCR) According to RECIST Version 1.1	Every 6 weeks until disease progression, up to approximately 24 months	DCR according to RECIST Version 1.1 as determined by Investigator assessment
Duration of Response (DR) According to RECIST Version 1.1	Every 6 weeks until disease progression, up to approximately 24 months	DR according to RECIST Version 1.1 as determined by Investigator assessment
Progression Free Survival (PFS) According to RECIST Version 1.1	Every 6 weeks until disease progression, up to approximately 24 months	PFS according to RECIST Version 1.1 as determined by Investigator assessment
Cmax of rociletinib metabolites at steady state	Cycle 2 Day 1 to Day 2
Tmax of rociletinib metabolites at steady state	Cycle 2 Day 1 to Day 2
AUC of rociletinib metabolites at steady state	Cycle 2 Day 1 to Day 2
Cmin of rociletinib metabolites at steady state	Cycle 2 Day 1 to Day 2
Overall Survival (OS)	Every 12 weeks until date of death, up to approximately 60 months
Longitudinal changes in blood based biomarkers (i.e. mutations in EGFR) in ctDNA	Biomarker samples will be collected from each subject approximately every 3 weeks, up to approximately 24 months

Locations (4): Washington University School of Medicine
🇺🇸
Saint Louis, Missouri, United States
Levine Cancer Institute
🇺🇸
Charlotte, North Carolina, United States
Tennessee Oncology, PLLC - The Sarah Cannon Research Institute
🇺🇸
Nashville, Tennessee, United States
Virginia Cancer Specialists
🇺🇸
Fairfax, Virginia, United States