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

A Phase 1/2 Study of the Safety and Efficacy of Rociletinib When Administered in Combination With Trametinib in Patients With Activating EGFR Mutation-positive Advanced or Metastatic Non-small Lung Cancer (NSCLC)

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

Study Overview

• Status: Terminated
• Conditions: Non-small Cell Lung Cancer
• Intervention / Treatment: Drug: Rociletinib; Drug: 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.

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Levine Cancer Institute
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology, PLLC - The Sarah Cannon Research Institute
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Virginia Cancer Specialists

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rociletinib and Trametinib	Drug: Rociletinib; Other Names: CO-1686; Drug: Trametinib; Other Names: Mekinist

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of treatment-emergent adverse events	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	Continuously, up to approximately 24 months
Objective Response Rate (ORR)	ORR according to RECIST Version 1.1 as determined by Investigator assessment	Every 6 weeks until disease progression, up to approximately 24 months
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
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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Response (DR) According to RECIST Version 1.1	DR according to RECIST Version 1.1 as determined by Investigator assessment	Every 6 weeks until disease progression, up to approximately 24 months
Disease Control Rate (DCR) According to RECIST Version 1.1	DCR according to RECIST Version 1.1 as determined by Investigator assessment	Every 6 weeks until disease progression, up to approximately 24 months
Progression Free Survival (PFS) According to RECIST Version 1.1	PFS according to RECIST Version 1.1 as determined by Investigator assessment	Every 6 weeks until disease progression, up to approximately 24 months
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
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

Collaborators and Investigators

• Sponsor: Clovis Oncology, Inc.
• Collaborators: Novartis Pharmaceuticals
• Investigators: Study Director: Paula O'Connor, MD, Clovis Oncology, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): September 30, 2015
• Primary Completion (Actual): May 5, 2016
• Study Completion (Actual): June 27, 2016

Study Registration Dates

• First Submitted: October 12, 2015
• First Submitted That Met QC Criteria: October 18, 2015
• First Posted (Estimate): October 20, 2015

Study Record Updates

• Last Update Posted (Actual): October 2, 2018
• Last Update Submitted That Met QC Criteria: September 28, 2018
• Last Verified: September 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Trametinib
• Other Study ID Numbers: CO-1686-033