Efficacy and Safety of Momelotinib Combined With Trametinib in Adults With Metastatic KRAS-mutated Non-Small Cell Lung Cancer (NSCLC) Who Have Failed Platinum-Based Chemotherapy Preceded by a Dose-finding Lead-in Phase

A Phase 1b With Expansion Study Evaluating the Efficacy and Safety of Momelotinib Combined With Trametinib in Subjects With Metastatic KRAS-mutated Non-Small Cell Lung Cancer (NSCLC) Who Have Failed Platinum-Based Chemotherapy Preceded by a Dose-finding Lead-in Phase

This study is conducted in two phases. The Dose-finding Lead-in Phase, Part A, will evaluate the safety and determine the maximum tolerated dose (MTD) of momelotinib (MMB) when combined with trametinib. Once the MTD of momelotinib (MMB) is determined, the study will proceed to the Dose-finding Lead-in Phase, Part B, to determine the MTD of trametinib. After the MTD is established, the study may proceed to an expansion phase to determine the efficacy, safety, and tolerability of MMB combined with trametinib at the MTD in participants with kirsten rat sarcoma viral oncogene homolog (KRAS) mutated metastatic non-small cell lung cancer (NSCLC). Each treatment cycle will consist of 28 days and treatment will continue in the absence of disease progression, unacceptable toxicity, consent withdrawal, or participant's refusal of treatment.

Study Overview

• Status: Terminated
• Conditions: Relapsed Metastatic KRAS-Mutated Non-Small Cell Lung Cancer
• Intervention / Treatment: Drug: Momelotinib (MMB); Drug: Trametinib

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States
    • Sacramento, California, United States
  • Massachusetts
    • Boston, Massachusetts, United States
  • Virginia
    • Fairfax, Virginia, United States
  • Washington
    • Spokane, Washington, United States

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

Key Inclusion Criteria:

• Individuals with KRAS-mutated metastatic or recurrent non-small cell lung cancer
• Radiologic documentation of disease progression
• Measurable disease per RECIST v1.1

• Adequate organ function defined as follows:

  • Hepatic: Total conjugated bilirubin ≤ 1.25 x upper limit of normal (ULN); aspartate transaminase (AST) and alanine transaminase (ALT) < 3 x upper limit of normal (ULN) or < 5 x ULN in the setting of liver metastases

• Hematological: Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L, platelet ≥ 100 x 10^9/L, hemoglobin ≥ 9 g/dL

  • Renal: Serum creatinine < 1.5 x ULN OR calculated creatinine clearance (CLcr) ≥ 60 ml/min
• Adequate left ventricular ejection fraction (LVEF) ≥ 50%
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
• Negative serum pregnancy test for females

Key Exclusion Criteria:

• Less than or equal to 3 weeks since receiving treatment with biologic, small molecule, chemotherapy or other agent for non-small cell lung cancer and 28 days since any prior immunotherapy (such as nivolumab)
• History of a concurrent or second malignancy, except for specified exceptions in the protocol or any other cancer that has been in complete remission for ≥ 5 years
• Known positive status for human immunodeficiency virus (HIV)
• Chronic active or acute viral hepatitis A, B, or C infection or hepatitis B or C carrier
• Presence of ≥ Grade 2 peripheral neuropathy
• Brain metastases, or spinal cord compression. Individuals with brain metastases are allowed if they have been treated with irradiation or surgery, are clinically stable without steroid treatment. Individuals with documented leptomeningeal disease are not eligible
• A history of uveitis and/or scleritis
• Retinal pathology beyond normal age-related processes
• Evidence of a retinal vein occlusion on ophthalmological exam or a history of retinal vein occlusion
• History of newly diagnosed or uncontrolled glaucoma/intraocular pressure > 21 mm Hg as measured by tonography
• Use of daily and/or chronic oral or ocular steroids. Individuals must be off daily steroids for at least 3 weeks prior to enrolling into the trial
• History of interstitial pneumonitis
• History of long QT syndrome or whose corrected QT interval (QTc) measured (Fridericia method) at screening is prolonged (> 480 ms for males and females)

Note: Other protocol defined Inclusion/Exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Momelotinib (MMB) dose escalation; Participants will receive momelotinib (MMB) plus trametinib. Momelotinib (MMB) dose will increase to find the MTD.	Drug: Momelotinib (MMB); Momelotinib (MMB) tablet(s) administered orally once or twice daily; Other Names: GS-0387; CYT387; Drug: Trametinib; Trametinib tablet administered orally once daily
Experimental: Trametinib dose escalation; Participants will receive momelotinib (MMB) plus trametinib. Trametinib dose will increase to find the MTD.	Drug: Momelotinib (MMB); Momelotinib (MMB) tablet(s) administered orally once or twice daily; Other Names: GS-0387; CYT387; Drug: Trametinib; Trametinib tablet administered orally once daily
Experimental: Momelotinib (MMB)+trametinib; Expansion Phase: participants will receive momelotinib (MMB) plus trametinib for the duration of the study.	Drug: Momelotinib (MMB); Momelotinib (MMB) tablet(s) administered orally once or twice daily; Other Names: GS-0387; CYT387; Drug: Trametinib; Trametinib tablet administered orally once daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
For the Dose-finding Lead-in Phase, incidence of dose limiting toxicities (DLTs)	Dose limiting toxicities (DLTs) refer to toxicities experienced during the first 28 days of treatment that have been judged to be clinically significant and at least possibly related to study treatment.	Up to 28 days
For Expansion Phase, disease control rate (DCR) at Week 8	Disease control rate (DCR) is defined as the proportion of participants who achieve a complete response (CR) or partial response (PR) or stable disease (SD) as assessed by Response Evaluation Criteria In Solid Tumor (RECIST) v1.1.	Week 8

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
For the Dose-finding Lead-in Phase, disease control rate (DCR) at Week 8		Week 8
For the Dose-finding Lead-in Phase, overall survival	Overall survival is defined as the interval from first dose of study drug to death from any cause.	Up to 2 years
For the Dose-finding Lead-in Phase, progression free survival (PFS)	Progression free survival (PFS) is defined as the interval from first dose date of study drug to the earlier of the first documentation of definitive disease progression or death from any cause.	Up to 2 years
For the Dose-finding Lead-in Phase, overall response rate (ORR)	Overall response rate (ORR) is defined as the proportion of participants who achieve a CR or PR as assessed by RECIST v1.1.	Up to 2 years
For the Dose-finding Lead-in Phase, plasma pharmacokinetics (PK) parameters of momelotinib (MMB) and major metabolite GS-644603 as measured by Cmax and AUCtau	This composite endpoint will measure the plasma PK profile of momelotinib (MMB) and GS-644603. The following parameters will be measured: Cmax: maximum observed concentration of drug in plasma; AUCtau: concentration of drug over time (area under the plasma concentration versus time curve over the dosing interval)	Days 1 and 15 (Cycle 1 only)
For Expansion Phase, overall survival		Up to 2 years
For Expansion Phase, progression free survival (PFS)		Up to 2 years
For Expansion Phase, overall response rate (ORR)		Up to 2 years

Collaborators and Investigators

• Sponsor: Sierra Oncology, Inc.

Publications and helpful links

General Publications

• Barbie DA, Spira A, Kelly K, Humeniuk R, Kawashima J, Kong S, Koczywas M. Phase 1B Study of Momelotinib Combined With Trametinib in Metastatic, Kirsten Rat Sarcoma Viral Oncogene Homolog-Mutated Non-Small-Cell Lung Cancer After Platinum-Based Chemotherapy Treatment Failure. Clin Lung Cancer. 2018 Nov;19(6):e853-e859. doi: 10.1016/j.cllc.2018.07.004. Epub 2018 Aug 4.

Study record dates

Study Major Dates

• Study Start (Actual): March 11, 2015
• Primary Completion (Actual): July 19, 2016
• Study Completion (Actual): February 27, 2017

Study Registration Dates

• First Submitted: October 3, 2014
• First Submitted That Met QC Criteria: October 3, 2014
• First Posted (Estimate): October 7, 2014

Study Record Updates

• Last Update Posted (Actual): February 1, 2019
• Last Update Submitted That Met QC Criteria: January 30, 2019
• Last Verified: January 1, 2019

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; N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide
• Other Study ID Numbers: GS-US-370-1297

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No