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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

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ClinicalTrials.gov Identifier: NCT02258607
Recruitment Status : Terminated
First Posted : October 7, 2014
Last Update Posted : February 1, 2019
Sponsor:
Information provided by (Responsible Party):
Sierra Oncology, Inc.

Tracking Information
First Submitted Date  ICMJE October 3, 2014
First Posted Date  ICMJE October 7, 2014
Last Update Posted Date February 1, 2019
Actual Study Start Date  ICMJE March 11, 2015
Actual Primary Completion Date July 19, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 8, 2015)
  • For the Dose-finding Lead-in Phase, incidence of dose limiting toxicities (DLTs) [ Time Frame: Up to 28 days ]
    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.
  • For Expansion Phase, disease control rate (DCR) at Week 8 [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: October 3, 2014)
  • For the Dose-finding Lead-in Phase, incidence of dose limiting toxicities (DLTs) [ Time Frame: Up to 28 days ]
    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.
  • For the Parallel Cohort Phase, disease control rate (DCR) at Week 8 [ Time Frame: 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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 30, 2019)
  • For the Dose-finding Lead-in Phase, disease control rate (DCR) at Week 8 [ Time Frame: Week 8 ]
  • For the Dose-finding Lead-in Phase, overall survival [ Time Frame: Up to 2 years ]
    Overall survival is defined as the interval from first dose of study drug to death from any cause.
  • For the Dose-finding Lead-in Phase, progression free survival (PFS) [ Time Frame: Up to 2 years ]
    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.
  • For the Dose-finding Lead-in Phase, overall response rate (ORR) [ Time Frame: Up to 2 years ]
    Overall response rate (ORR) is defined as the proportion of participants who achieve a CR or PR as assessed by RECIST v1.1.
  • 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 [ Time Frame: Days 1 and 15 (Cycle 1 only) ]
    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)
  • For Expansion Phase, overall survival [ Time Frame: Up to 2 years ]
  • For Expansion Phase, progression free survival (PFS) [ Time Frame: Up to 2 years ]
  • For Expansion Phase, overall response rate (ORR) [ Time Frame: Up to 2 years ]
Original Secondary Outcome Measures  ICMJE
 (submitted: October 3, 2014)
  • For the Dose-finding Lead-in Phase, disease control rate (DCR) at Week 8 [ Time Frame: Week 8 ]
  • For the Dose-finding Lead-in Phase, overall survival [ Time Frame: Up to 2 years ]
    Overall survival is defined as the interval from first dose of study drug to death from any cause.
  • For the Dose-finding Lead-in Phase, progression free survival (PFS) [ Time Frame: Up to 2 years ]
    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.
  • For the Dose-finding Lead-in Phase, overall response rate (ORR) [ Time Frame: Up to 2 years ]
    Overall response rate (ORR) is defined as the proportion of participants who achieve a CR or PR as assessed by RECIST v1.1.
  • For the Dose-finding Lead-in Phase, plasma pharmacokinetics (PK) parameters of MMB and major metabolite GS-644603 as measured by Cmax and AUCtau [ Time Frame: Days 1 and 15 (Cycle 1 only) ]
    This composite endpoint will measure the plasma PK profile of 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)
  • For the Parallel Cohort Phase, overall survival [ Time Frame: Up to 2 years ]
  • For the Parallel Cohort Phase, progression free survival (PFS) [ Time Frame: Up to 2 years ]
  • For the Parallel Cohort Phase, overall response rate (ORR) [ Time Frame: Up to 2 years ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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
Official Title  ICMJE 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
Brief Summary 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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Relapsed Metastatic KRAS-Mutated Non-Small Cell Lung Cancer
Intervention  ICMJE
  • 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
Study Arms  ICMJE
  • Experimental: Momelotinib (MMB) dose escalation
    Participants will receive momelotinib (MMB) plus trametinib. Momelotinib (MMB) dose will increase to find the MTD.
    Interventions:
    • Drug: Momelotinib (MMB)
    • Drug: Trametinib
  • Experimental: Trametinib dose escalation
    Participants will receive momelotinib (MMB) plus trametinib. Trametinib dose will increase to find the MTD.
    Interventions:
    • Drug: Momelotinib (MMB)
    • Drug: Trametinib
  • Experimental: Momelotinib (MMB)+trametinib
    Expansion Phase: participants will receive momelotinib (MMB) plus trametinib for the duration of the study.
    Interventions:
    • Drug: Momelotinib (MMB)
    • Drug: Trametinib
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: May 13, 2016)
21
Original Estimated Enrollment  ICMJE
 (submitted: October 3, 2014)
142
Actual Study Completion Date  ICMJE February 27, 2017
Actual Primary Completion Date July 19, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02258607
Other Study ID Numbers  ICMJE GS-US-370-1297
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Sierra Oncology, Inc.
Study Sponsor  ICMJE Sierra Oncology, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Gilead Study Director Gilead Sciences
PRS Account Sierra Oncology, Inc.
Verification Date January 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP