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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.

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.

Condition or disease Intervention/treatment Phase
Relapsed Metastatic KRAS-Mutated Non-Small Cell Lung Cancer Drug: Momelotinib (MMB) Drug: Trametinib Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 21 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : March 11, 2015
Actual Primary Completion Date : July 19, 2016
Actual Study Completion Date : February 27, 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer
Drug Information available for: Trametinib

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




Primary Outcome Measures :
  1. 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.

  2. 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.


Secondary Outcome Measures :
  1. For the Dose-finding Lead-in Phase, disease control rate (DCR) at Week 8 [ Time Frame: Week 8 ]
  2. 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.

  3. 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.

  4. 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.

  5. 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)

  6. For Expansion Phase, overall survival [ Time Frame: Up to 2 years ]
  7. For Expansion Phase, progression free survival (PFS) [ Time Frame: Up to 2 years ]
  8. For Expansion Phase, overall response rate (ORR) [ Time Frame: Up to 2 years ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02258607


Locations
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United States, California
Duarte, California, United States
Sacramento, California, United States
United States, Massachusetts
Boston, Massachusetts, United States
United States, Virginia
Fairfax, Virginia, United States
United States, Washington
Spokane, Washington, United States
Sponsors and Collaborators
Sierra Oncology, Inc.
Investigators
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Study Director: Gilead Study Director Gilead Sciences

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Sierra Oncology, Inc.
ClinicalTrials.gov Identifier: NCT02258607     History of Changes
Other Study ID Numbers: GS-US-370-1297
First Posted: October 7, 2014    Key Record Dates
Last Update Posted: February 1, 2019
Last Verified: January 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Trametinib
N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action