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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

NCT02258607

Description:

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.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Terminated

Phase:

Phase 1

Trial Eligibility

Document

Efficacy and Safety of Momelotinib and Momelotinib Combined With <span class="go-doc-concept go-doc-intervention">Trametinib</span> in Adults With Metastatic <span class="go-doc-concept go-doc-biomarker">KRAS</span>-<span class="go-doc-concept go-doc-keyword">mutated</span> Non-Small Cell <span class="go-doc-concept go-doc-disease">Lung Cancer</span> (NSCLC) Who Have Failed <span class="go-doc-concept go-doc-intervention">Platinum</span>-Based <span class="go-doc-concept go-doc-intervention">Chemotherapy</span> Preceded by a Dose-finding Lead-in Phase

Title

  • Brief Title: Efficacy and Safety of Momelotinib and 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: A Phase 1b Parallel Cohort Study Evaluating the Efficacy and Safety of Momelotinib and 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
  • Clinical Trial IDs

    NCT ID: NCT02258607

    ORG ID: GS-US-370-1297

    Trial Conditions

    Relapsed Metastatic KRAS-Mutated Non-Small Cell Lung Cancer

    Trial Interventions

    Drug Synonyms Arms
    MMB GS-0387, CYT387 MMB dose escalation, Trametinib dose escalation, MMB+trametinib, MMB
    Trametinib MMB dose escalation, Trametinib dose escalation, MMB+trametinib

    Trial Purpose

    This study will be 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 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 will proceed to the Parallel Cohort Phase to determine the efficacy,
    safety, and tolerability of MMB combined with trametinib at the MTD or MMB alone 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

    Trial Arms

    Name Type Description Interventions
    MMB dose escalation Experimental Participants will receive MMB plus trametinib. MMB dose will increase to find the MTD. MMB, Trametinib
    Trametinib dose escalation Experimental Participants will receive MMB plus trametinib. Trametinib dose will increase to find the MTD. MMB, Trametinib
    MMB+trametinib Experimental Parallel Cohort Phase: participants will receive MMB plus trametinib for the duration of the study. MMB, Trametinib
    MMB Experimental Parallel Cohort Phase, participants will receive MMB monotherapy for the duration of the study. MMB

    Eligibility Criteria

    Inclusion Criteria:

    - KRAS-mutated metastatic or recurrent non-small cell lung cancer, treated with one
    platinum-based chemotherapy

    -- The dose-finding Dose-finding Lead-in Phase study will allow individuals to enroll
    who have received 2 lines of prior chemotherapy

    - 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

    Exclusion Criteria:

    - Less than or equal to 3 weeks since receiving treatment with biologic, small
    molecule, immunotherapy, chemotherapy or other agent for non-small cell lung cancer

    - 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 or randomizing 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 (> 450 ms for males and females).

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    For the Dose-finding Lead-in Phase, incidence of dose limiting toxicities (DLTs)

    For the Parallel Cohort Phase, disease control rate (DCR) at Week 8

    Secondary Outcome Measures

    For the Dose-finding Lead-in Phase, disease control rate (DCR) at Week 8

    For the Dose-finding Lead-in Phase, overall survival

    For the Dose-finding Lead-in Phase, progression free survival (PFS)

    For the Dose-finding Lead-in Phase, overall response rate (ORR)

    For the Dose-finding Lead-in Phase, plasma pharmacokinetics (PK) parameters of MMB and major metabolite GS-644603 as measured by Cmax and AUCtau

    For the Parallel Cohort Phase, overall survival

    For the Parallel Cohort Phase, progression free survival (PFS)

    For the Parallel Cohort Phase, overall response rate (ORR)

    Trial Keywords