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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

Title

  • Brief Title: 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: 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

Clinical Trial IDs

  • ORG STUDY ID: GS-US-370-1297
  • NCT ID: NCT02258607

Conditions

  • Relapsed Metastatic KRAS-Mutated Non-Small Cell Lung Cancer

Interventions

DrugSynonymsArms
Momelotinib (MMB)GS-0387, CYT387Momelotinib (MMB) dose escalation
TrametinibMomelotinib (MMB) dose escalation

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Momelotinib (MMB) dose escalationExperimentalParticipants will receive momelotinib (MMB) plus trametinib. Momelotinib (MMB) dose will increase to find the MTD.
  • Momelotinib (MMB)
  • Trametinib
Trametinib dose escalationExperimentalParticipants will receive momelotinib (MMB) plus trametinib. Trametinib dose will increase to find the MTD.
  • Momelotinib (MMB)
  • Trametinib
Momelotinib (MMB)+trametinibExperimentalExpansion Phase: participants will receive momelotinib (MMB) plus trametinib for the duration of the study.
  • Momelotinib (MMB)
  • Trametinib

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:For the Dose-finding Lead-in Phase, incidence of dose limiting toxicities (DLTs)
Time Frame:Up to 28 days
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:For the Dose-finding Lead-in Phase, disease control rate (DCR) at Week 8
Time Frame:Week 8
Safety Issue:
Description:
Measure:For the Dose-finding Lead-in Phase, overall survival
Time Frame:Up to 2 years
Safety Issue:
Description:Overall survival is defined as the interval from first dose of study drug to death from any cause.
Measure:For the Dose-finding Lead-in Phase, progression free survival (PFS)
Time Frame:Up to 2 years
Safety Issue:
Description: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.
Measure:For the Dose-finding Lead-in Phase, overall response rate (ORR)
Time Frame:Up to 2 years
Safety Issue:
Description:Overall response rate (ORR) is defined as the proportion of participants who achieve a CR or PR as assessed by RECIST v1.1.
Measure: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)
Safety Issue:
Description: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)
Measure:For Expansion Phase, overall survival
Time Frame:Up to 2 years
Safety Issue:
Description:
Measure:For Expansion Phase, progression free survival (PFS)
Time Frame:Up to 2 years
Safety Issue:
Description:
Measure:For Expansion Phase, overall response rate (ORR)
Time Frame:Up to 2 years
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Terminated
Lead Sponsor:Sierra Oncology, Inc.

Last Updated

February 1, 2019