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

Study Overview
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Brief Summary
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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.

Official Title
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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

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

Intervention / Treatment
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* Drug: Momelotinib (MMB)
* Drug: Trametinib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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 |