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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

Primary Purpose

Relapsed Metastatic KRAS-Mutated Non-Small Cell Lung Cancer

Status

Terminated

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Momelotinib (MMB)

Trametinib

About this trial

This is an interventional treatment trial for Relapsed Metastatic KRAS-Mutated Non-Small Cell Lung Cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Arm Label

Momelotinib (MMB) dose escalation

Trametinib dose escalation

Momelotinib (MMB)+trametinib

Arm Description

Participants will receive momelotinib (MMB) plus trametinib. Momelotinib (MMB) dose will increase to find the MTD.

Participants will receive momelotinib (MMB) plus trametinib. Trametinib dose will increase to find the MTD.

Expansion Phase: participants will receive momelotinib (MMB) plus trametinib for the duration of the study.

Outcomes

Primary Outcome Measures

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.

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.

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

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)

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)

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

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

For Expansion Phase, progression free survival (PFS)

For Expansion Phase, overall response rate (ORR)

Full Information

NCT ID

NCT02258607

First Posted

October 3, 2014

Last Updated

January 30, 2019

Sponsor

Sierra Oncology LLC - a GSK company

1. Study Identification

Unique Protocol Identification Number

NCT02258607

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

Study Type

Interventional

2. Study Status

Record Verification Date

January 2019

Overall Recruitment Status

Terminated

Study Start Date

March 11, 2015 (Actual)

Primary Completion Date

July 19, 2016 (Actual)

Study Completion Date

February 27, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Sierra Oncology LLC - a GSK company

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Relapsed Metastatic KRAS-Mutated Non-Small Cell Lung Cancer

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

21 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Momelotinib (MMB) dose escalation

Arm Type

Experimental

Arm Description

Participants will receive momelotinib (MMB) plus trametinib. Momelotinib (MMB) dose will increase to find the MTD.

Arm Title

Trametinib dose escalation

Arm Type

Experimental

Arm Description

Participants will receive momelotinib (MMB) plus trametinib. Trametinib dose will increase to find the MTD.

Arm Title

Momelotinib (MMB)+trametinib

Arm Type

Experimental

Arm Description

Expansion Phase: participants will receive momelotinib (MMB) plus trametinib for the duration of the study.

Intervention Type

Drug

Intervention Name(s)

Momelotinib (MMB)

Other Intervention Name(s)

GS-0387, CYT387

Intervention Description

Momelotinib (MMB) tablet(s) administered orally once or twice daily

Intervention Type

Drug

Intervention Name(s)

Trametinib

Intervention Description

Trametinib tablet administered orally once daily

Primary Outcome Measure Information:

Title

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

Description

Time Frame

Up to 28 days

Title

For Expansion Phase, disease control rate (DCR) at Week 8

Description

Time Frame

Week 8

Secondary Outcome Measure Information:

Title

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

Time Frame

Week 8

Title

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

Description

Overall survival is defined as the interval from first dose of study drug to death from any cause.

Time Frame

Up to 2 years

Title

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

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.

Time Frame

Up to 2 years

Title

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

Description

Overall response rate (ORR) is defined as the proportion of participants who achieve a CR or PR as assessed by RECIST v1.1.

Time Frame

Up to 2 years

Title

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

Description

Time Frame

Days 1 and 15 (Cycle 1 only)

Title

For Expansion Phase, overall survival

Time Frame

Up to 2 years

Title

For Expansion Phase, progression free survival (PFS)

Time Frame

Up to 2 years

Title

For Expansion Phase, overall response rate (ORR)

Time Frame

Up to 2 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Gilead Study Director

Organizational Affiliation

Gilead Sciences

Official's Role

Study Director

Facility Information:

City

Duarte

State/Province

California

Country

United States

City

Sacramento

State/Province

California

Country

United States

City

Boston

State/Province

Massachusetts

Country

United States

City

Fairfax

State/Province

Virginia

Country

United States

City

Spokane

State/Province

Washington

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

30087028

Citation

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.

Results Reference

derived

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