An Open-label Study of GSK1120212 Compared With Docetaxel in Stage IV KRAS-mutant Non-small Cell Lung Cancer

Lung Cancer, Non-Small Cell Clinical Trial

Official title:

A Phase II, Open-label, Multicenter, Randomized Study to Assess the Efficacy and Safety of GSK1120212 Compared With Docetaxel in 2nd Line Subjects With Targeted Mutations (KRAS, NRAS, BRAF, MEK1) in Locally Advanced or Metastatic Non-small Cell Lung Cancer (NSCLC Stage IV)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01362296
• Other study ID #: 114653
• Status: Completed
• Phase: Phase 2
• First received: May 19, 2011
• Last updated: June 26, 2014
• Start date: September 2011
• Est. completion date: September 2013

Study information

• Verified date: June 2014
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationSouth Korea: Korea Food and Drug Administration (KFDA)Europe: European Medicines Agency
• Study type: Interventional

Clinical Trial Summary

This is a phase II, open-label, multicenter, randomized study to evaluate the efficacy and safety of GSK1120212 compared with docetaxel in the second line setting for subjects with locally advanced or metastatic (Stage IV) Non-small cell lung cancer (NSCLC) harboring a KRAS mutation who have failed one platinum-containing chemotherapy regimen. A small subset of NSCLC subjects harboring BRAF, NRAS, or MEK1 mutations will be randomized in addition to the primary KRAS population, for exploratory purposes.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 134
• Est. completion date: September 2013
• Est. primary completion date: September 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• At least 18 years old with histologically- or cytologically-confirmed diagnosis of adenocarcinoma Stage IV NSCLC with a positive mutational status for the KRAS, NRAS, BRAF, or MEK1 gene.

• Documented tumor progression after receiving at least one, but not more than one, prior approved platinum-containing chemotherapy regimen for advanced stage/metastatic NSCLC.

• Measurable disease per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

• Performance status score of 0 or 1 according to the Eastern Cooperative Oncology Group (ECOG) scale.

• Able to swallow and retain orally administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.

• Life expectancy of at least three months in the opinion of the investigator.

• Women of childbearing potential must have a negative serum pregnancy test within 14 days of randomization to study treatment and agree to use effective contraception. Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception from the time of randomization to study medication until at least four weeks after the last dose of study treatment.

• Adequate baseline organ function.

Exclusion Criteria:

• History of another malignancy.

• Any serious and/or unstable pre-existing medical disorder, psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures.

• Treatment with a BRAF or MEK inhibitor or docetaxel as monotherapy or as part of a combination regimen.

• Anti-cancer therapy (including chemotherapy and radiation therapy) within the last three weeks.

• History or current evidence / risk of retinal vein occlusion or central serous retinopathy.

• Any current or history of tumor manifestation in the Central Nervous System.

• History or evidence of cardiovascular risk, including QTcB >=480 msec, uncontrolled arrhythmias, acute coronary syndrome, coronary angioplasty, or stenting within 6 months prior to randomization, >=Class II congestive heart failure, treatment refractory hypertension, intra-cardiac defibrillators or permanent pacemakers or cardiac metastases.

• Known Human Immunodeficiency Virus, Hepatitis B Virus (HBV), or Hepatitis C Virus (HBC) infection (with the exception of chronic or cleared HBV and HCV infection).

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Cancer, Non-Small Cell
• Lung Neoplasms

Intervention

Drug:
• GSK1120212
Oral once daily
• docetaxel
IV once every 3 weeks

Locations

Country	Name	City	State
France	GSK Investigational Site	Marseille cedex 20
France	GSK Investigational Site	Paris Cedex 15
France	GSK Investigational Site	Paris Cedex 20
France	GSK Investigational Site	Paris cedex 5
France	GSK Investigational Site	Strasbourg
France	GSK Investigational Site	Toulouse Cedex 9
France	GSK Investigational Site	Villejuif
Greece	GSK Investigational Site	Athens
Greece	GSK Investigational Site	Athens
Greece	GSK Investigational Site	Heraklion, Crete
Greece	GSK Investigational Site	Neo Faliro
Greece	GSK Investigational Site	Thessaloniki
Hungary	GSK Investigational Site	Budapest
Hungary	GSK Investigational Site	Székesfehérvár
Hungary	GSK Investigational Site	Törökbálint
Italy	GSK Investigational Site	Genova	Liguria
Italy	GSK Investigational Site	Milano	Lombardia
Italy	GSK Investigational Site	Milano	Lombardia
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Netherlands	GSK Investigational Site	Amsterdam
Netherlands	GSK Investigational Site	Amsterdam
Netherlands	GSK Investigational Site	Breda
Netherlands	GSK Investigational Site	Groningen
Netherlands	GSK Investigational Site	Maastricht
Netherlands	GSK Investigational Site	Zwolle
Spain	GSK Investigational Site	Badalona
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Majadahonda (Madrid)
Spain	GSK Investigational Site	Pamplona
United States	GSK Investigational Site	Athens	Georgia
United States	GSK Investigational Site	Aurora	Colorado
United States	GSK Investigational Site	Austin	Texas
United States	GSK Investigational Site	Baltimore	Maryland
United States	GSK Investigational Site	Boston	Massachusetts
United States	GSK Investigational Site	Boston	Massachusetts
United States	GSK Investigational Site	Coeur d'Alene	Idaho
United States	GSK Investigational Site	Columbus	Ohio
United States	GSK Investigational Site	Detroit	Michigan
United States	GSK Investigational Site	Durham	North Carolina
United States	GSK Investigational Site	Fairfax	Virginia
United States	GSK Investigational Site	Houston	Texas
United States	GSK Investigational Site	Indianapolis	Indiana
United States	GSK Investigational Site	Jacksonville	Florida
United States	GSK Investigational Site	Lebanon	New Hampshire
United States	GSK Investigational Site	Memphis	Tennessee
United States	GSK Investigational Site	Minneapolis	Minnesota
United States	GSK Investigational Site	Orange	California
United States	GSK Investigational Site	Philadelphia	Pennsylvania
United States	GSK Investigational Site	Philadelphia	Pennsylvania
United States	GSK Investigational Site	Portland	Oregon
United States	GSK Investigational Site	Rochester	Minnesota
United States	GSK Investigational Site	Scottsdale	Arizona
United States	GSK Investigational Site	St Louis	Missouri
United States	GSK Investigational Site	Vancouver	Washington

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

United States,  France,  Greece,  Hungary,  Italy,  Korea, Republic of,  Netherlands,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-Free Survival (PFS) as Assessed by the Investigator (INV)	PFS is defined as the time from RAN until the earliest date of documented radiological PD or DT due to any cause. PD was assessed by the INV according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. PD is defined as at least a 20% increase in the sum of the diameters (SD) of target lesions with an absolute increase of at least 5 millimeters (mm) or the appearance of at least 1 new lesion, or the worsening of non-target lesions significant enough to require study treatment discontinuation. For participants (PAR) who did not have a documented date of PD or DT, PFS was censored at the date of the last adequate assessment. For PAR who received subsequent anti-cancer therapy prior to the date of documented PD or DT, PFS was censored at the date of the last adequate assessment prior to the initiation of therapy.	From randomization (RAN) until the earliest date of documented radiological disease progression (PD) or death (DT) due to any cause (maximum of 10.2 months)	No
Secondary	Number of Participants With the Indicated Worst-case On-therapy Change From Baseline in the Indicated Clinical Chemistry Parameters: Randomized Phase	Clinical chemistry parameters were summarized according to National Cancer Institutes (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade, version 4.0. Grade (G) 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to any G, G3, or G4 occurred. Clinical chemistry parameters included: albumin, alkaline phosphatase (ALKP), alanine amino transferase (ALT), aspartate amino transferase (AST), total bilirubin, calcium (hypercalcemia), calcium (hypocalcemia), creatine kinase, creatinine, glucose (hyperglycemia), glucose (hypoglycemia), potassium (hyperkalemia), potassium (hypokalemia), sodium (hypernatremia), and sodium (hyponatremia). Worst-case on-therapy changes from Baseline were summarized. Worst-case on-therapy was defined using the on-therapy window and changes were indentified using both scheduled and unscheduled assessments.	Baseline; Days 1, 8, and 15 of Cycle 1; and Day 1 of every cycle thereafter until treatment discontinuation of the Randomized Phase (up to Study Week 40)	No
Secondary	Number of Participants With the Indicated Worst-case On-therapy Change From Baseline in the Indicated Clinical Chemistry Parameters: Crossover Phase	Clinical chemistry parameters were summarized according to NCI CTCAE grade, version 4.0. Grade (G) 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to any grade, Grade 3, or Grade 4 occurred. Clinical chemistry parameters included: albumin, alkaline phosphatase (ALKP), alanine amino transferase (ALT), aspartate amino transferase (AST), total bilirubin, calcium (hypercalcemia), calcium (hypocalcemia), creatine kinase, creatinine, glucose (hyperglycemia), glucose (hypoglycemia), potassium (hyperkalemia), potassium (hypokalemia), sodium (hypernatremia), and sodium (hyponatremia). Worst-case on-therapy changes from Baseline were summarized. Worst-case on-therapy was defined using the on-therapy window and changes were indentified using both scheduled and unscheduled assessments.	Baseline; Days 1, 8, and 15 of Cycle 1; and Day 1 of every cycle thereafter until treatment discontinuation of the Crossover Phase (up to Study Week 19)	No
Secondary	Number of Participants With the Indicated Worst-case On-therapy Change From Baseline in the Indicated Hematology Parameters: Randomized Phase	Hematology parameters were summarized according to NCI CTCAE grade, version 4.0. Grade (G) 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to any G (IAG), G3, or G4 occurred. Hematology parameters included: haemoglobin (increased [inc]), haemoglobin (anemia), lymphocyte count (ct) (inc), lymphocyte ct (decreased [dec]), total absolute neutrophil count (ANC), platelet ct, and white blood cell count (WBC). Worst-case on-therapy changes from Baseline were summarized. Worst-case on-therapy was defined using the on-therapy window and changes were indentified using both scheduled and unscheduled assessments.	Baseline; Days 1, 8, and 15 of Cycle 1; and Day 1 of every cycle thereafter until treatment discontinuation of the Randomized Phase (up to Study Week 40)	No
Secondary	Number of Participants With the Indicated Worst-case On-therapy Change From Baseline in the Indicated Hematology Parameters: Crossover Phase	Hematology parameters were summarized according to NCI CTCAE grade, version 4.0. Grade (G) 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to any G (IAG), G3, or G4 occurred. Hematology parameters included: haemoglobin (increased [inc]), haemoglobin (anemia), lymphocyte count (ct) (inc), lymphocyte ct (decreased [dec]), total absolute neutrophil count (ANC), platelet ct, and white blood cell count (WBC). Worst-case on-therapy changes from Baseline were summarized. Worst-case on-therapy was defined using the on-therapy window and changes were indentified using both scheduled and unscheduled assessments.	Baseline; Days 1, 8, and 15 of Cycle 1; and Day 1 of every cycle thereafter until treatment discontinuation of the Crossover Phase (up to Study Week 19)	No
Secondary	Number of Participants With the Indicated Worst-case On-therapy Change From Baseline With Respect to Normal Ranges in the Indicated Clinical Chemistry Parameters: Randomized Phase	Data are presented for only those clinical chemistry parameters for which the following worst-case on-therapy changes from Baseline with respect to the normal range were observed: decrease to low, change to normal (CTN) or no change, or increase to high. Clinical chemistry parameters included: lactate dehydrogenase, total protein, and urea/blood urea nitrogen (BUN). Worst-case on-therapy changes from Baseline were summarized. Worst-case on-therapy was defined using the on-therapy window and changes were indentified using both scheduled and unscheduled assessments. Normal ranges for each parameter may vary depending on the laboratory (central versus local) and the participant (age, gender, etc.).	Baseline; Days 1, 8, and 15 of Cycle 1; and Day 1 of every cycle thereafter until treatment discontinuation of the Randomized Phase (up to Study Week 40)	No
Secondary	Number of Participants With the Indicated Worst-case On-therapy Change From Baseline With Respect to Normal Ranges in the Indicated Clinical Chemistry Parameters: Crossover Phase	Data are presented for only those clinical chemistry parameters for which the following worst-case on-therapy changes from Baseline with respect to the normal range were observed: decrease to low, change to normal (CTN) or no change, or increase to high. Clinical chemistry parameters included: lactate dehydrogenase, total protein, and urea/blood urea nitrogen (BUN). Worst-case on-therapy changes from Baseline were summarized. Worst-case on-therapy was defined using the on-therapy window and changes were indentified using both scheduled and unscheduled assessments. Normal ranges for each parameter may vary depending on the laboratory (central versus local) and the participant (age, gender, etc.).	Baseline; Days 1, 8, and 15 of Cycle 1; and Day 1 of every cycle thereafter until treatment discontinuation of the Crossover Phase (up to Study Week 19)	No
Secondary	Number of Participants With the Indicated Worst-case On-therapy Change From Baseline With Respect to Normal Ranges in the Indicated Hematology Parameters: Randomized Phase	Data are presented for only those hematology parameters for which the following worst-case on-therapy changes from Baseline with respect to the normal range were observed: decrease to low, change to normal (CTN) or no change, or increase to high. Hematology parameters included: atypical lymphs, atypical lymphs (percentage [%]), basophils, eosinophils, metamyelocytes, monocytes, myelocytes, neutrophil bands (%). Worst-case on-therapy changes from Baseline were summarized. Worst-case on-therapy was defined using the on-therapy window and changes were indentified using both scheduled and unscheduled assessments. Normal ranges for each parameter may vary depending on the laboratory (central versus local) and the participant (age, gender, etc.).	Baseline; Days 1, 8, and 15 of Cycle 1; and Day 1 of every cycle thereafter until treatment discontinuation of the Randomized Phase (up to Study Week 40)	No
Secondary	Number of Participants With the Indicated Worst-case On-therapy Change From Baseline With Respect to Normal Ranges in the Indicated Hematology Parameters: Crossover Phase	Data are presented for only those hematology parameters for which the following worst-case on-therapy changes from Baseline with respect to the normal range were observed: decrease to low, change to normal (CTN) or no change, or increase to high. Hematology parameters included: atypical lymphs, atypical lymphs (percentage [%]), basophils, eosinophils, metamyelocytes, monocytes, and myelocytes. Worst-case on-therapy changes from Baseline were summarized. Worst-case on-therapy was defined using the on-therapy window and changes were indentified using both scheduled and unscheduled assessments. Normal ranges for each parameter may vary depending on the laboratory (central versus local) and the participant (age, gender, etc.).	Baseline; Days 1, 8, and 15 of Cycle 1; and Day 1 of every cycle thereafter until treatment discontinuation of the Crossover Phase (up to Study Week 19)	No
Secondary	Number of Participants With Any Serious Adverse Event (SAE) or Non-serious Adverse Event (AE): Randomized Phase	An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury. Medical or scientific judgment should have been exercised in deciding whether reporting was appropriate in other situations. Refer to the general Adverse AE/SAE module for a complete list of AEs and SAEs.	From randomization until 30 days following discontinuation of study treatment regardless of initiation of a new cancer therapy or transfer to hospice (maximum of 19 months)	No
Secondary	Number of Participants With Any SAE or Non-serious AE: Crossover Phase	An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury. Medical or scientific judgment should have been exercised in deciding whether reporting was appropriate in other situations. Refer to the general Adverse AE/SAE module for a complete list of AEs and SAEs.	From the date of the first dose of study treatment in the Crossover Phase until 30 days following discontinuation of study treatment regardless of initiation of a new cancer therapy or transfer to hospice (maximum of 12 months)	No
Secondary	Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP): Randomized Phase	Systolic and diastolic blood pressure were measured at the following scheduled time points: Baseline; Days 1, 8, and 15 of Cycle 1 (Study Week 1); and Day 1 of every cycle thereafter until treatment discontinuation. The worst-case on-therapy was determined using both scheduled and unscheduled assessments during the on-therapy period. Change from Baseline was calculated as the value at post-Baseline time point minus the value at Baseline.	Baseline; Days 1, 8, and 15 of Cycle 1; and Day 1 of every cycle thereafter until treatment discontinuation of the Randomized Phase (up to Study Week 40)	No
Secondary	Change From Baseline in SBP and DBP: Crossover Phase	Systolic and diastolic blood pressure were measured at the following scheduled time points: Baseline; Days 1, 8, and 15 of Cycle 1 (Study Week 1); and Day 1 of every cycle therafter until treatment discontinuation. The worst-case on-therapy was determined using both scheduled and unscheduled assessments during the on-therapy period. Change from Baseline was calculated as the value at post-Baseline time point minus the value at Baseline.	Baseline; Days 1, 8, and 15 of Cycle 1; and Day 1 of every cycle thereafter until treatment discontinuation of the Crossover Phase (up to Study Week 19)	No
Secondary	Change From Baseline in Heart Rate: Randomized Phase	Heart rate was measured at the following scheduled time points: Baseline; Days 1, 8, and 15 of Cycle 1 (Study Week 1); and Day 1 of every cycle therafter until treatment discontinuation.The worst-case on-therapy was determined using both scheduled and unscheduled assessments during the on-therapy period. Change from Baseline was calculated as the value at post-Baseline time point minus the value at Baseline.	Baseline; Days 1, 8, and 15 of Cycle 1; and Day 1 of every cycle thereafter until treatment discontinuation of the Randomized Phase (up to Study Week 40)	No
Secondary	Change From Baseline in Heart Rate: Crossover Phase	Heart rate was measured at the following scheduled time points: Baseline; Days 1, 8, and 15 of Cycle 1 (Study Week 1); and Day 1 of every cycle therafter until treatment discontinuation.The worst-case on-therapy was determined using both scheduled and unscheduled assessments during the on-therapy period. Change from Baseline was calculated as the value at post-Baseline time point minus the value at Baseline.	Baseline; Days 1, 8, and 15 of Cycle 1; and Day 1 of every cycle thereafter until treatment discontinuation of the Crossover Phase (up to Study Week 19)	No
Secondary	Number of Participants With a Best Response of Either a Complete Response (CR) or Partial Response (PR) as Assessed by the Investigator: Randomized Phase	Response was assessed by the investigator according to RECIST, version 1.1, using confirmed and unconfirmed responses. Responders were defined as participants achieving either a CR (disappearance of all target and non-target lesions; any pathological lymph nodes must be <10 millimeters [mm] in the short axis; without the appearance of new lesions) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]). Participants with unknown or missing response were treated as non-responders.	From randomization until the first documented evidence of a CR or PR (maximum of 10.2 months)	No
Secondary	Number of Participants With a Best Response of Either a CR or PR as Assessed by the Investigator: Crossover Phase	Response was assessed by the investigator according to RECIST, version 1.1, using confirmed and unconfirmed responses. Responders were defined as participants achieving either a CR (disappearance of all target and non-target lesions; any pathological lymph nodes must be <10 millimeters [mm] in the short axis; without the appearance of new lesions) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]). Participants with unknown or missing response were treated as non-responders.	From the date of the first dose of study treatment in the Crossover Phase until the first documented evidence of a CR or PR (maximum of 4 months)	No
Secondary	Duration of Response (DOR) as Assessed by the Investigator: Randomized Phase	DOR was assessed by the investigator for participants with CR (disappearance of all target and non-target lesions; any pathological lymph nodes must be <10 mm in the short axis; without the appearance of new lesions) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]). DOR is defined as the time from the first documented evidence of CR or PR until the earliest date of documented radiological progression or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters (SD) of target lesions with an absolute increase of at least 5 millimeters (mm) or the appearance of at least 1 new lesion, or the worsening of non-target lesions significant enough to require study treatment discontinuation.	Time from the first documented evidence of CR or PR until the earliest date of documented radiological progression or death due to any cause (maximum of 10.2 months)	No
Secondary	Overall Survival (OS)	OS is defined as the interval of time between the date of randomization and the date of death due to any cause. For participants who did not die, OS was censored at the date of last contact.	Time interval between the date of randomization and the date of death due to any cause (maximum of 22 months)	No
Secondary	GSK1120212 Plasma Pharmacokinetic (PK) Concentration	Blood samples for PK analysis of GSK1120212 were collected at the following time points: Cycle 1 (Study Day 15), Cycle 2 (Study Day 22), Cycle 3 (Study Day 43), and Cycle 4 (Study Day 64). Post-dose PK samples collected on Day 15 of Cycle 1 occurred at least 1 hour apart. Participants were instructed to withhold the dose of GSK1120212 until after blood for PK samples had been drawn. Pre-dose samples were taken 15 minutes or less prior to taking the next dose (i.e., trough).	Day 15 of Cycle 1: pre-dose; 0.5-2 hours, 2-4 hours, and 4-8 hours post-dose; Day 1 of Cycle 2, Cycle 3 and Cycle 4: pre-dose	No