Cycle = 28 days:MK-2206:90 mg PO days 1, 8, 15, and 22 AZD6244 Hydrogen sulfate: 75 mg PO QD (every day) MK-2206 + AZD6244: MK-2206 and AZD6244 hydrogen sulfate are selective inhibitors of human AKT and MEK, respectively, with preclinical and clinical anti-tumor activity as single agents and in combination with a variety of drugs. Combination treatment in mouse cancer models harboring mutations in both the PI3K and RAS pathways was more potent compared to either agent used alone, and resulted in substantial tumor inhibition, including tumor regression.

Cycle = 28 days:MK-2206:135 mg PO days 1, 8, 15, and 22 AZD6244 Hydrogen sulfate: 100 mg PO QD
MK-2206 + AZD6244: MK-2206 and AZD6244 hydrogen sulfate are selective inhibitors of human AKT and MEK, respectively, with preclinical and clinical anti-tumor activity as single agents and in combination with a variety of drugs. Combination treatment in mouse cancer models harboring mutations in both the PI3K and RAS pathways was more potent compared to either agent used alone, and resulted in substantial tumor inhibition, including tumor regression.

Cycle = 28 days:MK-2206:90 mg PO days 1, 8, 15, and 22 AZD6244 Hydrogen sulfate: 75 mg PO QD
MK-2206 + AZD6244: MK-2206 and AZD6244 hydrogen sulfate are selective inhibitors of human AKT and MEK, respectively, with preclinical and clinical anti-tumor activity as single agents and in combination with a variety of drugs. Combination treatment in mouse cancer models harboring mutations in both the PI3K and RAS pathways was more potent compared to either agent used alone, and resulted in substantial tumor inhibition, including tumor regression.

TAC1

Cycle = 28 days:MK-2206: 135 mg PO days 1, 8, 15, and 22 AZD6244 Hydrogen sulfate: 100 mg PO QD
MK-2206 + AZD6244: MK-2206 and AZD6244 hydrogen sulfate are selective inhibitors of human AKT and MEK, respectively, with preclinical and clinical anti-tumor activity as single agents and in combination with a variety of drugs. Combination treatment in mouse cancer models harboring mutations in both the PI3K and RAS pathways was more potent compared to either agent used alone, and resulted in substantial tumor inhibition, including tumor regression.

TAC1A

Total

Sex: Female, Male

One participant selected White and Asian for Race, thus the category "More than one race" was selected. Six participants versus seven is noted in the "White" category and no participants is noted in the "Asian" category.

Race (NIH/OMB)

Ethnicity (NIH/OMB)

Region of Enrollment

A predetermined target inhibition reduction of 70% of both pERK and pAKT was deemed significant, thus tumor biopsies were performed at C1D1 or C1D22 post administration and evaluated using quantitative chemiluminescence immunoassay to measure pERK and pAKT levels in human tissue.

Cycle = 28 days:MK-2206: 135mg PO days 1, 8, 15, and 22 AZD6244 Hydrogen sulfate: 100 mg PO QD
MK-2206 + AZD6244: MK-2206 and AZD6244 hydrogen sulfate are selective inhibitors of human AKT and MEK, respectively, with preclinical and clinical anti-tumor activity as single agents and in combination with a variety of drugs. Combination treatment in mouse cancer models harboring mutations in both the PI3K and RAS pathways was more potent compared to either agent used alone, and resulted in substantial tumor inhibition, including tumor regression.

pERK and pAKT Levels in Tumor Biopsies on C1D1 and C1D22 Post-administration of the Combination of AZD6244 Hydrogen Sulfate and MK-2206 in Participants With Advanced Colorectal Cancer

Here is the number of participants with adverse events. For the detailed list of adverse events, see the adverse event module.

Number of Participants With Adverse Events

Overall Study

Dr. Shivaani Kummar

Colorectal Neoplasms

MK-2206 and AZD6244 hydrogen sulfate are selective inhibitors of human AKT and MEK, respectively, with preclinical and clinical anti-tumor activity as single agents and in combination with a variety of drugs. Combination treatment in mouse cancer models harboring mutations in both the PI3K and RAS pathways was more potent compared to either agent used alone, and resulted in substantial tumor inhibition, including tumor regression.

MK-2206 + AZD6244

National Institutes of Health Clinical Center, 9000 Rockville Pike

MK-2206 and AZD6244 in Patients With Advanced Colorectal Carcinoma

Pilot Study of the Combination of MK-2206, an AKT Inhibitor, and AZD6244, a MEK Inhibitor, in Patients With Advanced Colorectal Carcinoma

Shivaani Kummar, M.D.

Principal Investigator

National Cancer Institute (NCI)

KRAS Mutant patients randomized to combination therapy arm

KRAS Mutant patients randomized to monotherapy arm

Wild-Type KRAS patients randomized to monotherapy arm

Wild-Type KRAS patients randomized to combination therapy arm

KRAS Mutant patients randomized to combination therapy arm
AZD6244 + Erlotinib: For KRAS mutant patients and Wild-Type KRAS patients randomized to the combination arm (arms are stratified based on KRAS mutational status), AZD6244 150 mg qd (every day) + erlotinib mg qd.

KRAS Mut 2

KRAS Mutant patients randomized to monotherapy arm
AZD6244: For KRAS mutant patients randomized to the single agent arm, AZD6244 75 mg bid (twice a day).

KRAS Mut 1

Wild-Type KRAS patients randomized to monotherapy arm
Erlotinib: For Wild-Type KRAS patients randomized to the single agent arm, Erlotinib 150 mg qd

WT KRAS 1

Wild-Type KRAS patients randomized to combination therapy arm
AZD6244 + Erlotinib: For KRAS mutant patients and Wild-Type KRAS patients randomized to the combination arm (arms are stratified based on KRAS mutational status), AZD6244 150 mg qd + erl mg qd.

WT KRAS 2

Histology

EGFR (epidermal growth factor receptor); KRAS (Kirsten Rat Sarcoma Viral Oncogene homolog). KRAS G12A (e.g. G is glycine, 12 is the codon or position and A is amino acid alanine); C is cysteine, D is aspartic acid, K is lysine, R is arginine, S is serine, V is valine, Q is glutamine, H is histidine, and L is leucine.

Mutational Status

ECOG Performance Status criteria: Grade 0 is normal activity. Fully active, able to carry on all pre-disease performance without restriction. Grade 1 is symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature (e.g., light housework, office work). Grade 2 is in bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours.

Eastern Cooperative Oncology Group (ECOG)

No. of Prior Regimens

Smoking

Time between the first day of treatment to the day of disease progression. Progressive disease is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that's the smallest on study). In addition to the relative increase of 20% of at least 5mm. (Note: the appearance of one or more lesions is also considered progression).

Progression Free Survival

Objective response is complete response + partial response. Complete response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10mm. Partial response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

Objective Response

Here is the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.

KRAS Mutant patients randomized to combination therapy arm
AZD6244 + Erlotinib: For KRAS mutant patients and Wild-Type KRAS 2 patients randomized to the combination arm (arms are stratified based on KRAS mutational status), AZD6244 150 mg qd (every day) + erlotinib mg qd.

KRAS Mut 2 & WT KRAS 2

Disease control/stabilization is the percentage of participants with partial response (PR) + complete response (CR) + stable disease (SD). Partial response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Complete response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10mm. Stable disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. (Note: the appearance of one or more new lesions is also considered progressions.), taking as reference the smallest sum diameters.

Percentage of Participants With Disease Control/Stabilization

Time between the first day of treatment to the time of death.

Overall Survival

First the number of T cells that are CD4+ is determined by staining with an antibody to CD4 and measured in a flow cytometer. Then the number of Th17+ cells is determined by staining with an antibody to IL-17 and measured in a flow cytometer. Then the percentage of CD4+ cells that are also Th17 cells is determined as a simple ratio, i.e. Th17cells/CD4 cells. This ratio is reported here for each category of KRAS mutation status for whom we had patients.

Percentage of Th17 in Cluster of Differentiation 4 (CD4)+T Cells at Baseline in Relation to Response

Level of p-ERK was measured by the median channel cumber of fluorescence intensity. Data are relative to the level before therapy begins(C1D1).Then we see what the level was after therapy & compare. Every value after therapy is compared to pre-therapy, & every patient is their own control. To do that, we make C1D1 equal to 1 for every patient & then compare the pERK level after therapy by looking at the fold change in pERK level.

Number of Participants With a Reduction in Phosphorylated Extracellular Signal-Regulated Kinases (p-ERK) in Lymphocytes

Changes in a tumor's MIB-1 (Ki-67) rate was to be assessed by immunohistochemistry.

Number of Participants With Changes in a Tumor's MIB-1 (Ki-67) Rate

Fold change from cycle 1 day 1 was determined by TIM-3 expression level on Tregs measured by the median channel number of fluorescence intensity.

Change in T Cell Immunoglobulin Mucin 3 (TIM-3) on Tregs

The fold change from cycle 1 day 1 was determined by the level of CTLA-4 expression on Tregs measured by the median channel number of fluorescence intensity.

Change in Cytotoxic T-lymphocyte Associated Protein 4 (CTLA-4) Expression on Tregs

Fold change from cycle 1 day 1 was determined by the PD-1 expression level on Tregs measured by the median channel number of fluorescence intensity.

Change in Programmed Cell Death-1 (PD-1) Expression on Tregs

Fold change from cycle 1 day 1 was determined by programmed cell death-1 (PD-1) expression on CD8+ T cells measured by the median channel number of fluorescence intensity.

Change in Programmed Cell Death-1 (PD-1) Expression on Cluster of Differentiation 8 (CD8)+T Cells

p-ERK, p-AKt and PTEN protein expression testing was to be assessed by immunohistochemistry.

Phospho-ERK (p-ERK), Phospho Protein Kinase B (p-AKt) and Phosphatase and Tensin Homolog (PTEN) Expression Testing

Number of participants with over expression of EGFR and c-MET was to be assessed by fluoresense in situ hybridization (FISH).

KRAS Mutant patients randomized to combination therapy arm
AZD6244 + Erlotinib: For KRAS mutant patients and Wild-Type KRAS patients randomized to the combination arm (arms are stratified based on KRAS mutational status), AZD6244 150 mg qd (every day) + erl (erlotinib) mg qd.

Wild-Type KRAS patients randomized to monotherapy arm
Erlotinib: For Wild-Type KRAS patients randomized to the single agent arm, Erlotinib 150 mg qd (every day)

Wild-Type KRAS patients randomized to combination therapy arm
AZD6244 + Erlotinib: For KRAS mutant patients and Wild-Type KRAS patients randomized to the combination arm (arms are stratified based on KRAS mutational status), AZD6244 150 mg qd (every day) + erl (erlotinib) mg qd.

Number of Participants With Overexpression of Estimated Glomerular Filtration Rate (EGFR) and c-MET

Number of participants who underwent mutational analysis for EGFR, MEK 1, BRAF, and LKB1 was to be assessed by polymerase chain reaction (PCR).

Number of Participants Who Underwent Mutational Analysis for Estimated Glomerular Filtration Rate (EGFR), Mitogen-activated Protein Kinase 1 (MEK 1), Proto-oncogene B-Raf (BRAF), and LKB1

Dr. Arun Rajan

Non Small Cell Lung Carcinoma

For KRAS mutant patients randomized to the single agent arm, AZD6244 75 mg bid (twice a day).

AZD6244

For Wild-Type KRAS patients randomized to the single agent arm, Erlotinib 150 mg qd (every day)

Erlotinib

For KRAS mutant patients and Wild-Type KRAS patients randomized to the combination arm (arms are stratified based on KRAS mutational status), AZD6244 150 mg qd (every day) + erl (erlotinib) mg qd.

AZD6244 + Erlotinib

University of California, Davis

University of Southern California Health Sciences Campus

City of Hope Medical Group

University of Chicago Medical Center

Randomized Phase II Study of AZD6244 (Mitogen-activated Protein Kinase Inhibitor) MEK-Inhibitor With Erlotinib in KRAS Wild Type Advanced Non-Small Cell Lung Cancer (NSCLC) and a Randomized Phase II Study of AZD6244 With Erlotinib in Mutant KRAS Adva...

methyl ethyl ketone/sarcoma

MK-2206 and AZD6244 in Patients With Advanced Colorectal Carcinoma

Randomized Phase II Study of AZD6244 (Mitogen-activated Protein Kinase Inhibitor) MEK-Inhibitor With Erlotinib in KRAS Wild Type Advanced Non-Small Cell Lung Cancer (NSCLC) and a Randomized Phase II Study of AZD6244 With Erlotinib in Mutant KRAS Adva...

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