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Erlotinib Hydrochloride

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Tyrosine

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

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

Arun Rajan, M.D.

Background:

AZD6244 (ARRY-142886) is an investigational anticancer drug that is designed to block a critical component (MEK (methyl ethyl ketone)) of a pathway (MAP (mitogen-activated protein) kinase pathway) that causes some lung cancer cells to grow. The MAP kinase pathway could be overactive in a proportion of lung cancers, including some which also have another mutation in a protein known as KRAS (Kirsten rat sarcoma viral oncogene homolog). Approximately 20% of lung cancers have KRAS mutations which can make some cancer treatments including erlotinib, a standard anticancer treatment drug less effective. Researchers are interested in determining whether AZD6244 is effective in treating advanced NSCLC (non small cell lung cancer), including KRAS mutated lung cancer that has not responded to standard therapy.

Objectives:

To determine the effectiveness of AZD6244, either alone or in combination with erlotinib, in preventing tumor growth in individuals with NSCLC.

Eligibility:

Individuals at least 18 years of age who have been diagnosed with advanced NSCLC that has not responded to standard therapy.

Design:

* Participants will be screened with a medical history, physical examination, blood tests, imaging studies, and potentially, tumor biopsy tests to determine whether a participant's NSCLC contains mutations in the KRAS protein.
* Participants will be divided into two groups based on the status of the KRAS protein in their NSCLC tumor cells:
* Individuals with normal KRAS protein: Half will receive AZD6244 and erlotinib, and half will receive only erlotinib.
* Individuals with mutated KRAS protein: Half will receive AZD6244 and erlotinib, and half will receive only AZD6244.
* Participants will take their assigned medications daily (on an empty stomach in the morning and/or evening, depending on the treatment) for 28-day cycles of treatment. Participants will also keep a medication diary to record any side effects.
* Participants will have frequent blood tests during the first cycle of treatment, and will have imaging studies or other tests as required by the study researchers. Participants may also have an additional tumor biopsy after the end of the first treatment cycle.
* Treatment will continue until the disease progresses, significant side effects develop, the participant chooses to leave the study, or the researchers end the study....

Background:

Lung Cancer is the leading cause of death among both men and women. Of the approximately 172,000 patients that are diagnosed every year with non small cell lung cancer (NSCLC) in the US, 55% present with advanced stage disease. The current treatment for advanced NSCLC is first line chemotherapy with a platinum-based doublet. Second line treatment for recurrent or progressive disease includes treatment with chemotherapy or treatment with an oral EGFR (epidermal growth factor receptor) tyrosine kinase inhibitor. Several mechanisms of resistance to EGFR tyrosine kinase inhibitors have been discovered. Presence of KRAS mutations is one of them. AZD6244 (ARRY-142886) is an investigational drug that is orally available and targets the critical kinase (MEK) in the mitogen-activated protein (MAP) kinase signal transduction pathway which is activated in NSCLC and is downstream of EGFR.

Objectives:

* Determine the progression free survival (PFS) using the combination of AZD6244 and erlotinib in patients with wild type KRAS advanced NSCLC
* Determine the clinical response rate (PR (partial response) + CR (complete response)) either monotherapy AZD6244 or the combination AZD6244 plus erlotinib in patients with mutated KRAS advanced NSCLC
* Evaluate disease control rate (PR+CR+SD (stable disease)) and overall survival in both patient groups.
* Determine a safety profile for use of AZD6244 in combination with erlotinib in patients with advanced NSCLC.
* Measure serological markers to evaluate if these markers are correlated with tumor response.
* Measure changes in a tumors MIB-1 (Ki-67) rate and pERK levels in response to treatment with AZD6244.

Eligibility:

* Patients with pathologically confirmed NSCLC not amenable to potentially curative therapy and having progressed after being treated with at least one prior platinum containing chemotherapy regimen, or having refused cytotoxic chemotherapy.
* Progressive disease should be documented prior to enrollment on the study.
* Patient should not have more than 2 prior chemotherapy regimens.
* Measurable disease by RECIST (Response Evaluation Criteria in Solid Tumors) criteria.
* Adequate renal, cardiac, hepatic and hematopoietic functions
* No major surgery, radiotherapy, or chemotherapy within 28 days of enrollment.

Design:

* Patients will be stratified on the basis on their KRAS mutational status. Wild-Type KRAS patients will be randomized to receive either single agent erlotinib 150 mg/day or the combination of erlotinib 100 mg/day plus AZD6244 at 150 mg/day. KRAS mutant patients will be randomized to receive AZD6244 monotherapy at a dose of 75 mg twice per day, or the combination AZD6244 at 150 mg/day plus erlotinib 100 mg/day.
* Treatment will continue until disease progression.
* Toxicity will be assessed every cycle by the CTCAE (Common Terminology Criteria for Adverse Events) Version 4.0.
* Tumor assessments by RECIST 1.1 criteria will be performed every 2 cycles (one cycle is 28 days).
* Correlative studies including initial tumor mutational analysis and tissue immunohistochemistry (IHC) studies will be done on existing tumor blocks, or re-biopsied tissue prior to enrollment.
* Patients will be evaluated for the potential to undergo repeat tumor biopsy after 1 cycle of therapy. Tumors will be assessed for MIB-1 (Ki-67) and pERK levels by IHC.
* The study will accrue up to 40 patients with wild-type KRAS NSCLC and up to 60 patients with mutated KRAS NSCLC.

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...

Randomized Phase II Study of AZD6244 MEK-Inhibitor With Erlotinib in KRAS Wild Type and KRAS Mutant Advanced Non-Small Cell Lung Cancer

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

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.

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.

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.

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.

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

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

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

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).

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.

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

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.

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

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.

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.

University of California, Davis

University of Chicago

University of Southern California

City of Hope Medical Center

National Cancer Institute (NCI)

Principal Investigator

The combination of toxicities allows for a more robust understanding of the combined therapy toxicities. The dosage of the combination of erlotinib plus AZD6244 was the same whether the pt has a KRAS mutation versus KRAS wild type. KRAS is a molecular mutation and does not change whether or not a pt has toxicities to the combination of therapies.

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

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

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

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

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Lung Cancer Adenocarcinoma

Squamous cell

Histology

EGFR Mutated (L858R)

EGFR Wild Type

KRAS G12A

KRAS G12C

KRAS G12D

KRAS G12K

KRAS G12R

KRAS G12S

KRAS G12V

KRAS Q61H

KRAS Q61L

KRAS

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

Current

Former

Never-smoker

Smoking

Dr. Arun Rajan

Progression Free Survival

There were no partial or complete responses in the KRAS mut 1 arm.

Objective Response

Number of Participants With Adverse Events

Percentage of Participants With Disease Control/Stabilization

Overall Survival

No participants were analyzed in the WT KRAS 1 cohort because no samples were available for analysis. For all other cohorts, the numbers analyzed indicates some samples were either not drawn or could not be located.

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

4 patients in this group; statistically underpowered.

Cycle 1 Day 1

Cycle 1 day 2

Cycle 1 day 14

Re: number of participants analyzed: Samples were either not drawn or could not be located. WT KRAS 1/WT KRAS 2 are missing because the effect of treatment on the Ras-Raf-MEK-ERK pathway as measured by a reduction in phosphorylated extracellular signal-regulated kinases (p-ERK) in lymphocytes was evaluated in patients with KRAS-mutated tumors only.

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

Tumor MIB-1 (Ki-67) rate testing was not done because it was too costly.

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

Cycle 1 Day 2

Cycle 1 Day 14

These are exploratory results and a normal range has not been defined for fold change. No participants were analyzed in the WT KRAS 1 cohort because no samples were available for analysis. Missing numbers in the other cohorts were either not drawn, misplaced or the samples were not viable.

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

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

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

Cycel 1 Day 2

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

Zero participants were analyzed because most of the immunohistochemistry (IHC) specialty assays (e.g. IHC, fluoresense in situ hybridization (FISH), polymerase chain reaction (PCR) were not available (still are not performed in path) and required funding for development that was not provided.

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

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 Estimated Glomerular Filtration Rate (EGFR), Mitogen-activated Protein Kinase 1 (MEK 1), Proto-oncogene B-Raf (BRAF), and LKB1

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
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...	NCT01229150	Non Small Cell ...	AZD6244 Erlotinib AZD6244 + Erlot...	18 Years -	National Institutes of Health Clinical Center (CC)
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...	NCT01229150	Non Small Cell ...	AZD6244 Erlotinib AZD6244 + Erlot...	18 Years -	National Institutes of Health Clinical Center (CC)

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