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 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 10021810-C-0218
• Study Type: interventional
• Target: 89
• Locations: 1 country
• Sites: 5

Brief Summary

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....

Conditions

Non Small Cell Lung Carcinoma

Keywords

Kinase Signal Transduction Pathway; Tumor Mutational Analysis; Tissue Immunohistochemistry; MIB-1 (Ki-67) Rate; PERK Level; Lung Cancer; Non-Small Cell Lung Cancer

Outcome Measures

Primary Outcomes (2)

• Progression Free Survival

  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).

  2.1 to 4 months

• Objective Response

  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.

  Up to 37 months

Secondary Outcomes (5)

• Number of Participants With Adverse Events

  42 months

• Percentage of Participants With Disease Control/Stabilization

  3 cycles or up to 84 days

• Overall Survival

  Up to 26 months

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

  Pretreatment - Cycle 1 Day 1

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

  Cycle 1 Day 1 pre-treatment with Cycle 1 Day 2 (1 day after starting treatment), and Cycle 1 Day 14 (2 weeks after starting treatment)

Other Outcomes (8)

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

  At enrollment

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

  Cycle 1 Day 1 pre-treatment with Cycle 1 Day 2 (1 day after starting treatment), and Cycle 1 Day 14 (2 weeks after starting treatment)

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

  Cycle 1 Day 1 pre-treatment with Cycle 1 Day 2 (1 day after starting treatment), and Cycle 1 Day 14 (2 weeks after starting treatment)

Study Arms (4)

KRAS Mut 2

ACTIVE COMPARATOR

KRAS Mutant patients randomized to combination therapy arm

Drug: AZD6244 + Erlotinib

KRAS Mut 1

ACTIVE COMPARATOR

KRAS Mutant patients randomized to monotherapy arm

Drug: AZD6244

WT KRAS 1

ACTIVE COMPARATOR

Wild-Type KRAS patients randomized to monotherapy arm

Drug: Erlotinib

WT KRAS 2

ACTIVE COMPARATOR

Wild-Type KRAS patients randomized to combination therapy arm

Drug: AZD6244 + Erlotinib

Interventions

AZD6244 DRUG

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

KRAS Mut 1

Erlotinib DRUG

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

WT KRAS 1

AZD6244 + Erlotinib DRUG

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.

KRAS Mut 2; WT KRAS 2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have histologically or cytologically confirmed advanced (Stage IV) Non Small Cell Lung Cancer that has been verified by the enrolling institution s pathology department. Mixed histologies, with small cell lung cancer components are not eligible.
• Patients must have measurable disease by RECIST criteria, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as greater than or equal to 20 mm with conventional techniques or as greater than or equal to 10 mm with spiral CT (computed tomography) scan.
• Patients must have had at least one prior platinum-containing chemotherapy regimen, or have refused cytotoxic chemotherapy. Patients should have no more than two prior chemotherapy regimens. Chemotherapy regimens have no limit on the maximum or minimum number of cycles. Patients enrolled on the trial should have completed their last chemotherapy regimen at least 4 weeks ago. Patients should have completed radiation therapy at least 4 weeks prior to enrollment. Adjuvant and neoadjuvant chemotherapy does not count as prior chemotherapy for advanced disease if more than a year before enrollment.
• Age greater than or equal to 18 years, because no dosing or adverse event data are currently available on the use of AZD6244 (ARRY-142886) as monotherapy or in combination with erlotinib in patients less than 18 years of age. Children are excluded from this study but will be eligible for future pediatric phase 2 combination trials.
• Life expectancy of greater than 3 months.
• ECOG (Eastern Cooperative Oncology Group) performance status less than or equal to 2 (Karnofsky greater than or equal to 60%).
• Patients must have normal organ and marrow function as defined below:
• leukocytes greater than or equal to 3,000/mcL
• absolute neutrophil count greater than or equal to 1,500/mcL
• platelets greater than or equal to 100,000/mcL
• total bilirubin within normal institutional limits
• AST (aspartate aminotransferase) (SGOT (serum glutamic oxaloacetic transaminase)) /ALT (alanine aminotransferase) ((SGPT (serum glutamic pyruvic transaminase)) less than or equal to 2.5 X institutional upper limit of normal
• creatinine within normal institutional limits
• creatinine clearance greater than or equal to 60 mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal
• Patients must have adequate archival material from a previous biopsy to determine KRAS status at the time of enrollment, or undergo a biopsy of fresh tissue of the primary cancer lesion or a metastatic site in order to make this determination.

You may not qualify if:

• Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study or those who have not recovered to less than or equal to grade 1 toxicities from adverse events due to agents administered more than 4 weeks earlier.
• Patients may not be receiving any other investigational agents.
• In general, patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. However, patients who have completed primary treatment of their brain metastasis by surgery or radiotherapy and have been off steroids (with the exception of maintenance replacement steroids) and anti-seizure medications for greater than one month without progression of neurological symptoms are eligible for enrollment in this trial. Stability of treated brain metastases should be confirmed by repeat imaging studies (CT brain or MRI (magnetic resonance imaging) brain) performed at least one month after completion of treatment.
• Previous MEK (methyl ethyl ketone) inhibitor or prior treatment with EGFR TKI (tyrosine kinase inhibitor).
• Major surgery or significant traumatic injury occurring within 21 days prior to treatment.
• Abnormalities of the cornea based on history (e.g., dry eye syndrome, Sjogrens syndrome), congenital abnormality (e.g., Fuchs dystrophy), abnormal slit-lamp examination using a vital dye (e.g., fluorescein, Bengal-Rose), and/or an abnormal corneal sensitivity test (Schirmer test or similar tear production test).
• Gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV (intravenous) alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease.
• Patients with uncontrolled hypertension already on optimal medication, patients with class II or greater heart failure, any current or prior history of cardiomyopathy. Patient with baseline LVEF (left ventricular ejection fraction) less than 50%, atrial fibrillation, recent myocardial infarction, or unstable ischemic heart disease.
• Patients with QTc (corrected QT interval) interval greater than 450 msecs or other factors that increase the risk of QT (Q wave, T wave) prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome) including heart failure that meets New York Heart Association (NYHA) class III and IV definitions are excluded. This does not include QTc prolongation secondary to a paced rhythm. If a patient has a paced rhythm, QTc levels less than or equal to 500 (Grade 1) are allowed and patients with QTc \> 500 are excluded.
• Required use of a concomitant medication that can prolong the QT interval. A comprehensive list of agents with the potential to cause QTc prolongation can be found at http://www.arizonacert.org/medical-pros/drug-lists/drug-lists.htm.
• Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g. inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, Hepatitis B or C, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant women are excluded from this study because AZD6244 is a MEK- Inhibitor agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with AZD6244, breastfeeding should be discontinued if the mother is treated with AZD6244. These potential risks may also apply to other agents used in this study.
• HIV (human immunodeficiency virus) -positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD6244. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
• Both men and women and members of all races and ethnic groups are eligible for this trial.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead
• University of California, Davis: collaborator
• University of Chicago: collaborator
• University of Southern California: collaborator
• City of Hope Medical Center: collaborator

Study Sites (5)

University of California, Davis

Davis, California, 95616, United States

Location

University of Southern California Health Sciences Campus

Los Angeles, California, 90033, United States

Location

City of Hope Medical Group

South Pasadena, California, 91030, United States

Location

University of Chicago Medical Center

Chicago, Illinois, 60637, United States

Location

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin. 2009 Jul-Aug;59(4):225-49. doi: 10.3322/caac.20006. Epub 2009 May 27.

  PMID: 19474385 BACKGROUND

• Carbone DP, Minna JD. Chemotherapy for non-small cell lung cancer. BMJ. 1995 Oct 7;311(7010):889-90. doi: 10.1136/bmj.311.7010.889. No abstract available.

  PMID: 7580533 BACKGROUND

• Rodriguez J, Cortes J, Calvo E, Azinovic I, Fernandez-Hildago O, Martinez-Monge R, Garzon C, de Irala J, Martinez-Aguillo M, Ramon Y Cajal T, Brugarolas A. Paclitaxel, cisplatin, and gemcitabine combination chemotherapy within a multidisciplinary therapeutic approach in metastatic nonsmall cell lung carcinoma. Cancer. 2000 Dec 15;89(12):2622-9. doi: 10.1002/1097-0142(20001215)89:123.0.co;2-x.

  PMID: 11135224 BACKGROUND

• Carter CA, Rajan A, Keen C, Szabo E, Khozin S, Thomas A, Brzezniak C, Guha U, Doyle LA, Steinberg SM, Xi L, Raffeld M, Tomita Y, Lee MJ, Lee S, Trepel JB, Reckamp KL, Koehler S, Gitlitz B, Salgia R, Gandara D, Vokes E, Giaccone G. Selumetinib with and without erlotinib in KRAS mutant and KRAS wild-type advanced nonsmall-cell lung cancer. Ann Oncol. 2016 Apr;27(4):693-9. doi: 10.1093/annonc/mdw008. Epub 2016 Jan 22.

  PMID: 26802155 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Lung Neoplasms

Interventions

AZD 6244; Erlotinib Hydrochloride

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Dr. Arun Rajan
• Organization: National Cancer Institute

rajana@mail.nih.gov

301-594-5322

Study Officials

• Arun Rajan, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: October 26, 2010
• First Posted: October 27, 2010
• Study Start: October 26, 2010
• Primary Completion: September 30, 2013
• Study Completion: November 21, 2015
• Last Updated: May 23, 2017
• Results First Posted: October 29, 2014

Record last verified: 2017-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (5)