Clinical trial NCT01229150
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
Sponsor: National Cancer Institute (NCI)
Start date: 2010-10-26; Completion date: 2015-11-21
Enrollment: 89 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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....

Detailed description:
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.

Arms: arm 1: KRAS Mutant patients randomized to combination therapy arm arm 2: KRAS Mutant patients randomized to monotherapy arm arm 3: Wild-Type KRAS patients randomized to monotherapy arm arm 4: Wild-Type KRAS patients randomized to combination therapy arm
Interventions: intervention 1: AZD6244 intervention 2: Erlotinib intervention 3: AZD6244 + Erlotinib
Intervention descriptions: intervention 1: For KRAS mutant patients randomized to the single agent arm, AZD6244 75 mg bid (twice a day). intervention 2: For Wild-Type KRAS patients randomized to the single agent arm, Erlotinib 150 mg qd (every day) intervention 3: 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.

Protocol documents: