Phase 2
N=79
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...
Non Small Cell Lung Carcinoma
Bottom Line
View on ClinicalTrials.gov: NCT01229150 ↗Enrolled (actual)
79
Serious AEs
59.5%
Results posted
Oct 2014
Primary outcome: Primary: Progression Free Survival — 2.3; 4.0; 2.4; 2.1 Months — p=0.24
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 2
- Interventions
- AZD6244 (Drug); Erlotinib (Drug); AZD6244 + Erlotinib (Drug)
- Age
- Adult, Older Adult · 18+ yrs
- Sex
- All
- Sponsor
- National Cancer Institute (NCI)
- Primary completion
- Sep 2013
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Progression Free Survival |
2.3; 4.0; 2.4; 2.1 | 0.24 |
| PRIMARY Objective Response |
3; 0; 1; 2 | — |
| SECONDARY Number of Participants With Adverse Events |
49; 9; 18 | — |
| SECONDARY Percentage of Participants With Disease Control/Stabilization |
43; 89; 47; 35.3 | — |
| SECONDARY Overall Survival |
21.8; 10.5; 6.3; 12.9 | 0.51 |
| SECONDARY Percentage of Th17 in Cluster of Differentiation 4 (CD4)+T Cells at Baseline in Relation to Response |
0.19; 0.11; 0.34 | — |
| SECONDARY Number of Participants With a Reduction in Phosphorylated Extracellular Signal-Regulated Kinases (p-ERK) in Lymphocytes |
NA; NA; 17; 4; 14; 2 | <0.0007 sig |
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....
Eligibility Criteria
- INCLUSION CRITERIA:
- 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
OR
- 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.
- The effects of AZD6244 and erlotinib on the developing human fetus at the recommended therapeutic dose are unknown. However preclinical data showing adverse effects on fetal survival and development with AZD6244 have been reported. For this reason since there is a potential risk of teratogenicity, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation, and for four weeks after dosing with AZD6244 ceases. Women of child-bearing potential must have a negative pregnancy test prior to entry. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Please note that the AZD6244 manufacturer recommends that adequate contraception for male patients should be used for 16 weeks post-last dose due to sperm life cycle.
- Ability to understand and the willingness to sign a written informed consent document.
EXCLUSION CRITERIA
- 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
Data sourced from ClinicalTrials.gov (NCT01229150). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.