Osimertinib and Navitoclax in Treating Patients With EGFR-Positive Previously Treated Advanced or Metastatic Non-small Cell Lung Cancer
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT02520778|
Recruitment Status : Active, not recruiting
First Posted : August 13, 2015
Last Update Posted : June 25, 2020
|Condition or disease||Intervention/treatment||Phase|
|Advanced Lung Non-Squamous Non-Small Cell Carcinoma Metastatic Lung Non-Squamous Non-Small Cell Carcinoma Stage III Lung Non-Small Cell Cancer AJCC v7 Stage IIIA Lung Non-Small Cell Cancer AJCC v7 Stage IIIB Lung Non-Small Cell Cancer AJCC v7 Stage IV Lung Non-Small Cell Cancer AJCC v7||Drug: Navitoclax Drug: Osimertinib||Phase 1|
I. To determine the safety and tolerability of osimertinib (AZD9291) in combination with navitoclax in patients with EGFR-mutant non-small cell lung cancer (NSCLC) following resistance to prior EGFR-tyrosine kinase inhibitor (EGFR TKI).
II. To evaluate the feasibility of treatment with AZD9291 plus navitoclax for patients with T790M-mediated acquired resistance to EGFR TKI.
I. To study the pharmacokinetic profile of the combination of AZD9291 plus navitoclax.
II. To observe and record anti-tumor activity.
I. To study plasma genotype levels as a response biomarker in patients with EGFR-mutant lung cancer.
II. To explore tissue biomarkers of apoptosis and their association with treatment response.
OUTLINE: This is a phase Ib, dose-escalation study followed by a dose-expansion study.
Patients receive navitoclax orally (PO) once daily (QD) on days 1-28 and osimertinib PO QD on days 4-28 (days 1-28 during dose-expansion). Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||50 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase 1B Study of AZD9291 in Combination With Navitoclax in EGFR-Mutant Non-Small Cell Lung Cancer Following Resistance to Initial EGFR Kinase Inhibitor|
|Actual Study Start Date :||March 31, 2016|
|Estimated Primary Completion Date :||July 30, 2020|
Experimental: Treatment (navitoclax, osimertinib)
Patients receive navitoclax PO QD on days 1-28 and osimertinib PO QD on days 4-28 (days 1-28 during dose-expansion). Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity
- Incidence of toxicity (dose escalation) [ Time Frame: Up to 2 years ]Incidence of toxicity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. Frequency and severity of adverse events will be tabulated using counts and proportions detailing frequently occurring, serious and severe events of interest. Adverse events will be summarized using all adverse events experienced, although a sub-analysis may be conducted including only those adverse events in which the treating physician deems possibly, probably or definitely attributable to one or both study treatments.
- Feasibility of the combination therapy in T790M+ lung cancer (dose expansion) [ Time Frame: Up to 12 weeks (3 cycles of treatment) ]Will be measured as at least 50% of patients achieving the expected dose duration and intensity. The proportion of patients completing 3 courses of therapy with > 75% of total dose of each drug will be quantified. The combination dosing will be considered potentially feasible if at least 50% of patients achieve the expected dose duration and intensity (95% confidence interval 30%-70%).
- Pharmacokinetics parameters (maximum observed plasma drug concentration, area-under-the concentration-time-curve, trough drug concentration at steady state, and half-life) of osimertinib in combination with navitoclax [ Time Frame: Pre-dose, 1, 2, 4, 6, and 8 hours after navitoclax administration (day 3 of cycle 1 and day 1 of cycle 2) ]Pharmacokinetic calculations will incorporate consideration of the dosing change in navitoclax between the two measurement days.
- Objective response rate [ Time Frame: Baseline up to 30 days after completion of study drug ]Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST). Calculated in the 20 patient expansion cohort and compared to the expected response rate of 61% in T790M+ lung cancer.
- Change in plasma concentration of EGFR T790M and other EGFR mutations [ Time Frame: Baseline to up to 2 years ]Change in plasma concentration of EGFR T790M and other EGFR mutations will be studied in an exploratory fashion and compared to tumor response on imaging.
- Biomarkers of apoptosis such as BCL2-like 1 (BCL-XL) and BCL2-like 11 (apoptosis facilitator) (BIM) levels in tumor tissue [ Time Frame: Baseline ]Biomarkers of apoptosis such as BCL-XL and BIM levels will be measured in tumor tissue and correlated with response in an exploratory fashion, under the hypothesis that navitoclax will have greater activity in cancers with high BCL-XL levels and inadequate apoptotic response.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02520778
|Principal Investigator:||Pasi A Janne||Dana-Farber - Harvard Cancer Center LAO|