This is a study for patients with advanced non-small cell lung cancer with changes to their cancer cells called EGFR mutations. Mutated EGFR is important in the growth of cancer cells. Medical studies have shown that patients with EGFR mutation-positive lung cancer gain more benefit from targeted therapy drugs such as EGFR inhibitors than with standard chemotherapy. However, a significant proportion of patients carrying these sensitizing mutations do not respond well to the first-generation EGFR-TKIs (erlotinib and gefitinib), indicating the existence of intrinsic resistance mechanisms. Moreover, despite initial response to EGFR-TKIs, acquired resistance is inevitable in all patients. The investigators have recently shown that Cripto-1 overexpression in EGFR mutant NSCLC contributes to the intrinsic resistance to EGFR-TKIs through activation of the SRC oncogene. They have also shown that a combination of an EGFR-TKI (both erlotinib and osimertinib) and a Src inhibitor are synergistic in Cripto-1 overexpressing tumors in the laboratory. This study will be testing a combination of two drugs, dasatinib and osimertinib, to overcome resistance to EGFR-TKIs. Osimertinib (AZD9291) is a third-generation EGFR-TKI, which selectively blocks the activity of EGFR mutants, but spares that of wild type. The advantage of using osimertinib is that it inhibits not only the sensitizing EGFR mutations, but also the T790M mutant, which is the most common mechanism of acquired resistance. Dasatinib is a potent, orally available ABL1/SRC TKI, approved for the treatment of chronic myeloid leukemia (CML) in first-line and in patients with imatinib-resistant disease or intolerant, and is being actively studied in patients with advanced solid tumors. The first part of the study will involve finding the highest dose of dasatinib that can be given with osimertinib without causing severe side effects, finding out the side effects seen by giving dasatinib at different dose levels with osimertinib, and measuring the levels of dasatinib and osimertinib in blood at different dose levels. The second part will determine the effects of the combination of dasatinib and osimertinib and determine if the amount of Cripto-1 protein in your tumor or blood makes you more likely to have a good response to the combination of dasatinib and osimertinib.
Name: Dasatinib
Description: oral every dayType: DrugPhase I and Phase II
Name: Osimertinib
Description: oral every dayType: DrugPhase I and Phase II
Description: Number of patients with drug related adverse events and number of patients who can tolerate dosing of dasatinib when given in combination with osimertinib
Measure: Phase I : Number of patients with drug-related adverse events as assessed by CTCAEv4.0 Time: 9 monthsDescription: The rate of patients non-responding (progressive disease or stable disease lasting 4 months or less) to the combination of osimertinib and dasatinib
Measure: Phase II : Number of patients that do not progress according to RECIST v1.1 Time: 9 monthsDescription: Number of patients with treatment-related adverse events in the phase II study, who are treated at the same dose that has been selected based on the phase I part
Measure: Number of patients with treatment-related adverse events in the phase II study Time: 18 monthsDescription: To describe the concentration of osimertinib when administered with dasatinib. Blood is obtained from patients before each cycle and 4 hours after start of the first 2 cycles.
Measure: Concentration of orimertinib in blood Time: 18 monthsDescription: Determination of the time between the start of the experimental treatment and progression of the tumor
Measure: Progression-free survival Time: 3 yearsDescription: Determination of the time between start of the experimental treatment and death
Measure: Overall survival Time: 3 yearsDescription: Determination of the duration of the response to the treatment, calculated from start of treatment in case of partial response and from the declaration of complete response in case of complete response. The end of the response will be when the tumor progresses
Measure: Duration of response Time: 3 yearsSingle Group Assignment
There are 3 SNPs
- Presence of sensitizing EGFR mutations (deletion in exon 19, L858R in exon 21, G719X, and L861Q). --- L858R ---
The most predominant EGFR mutations are in-frame deletions in exon-19 and L858R missense mutation, and patients carrying these mutations are mostly sensitive to the EGFR-targeted tyrosine kinase inhibitors (TKIs). --- L858R ---
The advantage of using AZD9291 is that it inhibits not only the mutants of exon-19 deletion and L858R, but also the T790M mutant, which is the most common mechanism of acquired resistance. --- L858R ---
- Presence of sensitizing EGFR mutations (deletion in exon 19, L858R in exon 21, G719X, and L861Q). --- L858R --- --- L861Q ---
The advantage of using osimertinib is that it inhibits not only the sensitizing EGFR mutations, but also the T790M mutant, which is the most common mechanism of acquired resistance. --- T790M ---
Patients with the T790M mutation will also be eligible. --- T790M ---
The advantage of using AZD9291 is that it inhibits not only the mutants of exon-19 deletion and L858R, but also the T790M mutant, which is the most common mechanism of acquired resistance. --- L858R --- --- T790M ---