Dasatinib and Osimertinib (AZD9291) in Advanced Non-Small Cell Lung Cancer With EGFR Mutations
Status:
Active, not recruiting
Trial end date:
2021-11-01
Target enrollment:
Participant gender:
Summary
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.
Phase:
Phase 1/Phase 2
Details
Lead Sponsor:
Chul Kim Giuseppe Giaccone
Collaborators:
AstraZeneca Bristol-Myers Squibb Hackensack Meridian Health Hackensack University Medical Center Walter Reed National Military Medical Center