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Report for Clinical Trial NCT02954523

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

Phase I/II Study of Dasatinib and Osimertinib (AZD9291) in Patients With Advanced Non-small Cell Lung Cancer With EGFR Mutations

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.

NCT02954523 EGFR Gene Mutation Nonsmall Cell Lung Cancer
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

2 Interventions

Name: Dasatinib

Description: oral every day

Type: Drug

Phase I and Phase II

Name: Osimertinib

Description: oral every day

Type: Drug

Phase I and Phase II


Primary Outcomes

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 months

Description: 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 months

Secondary Outcomes

Description: 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 months

Description: 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 months

Description: Determination of the time between the start of the experimental treatment and progression of the tumor

Measure: Progression-free survival

Time: 3 years

Description: Determination of the time between start of the experimental treatment and death

Measure: Overall survival

Time: 3 years

Description: 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 years

Purpose: Treatment

Single Group Assignment


There are 3 SNPs

SNPs


1 L858R

- 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 ---


2 L861Q

- Presence of sensitizing EGFR mutations (deletion in exon 19, L858R in exon 21, G719X, and L861Q). --- L858R --- --- L861Q ---


3 T790M

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 ---



HPO Nodes


HPO:
Neoplasm of the lung
Genes 61
REST GPC3 WT1 HPGD BRAF PIK3CA TP53 TRIM28 RB1 TRIP13 SLCO2A1 AKT1 CASP8 KRAS TSC1 POU6F2 EWSR1 PRKN LMNA NAB2 TERT TSC2 SLC22A18 BRCA2 PPP2R1B STAT6 STK11 MUC5B ERBB2 TSC2 MBTPS2 BAP1 TSC2 DICER1 PDGFRB PERP EGFR TSC1 DIS3L2 NOTCH3 KEAP1 DICER1 DICER1 WT1 TSC1 C11ORF95 IRF1 CYP2A6 WRN RELA WT1 PTEN SFTPC SFTPA2 ERCC6 TRPV3 TP53 H19 TRIM28 FASLG MAP3K8
Non-small cell lung carcinoma
Genes 3
TP53 TP53 BAP1