A Phase 1/2 interventional study of Dasatinib and Osimertinib in EGFR Gene Mutation and Nonsmall Cell Lung Cancer, sponsored by Chul Kim. Terminated at 2 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2024-07-05.
Sponsored by Chul Kim · Phase 1/2, Interventional, and Treatment
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.
The treatment of patients with advanced non-small cell lung cancer is unsatisfactory. The median survival is approximately 12 months with standard chemotherapy. Epidermal growth factor receptor (EGFR) mutations are one of the most frequent genetic abnormalities observed in non-small cell lung cancer (NSCLC), especially in adenocarcinoma subtype. 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). 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. Novel treatment strategies need to be developed to overcome resistance to EGFR-TKIs. The investigators have recently shown that Cripto-1 overexpression in EGFR mutant NSCLC contributes to the intrinsic resistance to EGFR-TKIs through SRC activation. They have also shown that a combination of an EGFR-TKI (both erlotinib and AZD9291) and a Src inhibitor are synergistic in vitro and in vivo in Cripto-1 overexpressing tumors. 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 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. 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.
This is an open-label, non-randomized, prospective phase I/II trial. The phase I portion will follow a standard 3+3 design for the phase I portion and one-sample group sequential multiple testing procedure for the phase II portion.
7,243 studies on the registry are indexed under Lung Neoplasms; 1,557 are open to participants now.
This study's enrollment of 10 is below the median of 60 across 5,295 interventional studies indexed under Lung Neoplasms.
Browse Lung Neoplasms studies →This is the only study on the registry with Chul Kim as lead sponsor.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
Uncontrolled or significant cardiovascular disease, including any of the following:
History of significant bleeding disorder unrelated to CML, including:
Osimertinib (AZD9291) will be given at a 80mg/day dose taken orally across all levels of the dose escalation schedule. Dasatinib is taken orally and will be given at up to 4 dose levels. Level 1 (the starting dose - 50 mg twice daily). Dose escalation will only include 2 dose levels (Levels 1 and 2); in addition there will be 2 dose levels below the starting dose level if dose reductions are necessary (Levels -1 and -2). There is no limit to the number of cycles a patient can receive.
Drug: Dasatinib · Drug: Osimertinib
Osimertinib (AZD9291) will be given at a 80mg/day dose taken orally across all levels of the dose escalation schedule. Dasatinib is taken orally and will be given at up to 4 dose levels. Level 2 (70 mg twice daily). Dose escalation will only include 2 dose levels (Levels 1 and 2); in addition there will be 2 dose levels below the starting dose level if dose reductions are necessary (Levels -1 and -2). There is no limit to the number of cycles a patient can receive.
Drug: Dasatinib · Drug: Osimertinib
Osimertinib (AZD9291) will be given at a 80mg/day dose taken orally across all levels of the dose escalation schedule. Dasatinib is taken orally and will be given at up to 4 dose levels. Level -1 (70 mg once daily). Dose escalation will only include 2 dose levels (Levels 1 and 2); in addition there will be 2 dose levels below the starting dose level if dose reductions are necessary (Levels -1 and -2). There is no limit to the number of cycles a patient can receive.
Drug: Dasatinib · Drug: Osimertinib
Osimertinib (AZD9291) will be given at a 80mg/day dose taken orally across all levels of the dose escalation schedule.d Dasatinib is taken orally and will be given at up to 4 dose levels. Level -2 (50 mg once daily). Dose escalation will only include 2 dose levels (Levels 1 and 2); in addition there will be 2 dose levels below the starting dose level if dose reductions are necessary (Levels -1 and -2). There is no limit to the number of cycles a patient can receive.
Drug: Dasatinib · Drug: Osimertinib
The phase II portion of the study will use the maximum tolerated dose of dasatinib determined in the phase I portion. Osimertinib (AZD9291) will be given at the same 80mg dose as the phase I portion. There is no limit to the number of cycles a patient can receive.
Drug: Dasatinib · Drug: Osimertinib
oral every day
Also known as: BMS-354825
oral every day
Also known as: AZD9291
Phase I : Number of Patients With Drug-related Adverse Events as Assessed by CTCAEv4.0
Number of patients with drug related adverse events (Dose Limiting Toxicities) on dasatinib when given in combination with osimertinib
Time frame: Cycle 1 (28 day cycle)
Phase II : Number of Patients That do Not Progress According to RECIST v1.1
The rate of patients non-responding (progressive disease or stable disease lasting 4 months or less) to the combination of osimertinib and dasatinib
Time frame: 9 months
Number of Patients With Treatment-related Adverse Events in the Phase II Study
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
Time frame: 18 months
Concentration of Osimertinib in Blood (Cmax)
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.
Time frame: 0 hour, 4 hours post dose
Progression-free Survival
Determination of the time between the start of the experimental treatment and progression of the tumor
Time frame: 3 years
Overall Survival
From the date of start of the experimental treatment until the date of death from any cause, whichever came first, assessed up to 47 months.
Time frame: 47 months
Duration of Response
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
Time frame: 3 years
| Milestone | Phase IPhase I- Dasatinib Dose Level 2 | Phase 1- DasatinibDose Level 1 | Phase 1- DasatinibDose Level -1 |
|---|---|---|---|
| Started | 3 | 6 | 1 |
| Completed | 3 | 6 | 1 |
| Not completed | 0 | 0 | 0 |
Number of patients with drug related adverse events (Dose Limiting Toxicities) on dasatinib when given in combination with osimertinib
| participants | Phase I- Dasatinib Dose Level 2 | Phase 1- Dasatinib Dose Level 1 | Phase 1- Dasatinib Dose Level -1 |
|---|---|---|---|
| Phase I : Number of Patients With Drug-related Adverse Events as Assessed by CTCAEv4.0 | 0 | 3 | 0 |
The rate of patients non-responding (progressive disease or stable disease lasting 4 months or less) to the combination of osimertinib and dasatinib
No measurements were reported for this outcome.
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
No measurements were reported for this outcome.
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.
| nM/mL | Phase I- Dose Level 1 | Phase 1- Dose Level 2 | Phase 1- Dose Level -1 |
|---|---|---|---|
| Concentration of Osimertinib in Blood (Cmax) | 211.5 (166 to 314) | 355 (345 to 365) | 107 (107 to 107) |
Determination of the time between the start of the experimental treatment and progression of the tumor
| months | Phase I- Dose Level 1 | Phase I- Dose Level 2 | Phase I- Dose Level -1 |
|---|---|---|---|
| Progression-free Survival | 24.7 (3.7 to 31.3) | 10.1 (4.5 to 16.7) | 10.5 (10.5 to 10.5) |
From the date of start of the experimental treatment until the date of death from any cause, whichever came first, assessed up to 47 months.
| months | Dose Level 1 | Phase I- Dose Level 2 | Phase I- Dose Level -1 |
|---|---|---|---|
| Overall Survival | 36.1 (23.5 to 46.6) | 16.9 (7.4 to 36.6) | 28.7 (28.7 to 28.7) |
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
| months | Phase I- Dose Level 1 | Phase I- Dose Level 2 | Phase 1 - Dose Level -1 |
|---|---|---|---|
| Duration of Response | 27.8 (18.6 to 31.9) | 12.2 (8.4 to 15.9) | 8.7 (8.7 to 8.7) |
Collected over Up to 6 years.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Phase I- Dose Level 1 | 1/6 (16.7%) | 4/6 (66.7%) | 6/6 (100%) |
| Phase I- Dose Level 2 | 2/3 (66.7%) | 2/3 (66.7%) | 3/3 (100%) |
| Phase I- Dose Level -1 | 1/1 (100%) | 0/1 (0%) | 1/1 (100%) |
| Event | Phase I- Dose Level 1 | Phase I- Dose Level 2 | Phase I- Dose Level -1 |
|---|---|---|---|
| Intra-abdominal hemorrhageGastrointestinal disorders | 0/6 | 1/3 | — |
| Vascular disorders - Other, specifyVascular disorders | 0/6 | 1/3 | — |
| Atrial fibrillationCardiac disorders | 1/6 | 0/3 | — |
| AppendicitisInfections and infestations | 1/6 | 0/3 | — |
| Pericardial effusionCardiac disorders | 1/6 | 0/3 | — |
| Central nervous system necrosisNervous system disorders | 1/6 | 0/3 | — |
| Central nervous system necrosisNervous system disorders | 1/6 | 0/3 | — |
| Ejection fraction decreasedInvestigations | 1/6 | 0/3 | — |
| Hemorrhoidal hemorrhageGastrointestinal disorders | 1/6 | 0/3 | — |
| Lung infectionInfections and infestations | 1/6 | 0/3 | — |
| Event | Phase I- Dose Level 1 | Phase I- Dose Level 2 | Phase I- Dose Level -1 |
|---|---|---|---|
| Acute kidney injuryRenal and urinary disorders | 1/6 | 0/3 | 1/1 |
| Alanine aminotransferase increasedInvestigations | 4/6 | 2/3 | 1/1 |
| AnorexiaMetabolism and nutrition disorders | 3/6 | 0/3 | 1/1 |
| Aspartate aminotransferase increasedInvestigations | 4/6 | 2/3 | 1/1 |
| DiarrheaGastrointestinal disorders | 6/6 | 3/3 | 1/1 |
| NauseaGastrointestinal disorders | 3/6 | 1/3 | 1/1 |
| Neutrophil count decreasedBlood and lymphatic system disorders | 3/6 | 2/3 | 1/1 |
| PalpitationsCardiac disorders | 2/6 | 0/3 | 1/1 |
| ParonychiaInfections and infestations | 3/6 | 0/3 | 1/1 |
| Platelet count decreasedInvestigations | 4/6 | 1/3 | 1/1 |
| Age, Categorical(Participants) | Phase I- Dasatinib Dose Level 2 | Phase 1- Dasatinib Dose Level 1 | Phase 1- Dasatinib Dose Level -1 | Total |
|---|---|---|---|---|
| <=18 years | 0 | 0 | 0 | 0 |
| Between 18 and 65 years | 2 | 1 | 0 | 3 |
| >=65 years | 1 | 5 | 1 | 7 |
| Sex: Female, Male(Participants) | Phase I- Dasatinib Dose Level 2 | Phase 1- Dasatinib Dose Level 1 | Phase 1- Dasatinib Dose Level -1 | Total |
|---|---|---|---|---|
| Female | 3 | 5 | 1 | 9 |
| Male | 0 | 1 | 0 | 1 |
| Ethnicity (NIH/OMB)(Participants) | Phase I- Dasatinib Dose Level 2 | Phase 1- Dasatinib Dose Level 1 | Phase 1- Dasatinib Dose Level -1 | Total |
|---|---|---|---|---|
| Hispanic or Latino | 0 | 0 | 0 | 0 |
| Not Hispanic or Latino | 3 | 6 | 1 | 10 |
| Unknown or Not Reported | 0 | 0 | 0 | 0 |
| Race (NIH/OMB)(Participants) | Phase I- Dasatinib Dose Level 2 | Phase 1- Dasatinib Dose Level 1 | Phase 1- Dasatinib Dose Level -1 | Total |
|---|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 | 0 |
| Asian | 2 | 2 | 0 | 4 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 | 0 |
| Black or African American | 0 | 0 | 0 | 0 |
| White | 1 | 3 | 1 | 5 |
| More than one race | 0 | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 1 | 0 | 1 |
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