Description:
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.
Title
- Brief Title: Dasatinib and Osimertinib (AZD9291) in Advanced Non-Small Cell Lung Cancer With EGFR Mutations
- Official Title: Phase I/II Study of Dasatinib and Osimertinib (AZD9291) in Patients With Advanced Non-small Cell Lung Cancer With EGFR Mutations
Clinical Trial IDs
- ORG STUDY ID:
2016-0493
- NCT ID:
NCT02954523
Conditions
- EGFR Gene Mutation
- Nonsmall Cell Lung Cancer
Interventions
Drug | Synonyms | Arms |
---|
Dasatinib | BMS-354825 | Phase I and Phase II |
Osimertinib | AZD9291 | Phase I and Phase II |
Purpose
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.
Detailed Description
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.
Trial Arms
Name | Type | Description | Interventions |
---|
Phase I and Phase II | Experimental | 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 (50 mg once daily), Level -1 (70 mg once daily), Level 1 (the starting dose - 50 mg twice daily), 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.
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. | |
Eligibility Criteria
Inclusion Criteria:
- Patients must have cytologically or histologically confirmed advanced NSCLC. Patients
with mixed histology containing a small cell lung cancer component are not eligible.
- Patients must have adequate archival material from a previous biopsy to determine EGFR
mutation status and Cripto-1 expression, or undergo a biopsy of fresh tissue of the
primary cancer or a metastatic site in order to make these determinations, if archival
material is not available.
- Presence of sensitizing EGFR mutations (deletion in exon 19, L858R in exon 21, G719X,
and L861Q). Patients with the T790M mutation will also be eligible.
- No prior treatment with an EGFR TKI for the advanced NSCLC.
- ECOG performance status of 0-2.
- Patients must have measurable disease by RECIST criteria, defined as at least one
lesion that can be accurately measured in at least one dimension (longest diameter to
be recorded) as >20 mm with conventional techniques or as >10 mm with spiral CT scan.
See Section 7.1.2 for the evaluation of measurable disease.
- Prior systemic treatment is allowed, but toxicities of prior therapy must be resolved
to grade 1 or less as per Common Terminology Criteria for Adverse Events (CTCAE)
version 4.03.
- Adequate organ and bone marrow function (hemoglobin > 9 g/dL; absolute neutrophil
count > 1.5 x 109/L; platelet counts > 100 x 109/L; serum bilirubin < 2 x ULN; alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x ULN or < 5 x ULN
if liver metastases; calculated creatinine clearance > 50 mL/min).
- No uncontrolled arrhythmia; no myocardial infarction in the last 6 months.
- Life expectancy of at least 12 weeks.
- Age > 18 years.
- Ability to understand and willingness to sign a written informed consent document.
Exclusion Criteria:
- Patients who have had radiotherapy (except for palliative reasons), immunotherapy or
chemotherapy during the previous 4 weeks (6 weeks for nitrosoureas or mitomycin)
before treatment, or those who have ongoing toxic manifestations of previous
treatments, with the exception of alopecia, of grade higher than 1.
- Major thoracic or abdominal surgery from which the patient has not sufficiently
recovered yet.
- Untreated and uncontrolled second tumor in the past 2 years.
- Logistical or psychological hindrance to participation in clinical research.
- Patients with untreated symptomatic brain metastases may be eligible if symptoms do
not require urgent surgery or radiation, and no steroids are necessary.
- Patients with evidence of interstitial lung disease (bilateral, diffuse, parenchymal
lung disease).
- Pleural or pericardial effusions of any grade at study entry. Subjects previously
diagnosed with pleural/pericardial effusion of any grade resolved at the time of study
entry are allowed.
- Ability to become pregnant (or already pregnant or lactating). Women and men who want
to participate have to agree to use two highly effective forms of contraceptive prior
to study entry, for the duration of study participation, and for 30 days following
completion of therapy, to be eligible. Women of childbearing potential (WOCBP) must
have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or
equivalent units of HCG) within 24 hours prior to the start of study drug.
- At high medical risk because of non-malignant systemic disease including uncontrolled
infection.
- Known to be serologically positive for hepatitis B, hepatitis C or HIV.
- Uncontrolled or significant cardiovascular disease, including any of the following:
- QTc interval > 480 msec (mean value and manually verified) at 3 or more time
points within a 24 hour period if necessary.
- Diagnosed or expected congenital long QT syndrome.
- Concurrent congestive heart failure, prior history of class III/IV cardiac
disease (New York Heart Association).
- Left ventricular ejection fraction < 50%
- Prior history of cardiac ischemia or cardiac arrhythmia within the last 6 months.
Coronary angioplasty or stenting in the previous 12 months.
- Any history of second or third degree heart block (may be eligible if the subject
currently has a pacemaker).
- Uncontrolled hypertension defined as inability to maintain blood pressure below
the limit of 140/90 mmHg.
- Known pulmonary hypertension.
- History of significant bleeding disorder unrelated to CML, including:
- Diagnosed congenital bleeding disorders (e.g. von Willebrand's disease)
- Diagnosed acquired bleeding disorder within one year (e.g. acquired anti-factor
VII antibodies)
- Any other medical condition that in the Investigator's opinion would not make the
patient a good candidate for the study.
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Phase I : Number of patients with drug-related adverse events as assessed by CTCAEv4.0 |
Time Frame: | 9 months |
Safety Issue: | |
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 |
Secondary Outcome Measures
Measure: | Number of patients with treatment-related adverse events in the phase II study |
Time Frame: | 18 months |
Safety Issue: | |
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: | Concentration of orimertinib in blood |
Time Frame: | 18 months |
Safety Issue: | |
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: | Progression-free survival |
Time Frame: | 3 years |
Safety Issue: | |
Description: | Determination of the time between the start of the experimental treatment and progression of the tumor |
Measure: | Overall survival |
Time Frame: | 3 years |
Safety Issue: | |
Description: | Determination of the time between start of the experimental treatment and death |
Measure: | Duration of response |
Time Frame: | 3 years |
Safety Issue: | |
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 |
Details
Phase: | Phase 1/Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Active, not recruiting |
Lead Sponsor: | Chul Kim |
Trial Keywords
- NSCLC
- Non-small cell
- Lung Cancer
- Dasatinib
- Osimertinib
- AZD9291
- EGFR Mutations
- Epidermal growth factor receptor (EGFR)
Last Updated
July 29, 2021