Dasatinib and Osimertinib (AZD9291) in Advanced Non-Small Cell Lung Cancer With EGFR Mutations

Phase 1

Terminated

Conditions: EGFR Gene Mutation
Nonsmall Cell Lung Cancer

Interventions: Drug: Dasatinib
Drug: Osimertinib

Registration Number: NCT02954523

Lead Sponsor: Chul Kim

Brief 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.

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 10

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Phase I- Dasatanib Dose Level 1	Dasatinib	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.
Phase I- Dasatanib Dose Level 1	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 (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.
Phase I- Dasatanib Dose Level 2	Dasatinib	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.
Phase I- Dasatanib Dose Level 2	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.
Phase I- Dasatanib Dose Level -1	Dasatinib	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.
Phase I- Dasatanib Dose Level -1	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.
Phase I- Dasatanib Dose Level -2	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.
Phase II- Maximum tolerated dose	Dasatinib	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.
Phase I- Dasatanib Dose Level -2	Dasatinib	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.
Phase II- Maximum tolerated dose	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.

Primary Outcome Measures

Name	Time	Method
Phase II : Number of Patients That do Not Progress According to RECIST v1.1	9 months	The rate of patients non-responding (progressive disease or stable disease lasting 4 months or less) to the combination of osimertinib and dasatinib
Phase I : Number of Patients With Drug-related Adverse Events as Assessed by CTCAEv4.0	Cycle 1 (28 day cycle)	Number of patients with drug related adverse events (Dose Limiting Toxicities) on dasatinib when given in combination with osimertinib

Secondary Outcome Measures

Name	Time	Method
Progression-free Survival	3 years	Determination of the time between the start of the experimental treatment and progression of the tumor
Concentration of Osimertinib in Blood (Cmax)	0 hour, 4 hours post dose	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.
Overall Survival	47 months	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.
Duration of Response	3 years	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
Number of Patients With Treatment-related Adverse Events in the Phase II Study	18 months	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

Trial Locations

Locations (2): John Theurer Cacner Center at Hackensack University Medical Center
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Hackensack, New Jersey, United States
Georgetown Lombardi Comprehensive Cancer Center
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Washington, District of Columbia, United States