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

NCT02954523 | Terminated Phase 1 Results DMC FDA Drug

• 1 other identifier: 2016-0493
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 2

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.

Conditions

EGFR Gene Mutation; Nonsmall Cell Lung Cancer

Keywords

NSCLC; Non-small cell; Lung Cancer; Dasatinib; Osimertinib; AZD9291; EGFR Mutations; Epidermal growth factor receptor (EGFR)

Outcome Measures

Primary Outcomes (2)

• 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

  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

  9 months

Secondary Outcomes (5)

• Number of Patients With Treatment-related Adverse Events in the Phase II Study

  18 months

• Concentration of Osimertinib in Blood (Cmax)

  0 hour, 4 hours post dose

• Progression-free Survival

  3 years

• Overall Survival

  47 months

• Duration of Response

  3 years

Study Arms (5)

Phase I- Dasatanib Dose Level 1

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 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

Phase I- Dasatanib Dose Level 2

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 (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

Phase I- Dasatanib Dose Level -1

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 -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

Phase I- Dasatanib Dose Level -2

EXPERIMENTAL

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

Phase II- Maximum tolerated dose

EXPERIMENTAL

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

Interventions

Dasatinib DRUG

oral every day

Also known as: BMS-354825

Phase I- Dasatanib Dose Level -1; Phase I- Dasatanib Dose Level -2; Phase I- Dasatanib Dose Level 1; Phase I- Dasatanib Dose Level 2; Phase II- Maximum tolerated dose

Osimertinib DRUG

oral every day

Also known as: AZD9291

Phase I- Dasatanib Dose Level -1; Phase I- Dasatanib Dose Level -2; Phase I- Dasatanib Dose Level 1; Phase I- Dasatanib Dose Level 2; Phase II- Maximum tolerated dose

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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%

Sponsors & Collaborators

• Chul Kim: lead
• AstraZeneca: collaborator
• Bristol-Myers Squibb: collaborator
• Walter Reed National Military Medical Center: collaborator
• Hackensack Meridian Health: collaborator

Study Sites (2)

Georgetown Lombardi Comprehensive Cancer Center

Washington D.C., District of Columbia, 20007, United States

Location

John Theurer Cacner Center at Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

Location

Related Publications (1)

• Kim C, Liu SV, Crawford J, Torres T, Chen V, Thompson J, Tan M, Esposito G, Subramaniam DS, Giaccone G. A Phase I Trial of Dasatinib and Osimertinib in TKI Naive Patients With Advanced EGFR-Mutant Non-Small-Cell Lung Cancer. Front Oncol. 2021 Sep 8;11:728155. doi: 10.3389/fonc.2021.728155. eCollection 2021.

  PMID: 34568058 DERIVED

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Lung Neoplasms

Interventions

Dasatinib; osimertinib

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines

Results Point of Contact

• Title: Chul Kim
• Organization: Georgetown University

Chul.Kim@gunet.georgetown.edu

12024442223

Study Officials

• Giuseppe Giaccone, MD PhD

  Associate Director for Clinical Research, Lombardi Comprehensive Cancer Center

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: October 25, 2016
• First Posted: November 3, 2016
• Study Start: October 1, 2016
• Primary Completion: August 1, 2018
• Study Completion: March 3, 2023
• Last Updated: July 5, 2024
• Results First Posted: July 5, 2024

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)