Non-Small Cell Lung Cancer With Mutation in Epidermal Growth Factor Receptor
Conditions
Keywords
NSCLC, Non-Small Cell Lung Cancer, osimertinib, cyclosporine A, CsA
Brief summary
This single-site, biomarker-enriched, randomized Phase II study will evaluate osimertinib with or without cyclosporine A (CsA) in metastatic epidermal growth factor receptor (EGFR )-mutant non-small cell lung cancer (NSCLC) \[exon 19 deletion or L858R\]. All consented, baseline circulating tumor DNA (ctDNA)-positive patients receive a 3-week osimertinib run-in; those with persistent ctDNA ("shedders") are randomized 1:1 to continue osimertinib or osimertinib+CsA. Plasma is collected approximately every 3 weeks in both arms for molecular response monitoring. The investigators plan to enroll 60 patients with approximately 40 "shedders" randomized with 20 enrolled in each arm. All patients will be treated with osimertinib daily throughout the study; the combination of osimertinib+CsA will receive CsA. Imaging will be performed as per standard of care.
Interventions
DRUGOsimertinib
80 mg by mouth daily
1.5 mg/kg by mouth twice daily
DEVICEctDNA Biopsy Panel
Panel repeated every 3 weeks.
Sponsors
NYU Langone Health
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age≥18 years, able to give informed consent. * Standard of care (SOC) biopsy-proven metastatic non-small cell lung cancer, confirmed at NYU Langone Health (NYULH) * Somatic activating mutation in EGFR exon 19 deletion or EGFR L858R in pre-treatment tumor biopsy or cytology from pleural fluid or cfDNA as detected by SOC testing. * Either have not started a prior EGFR TKI therapy, or may have started osimertinib within 3 weeks of confirming eligibility and enrollment criteria of measurable disease per approval of PI, with no prior chemotherapy for treatment of metastatic disease (adjuvant therapy \> 6 months prior to study start is acceptable). * Measurable (RECIST 1.1) indicator lesion not previously irradiated, with measurable disease determined per treating investigator. If a patient has already started on osimertinib there must be available pre-osimertinib baseline tumor assessments, to be utilized for RECIST 1.1 assessment. * ECOG performance status of 0-2 * Adequate organ function * Willing to use highly effective contraceptive measures if of child-bearing potential or if the patient's sexual partner is a woman of child-bearing potential
Exclusion criteria
* Pregnant or lactating women * Any radiotherapy within 1 week prior to starting treatment on protocol. The washout window only applies for patients who have not started Osimertinib. No washout window needed if the patients started on Osimertinib. They should continue on Osimertinib. If patients received radiation prior to Osimertinib, they should wait for 7 days from the last day of radiation to start Osimertinib. If patients are already on osimertinib at the time of initial consent and they happened to also have radiation prior to starting on osimertinib, they do not need a washout in order to meet eligibility criteria for the study. * Any major surgery within 2 weeks of starting treatment on protocol. The washout window only applies for patients who have not started Osimertinib. * Treatment with an investigational drug within five half-lives of the compound or 3 months, whichever is greater. * Currently receiving (or unable to stop prior to receiving the first dose of study treatment) medications or herbal supplements known to be strong inducers of CYP3A4. All patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects on CYP3A4. * Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the investigator's opinion makes it undesirable for the patient to participate in the trial. * Active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required. * Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the tablets or previous significant bowel resection that would preclude adequate absorption of Osimertinib or cyclosporine A. * Mean resting corrected QT interval (QTcF) \> 470 msec * Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG e.g. complete left bundle branch block, third degree heart block and second degree heart block. * Patient with any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, electrolyte abnormalities (including: Serum/Plasma potassium \<LLN, Serum/Plasma Magnesium \<LLN; Serum/Plasma Calcium \<LLN), congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause Torsades de Pointes. If concomitant medication can not be discontinued, please notify and confirm with MSK PI prior to enrollment. * Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease. * History of hypersensitivity to active or inactive excipients of osimertinib or drugs with a similar chemical structure or class to osimertinib. * History of hypersensitivity to active or inactive excipients of cyclosporine A or drugs with a similar chemical structure or class to cyclosporine A. * History of autoimmune disease (excluding Hashimoto's thyroiditis).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients Achieving Complete Clearance of Plasma EGFR Mutations | Up to Year 2 | The proportion of patients achieving complete clearance of plasma EGFR mutations at the first post-randomization assessment and confirmed in serial ctDNA monitoring at specified timepoints (every 3 weeks up to treatment discontinuation). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | Up to Year 2 | ORR based on RECIST 1.1 criteria; defined as the proportion of patients who achieve a Complete Response (CR) or a Partial Response (PR) as their best overall response. |
| Progression-Free Survival (PFS) | Up to Year 2 | Measured as time from randomization to disease progression or death. |
| Overall Survival (OS) | Up to Year 2 | Measured as time from randomization to death. |
Countries
United States
Contacts
CONTACTElaine Shum, MD
PRINCIPAL_INVESTIGATORElaine Shum, MD
NYU Langone Health
Outcome results
None listed