Screening portion:
Patients will begin on single agent osimertinib obtained commercially at the standard dose of
80mg orally daily. Osimertinib monotherapy is currently standard of care first-line treatment
for patients with metastatic EGFR-mutant lung cancers. During the screening portion of the
study, patients will be treated per standard practice as decided by the treating physician
using the guidance of the osimertinib product label. The patient will proceed with three
cycles (21 days per cycle) of single agent osimertinib. Patients will be seen on C1D1 for
osimertinib start (telemedicine visits for C1D1 assessments are acceptable)
Randomization/treatment portion:
Patients will be randomized to continue osimertinib alone (Arm A) or addition of
carboplatin/pemetrexed chemotherapy to osimertinib (Arm B).Randomization will be accomplished
by the method of random permuted block and patients will be stratified by type of EGFR
mutation (EGFR exon 19/EGFR L858R or other) and presence of CNS metastases (absent, present).
Randomization will occur after data is available to identify the patients with persistent
EGFR ctDNA detected in the C2D1 plasma sample; only patients with persistent EGFR ctDNA will
be randomized. Subject's eligibility prior to randomization will be at the discretion of the
individual sites enrolling the patients. EGFR mutation can be confirmed at outside
institutions: while pathology confirmation will occur at the enrolling institution, the
required documentation of EGFR can occur internal or external to the enrolling institution.
For those patients without detectable ctDNA at C2D1, the end of treatment assessments will
not include CT scan or ctDNA sampling.
Inclusion Criteria: Inital
- Age ≥ 18 years
- Biopsy proven metastatic non-small cell lung cancer, confirmed at enrolling
institution
- Somatic activating mutation in EGFR in pre-treatment tumor biopsy/ cytology from
pleural fluid or cfDNA
- 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.
- Karnofsky performance status (KPS)≥70%,
- Ability to swallow oral medications
- Adequate organ function (use of G-CSF and/or transfusion to meet these criteria are
not allowed)
- Hemoglobin ≥ 9 g/dL
- Platelets ≥ 150,000mm^3 or 150 x 10^9/L
- AST, ALT ≤ 2.5 x ULN with no liver metastases or < 5x ULN with the presence of
liver metastases
- Total bilirubin ≤ 1.5 x ULN if no liver metastases or < 3 x ULN in the presence
of documented Gilbert's Syndrome (unconjugated hyperbilirubinemia) or liver
metastases
- Absolute neutrophil count (ANC) ≥ 1500 cells/mm^3
- Creatinine ≤ ULN OR calculated creatinine clearance ≥ 60ml/min calculated by
Cockcroft and Gault equation
- Creatinine clearance ≥ 60 mL/min calculated by Cockcroft and Gault equation
- 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:
- Female subjects should be using highly effective contraceptive measures, and must
have a negative pregnancy test and not be breast-feeding prior to start of dosing
if of child-bearing potential or must have evidence of non-child-bearing
potential by fulfilling one of the following criteria at screening:
- Post-menopausal defined as aged more than 50 years and amenorrheic for at least
12 months following cessation of all exogenous hormonal treatments
- Women under 50 years old would be consider postmenopausal if they have been
amenorrheic for 12 months or more following cessation of exogenous hormonal
treatments and with LH and FSH levels in the post-menopausal range for the
institution
- Documentation of irreversible surgical sterilization by hysterectomy, bilateral
oophorectomy or bilateral salpingectomy but not tubal ligation
- Male subjects should be willing to use barrier contraception
Exclusion Criteria: Initial
- Pregnant or lactating women
- Any radiotherapy within 1 week of starting treatment on protocol.
- Any major surgery within 2 weeks of starting treatment on protocol.
- Any evidence of clinically significant interstitial lung disease
- 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 unresolved toxicities from prior therapy greater than CTCAE grade 1 at the time of
starting study treatment, with the exception of alopecia and grade 2 prior
platinum-therapy- related neuropathy
- 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.
- Any of the following cardiac criteria:
- Mean resting corrected QT interval (QTc) > 470 msec where QT interval is
corrected for heart rate using Frederica's formula (QTcF).
- 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
- 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.
- Judgment by the investigator that the patient should not participate in the study if
the patient is unlikely to comply with study procedures, restrictions and
requirements.
Inclusion Criteria: Randomization
- Patients with detectable plasma EGFR mutations at C2D1
- Karnofsky performance status (KPS) ≥ 70%
- Adequate organ function
- Hemoglobin ≥ 9 g/dL
- Platelets ≥ 100,000mm^3 or 100 x 10^9/L
- Creatinine ≤ ULN OR calculated creatinine clearance ≥ 60ml/min
- AST, ALT ≤ 3x ULN with no liver metastases or ≤ 5x ULN with the presence of liver
metastases
- Total bilirubin ≤ 1.5 x ULN if no liver metastases or ≤ 3 x ULN in the presence
of documented Gilbert's Syndrome (unconjugated hyperbilirubinemia) or liver
metastases
- Absolute neutrophil count (ANC) ≥ 1500 cells/mm3Must have at least stable disease
per RECIST 1.1 assessment prior to initiating chemotherapy at C4D1
- Eligibility testing (KPS, bloodwork) should be tested at C3D1. If the subject's
evaluation does not meet eligibility criteria, any result obtained between C3 and
C4 can be used
Please note: All 'Initial' Exclusion Criteria must be re-confirmed prior to randomization.
