Trial of Local Consolidation Therapy (LCT) After Osimertinib for Patients With EGFR Mutant Metastatic Non-Small Cell Lung Cancer (NSCLC)

Conditions:Lung Cancer, Lung Cancer, Cancer
Therapuetic Areas:Oncology
Age Range:18 - Any
Start Date:January 17, 2018
End Date:January 2023
Contact:Daniel Gomez, MD

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Randomized Phase II Trial of Local Consolidation Therapy (LCT) After Osimertinib for Patients With EGFR Mutant Metastatic Non-Small Cell Lung Cancer (NSCLC)

The goal of this research is to learn if receiving local consolidation therapy (LCT--
surgery, radiation, or a combination of radiation and surgery) after receiving osimertinib
can help to control non-small cell lung cancer (NSCLC) compared to continued treatment with
osimertinib alone. The safety of this treatment will also be studied.

This is an investigational study. Osimertinib is FDA approved and commercially available for
the treatment of NSCLC. It is considered investigational to give surgery and/or radiation
after osimertinib to patients with NSCLC.

Up to 143 participants will be enrolled in this multicenter study. Up to 143 may take part at
MD Anderson.

Study Groups and Study Drug Administration:

If you are found to be eligible to take part in this study, you will be randomly assigned (as
in the flip of a coin) to 1 of 2 groups. This is done because no one knows if one group is
better, the same, or worse than the other.

- Group 1 will receive LCT after treatment with osimertinib. The study doctor will decide
if you will have radiation alone, surgery alone, or radiation combined with surgery.
However, if the doctor thinks it is in your best interest, you may be able to continue
taking osimertinib in addition to LCT.

- Group 2 will not receive LCT after osimertinib. Instead, you will continue treatment
with osimertinib.

All participants will take osimertinib by mouth every day for about 6-12 weeks as part of
your standard care. This is called Induction Therapy.

Group 1:

Depending on what the study doctor thinks is in your best interest, you will receive surgery,
radiation, or both after you complete Induction Therapy.

- If you have surgery, you will be given a separate consent form to sign that describes
the surgical procedure and its risks in more detail. The type of surgery you will have
will depend on the status of the disease and what the doctor thinks is in your best
interest. If you are also receiving osimertinib, you will need to stop taking it for
about 7 days before surgery.

- If you have radiation therapy, about 1-2 weeks before you begin radiation therapy, you
will have a procedure called a simulation. During the simulation, the exact location for
the radiation therapy will be planned. The simulation procedure takes about 1 hour. You
will receive radiation every day for 5 days in a row(Monday through Friday) up to 8
weeks, depending on the location and status of the disease. The radiation only takes a
few minutes to administer each day. However, you should expect to stay in the clinic for
1 hour each day. You will be given a separate consent form to sign that describes the
radiation therapy and its risks in more detail. The type of radiation therapy you will
have will depend on the status of the disease.

If you have both radiation therapy and surgery, the study doctor will tell you which you will
have first.

Group 2:

You will continue to take osimertinib by mouth every day.

Length of Treatment:

You may continue receiving osimertinib or as long as the doctor thinks it is in your best
interest. If you are in Group 1, you may receive surgery one (1) time and/or radiation
therapy for up to 8 weeks. You will no longer be able to receive the study treatment if the
disease gets worse, if intolerable side effects occur, or if you are unable to follow study

Your participation on the study will be over after the follow-up visits.

Study Visits:

About every 4 weeks during Induction Therapy:

- You will have a physical exam.

- Blood (about 2 teaspoons) will be drawn for routine tests.

- You will have an EKG.

About every 8 weeks:

- You will have a physical exam.

- Blood (about 2 teaspoons) will be drawn for routine tests.

- You will have an EKG.

Every 8 weeks during Induction Therapy and then every 8 weeks after that, you will have a CT
or PET/CT scan to check the status of the disease.

Every 3 months, you will have an ECHO or MUGA scan.

Follow-Up Visits:

Within 30 days after study treatment:

- You will have a physical exam.

- Blood (about 2 teaspoons) will be drawn for routine tests.

- You will have an EKG.

Long-Term Follow-Up:

Every 6 months, you will be asked how you are doing and if you have had any side effects.
This may be done by collecting information from your medical record or the study staff may
call you. If you are called, this call should last about 5-10 minutes.

If you stopped the study treatment for reasons other than the disease getting worse, you will
continue to have CT or PET/CT scans as described above. If the disease get worse, you will
stop having these scans; although the study doctor may ask you to have another CT or PET/CT
scan as part of your standard care if needed.

Inclusion Criteria:

1. Age >/= 18

2. Histologically or cytologically confirmed non-small cell lung cancer

3. Stage IIIB/IV or recurrent non-small cell lung cancer which is not amenable to
curative intent therapy.

4. Patients must have one of the following: (A) NSCLC which harbours EGFR Exon 19
deletion or L858R mutation. This subset of patients must be TKI naive; OR (B) NSCLC
which harbours an EGFR T790M mutation that was acquired following progression on
erlotinib, gefitinib or afatinib. This subset of patients must have not received prior
third generation TKI. NOTE: EGFR mutation must be documented by a Clinical Laboratory
Improvement Amendments (CLIA) certified test.

5. Eastern Cooperative Oncology Group (ECOG) performance status
6. Measurable disease by RECIST 1.1

7. Candidate for local consolidation therapy to at least one site of disease.

8. Signed and dated written informed consent prior to admission to the study in
accordance with ICH-GCP guidelines and to the local legislation.

9. Ability to take pills by mouth.

10. Females of childbearing potential: (1) must not be breast feeding; (2) must have a
negative serum or urine pregnancy test; and (3) must agree to use adequate
contraception for a minimum of two weeks prior to receiving study medication until 3
months after discontinuation of the study medication. NOTE: Acceptable methods of
contraception include total and true sexual abstinence, hormonal contraceptives that
are not prone to drug-drug interactions (IUS Levonorgestrel Intra Uterine System
(Mirena), Medroxyprogesterone injections (Depo-Provera)), copper-banded intra-uterine
devices, and vasectomized partner. All hormonal methods of contraception should be
used in combination with the use of a condom by their sexual male partner. Females of
childbearing potential are defined as those who are not surgically sterile (ie,
bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or
postmenopausal (defined as 12 months with no menses without an alternative medical

11. Continued from #10: Women will be considered post-menopausal if they have been
amenorrheic for the past 12 months without an alternative medical cause. The following
age-specific requirements must also apply: Women < 50 years old: they would be
considered post-menopausal if they have been amenorrheic for the past 12 months or
more following cessation of exogenous hormonal treatments. The levels of Luteinizing
Hormone (LH) and Follicle-Stimulating Hormone (FSH) must also be in the
post-menopausal range (as per the institution). Women >/= 50 years old: they would be
consider post-menopausal if they have been amenorrheic for the past 12 months or more
following cessation of all exogenous hormonal treatments, or have had
radiation-induced oophorectomy with the last menses > 1 year ago, or have had
chemotherapy-induced menopause with >1 year interval since last menses, or have had
surgical sterilization by either bilateral oophorectomy or hysterectomy.

12. 10. Non-sterilized males who are sexually active with a female partner of childbearing
potential must use adequate contraception for the duration of the study and 3 month
after the last dose of study medication. Adequate contraception methods include: birth
control pills (eg combined oral contraceptive pill), barrier protection (eg condom
plus spermicide, cervical/vault cap or intrauterine device), and abstinence. Patients
should not father a child for 6 months after completion of the study medication.
Patients should refrain from donating sperm from the start of dosing until 6 months
after discontinuing the study medication. If male patients wish to father children
they should be advised to arrange for freezing of sperm samples prior to the start of
the study medication.

13. Life expectancy >=12 weeks

14. To be eligible for randomization, patients must: (a) Meet all the inclusion criteria;
(b) Have no progression of disease after 6-12 weeks of osimertinib per RECIST 1.1. (To
assess for progressive disease patients must have the following imaging: 1) either a
PET/CT scan or a CT scan of the chest/abdomen/pelvis (or CT chest) and 2) a CT scan or
an MRI of the brain); and (c) Have target lesions (lesions that will be treated with
LCT if the patient is randomized to that arm). Patients that have a CR to front-line
osimertinib (e.g. no visible disease to target) will continue to be followed for
progression on study but will not be randomized.

Exclusion Criteria:

1. Previous treatment with osimertinib, or a 3rd generation EGFR TKI. NOTE: Patients who
are receiving initial osimertinib (6-12 weeks) outside this study are not excluded.

2. Patients currently receiving (or unable to stop use prior to receiving the first dose
of study treatment) medications or herbal supplements known to be potent inducers of
CYP3A4 (at least 3 week prior). All patients must try to avoid concomitant use of any
medications, herbal supplements and/or ingestion of foods with known inducer effects
on CYP3A4.

3. Patients with symptomatic CNS metastases who are neurologically unstable.

4. Any unresolved toxicities from prior therapy greater than CTCAE grade 1 (with the
exception of alopecia grade 2) at the time of starting study treatment.

5. 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 subject to participate in the trial or which would jeopardize
compliance with the protocol, or active infection including hepatitis B, hepatitis C
and human immunodeficiency virus (HIV). Screening for chronic conditions is not

6. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to
swallow the formulated product or previous significant bowel resection that would
preclude adequate absorption of osimertinib.

7. Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation
pneumonitis which required steroid treatment, or any evidence of clinically active
interstitial lung disease.

8. Patients with uncharacterized eye disorders.

9. Males and females of reproductive potential who are not using and effective method of
birth control and females who are pregnant or breastfeeding or have a positive (urine
or serum) pregnancy test prior to study entry.

10. History of hypersensitivity of osimertinib (or active or inactive excipients of
osimertinib or drugs with a similar chemical structure or class to osimertinib)

11. 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 requirement.

12. Inadequate bone marrow or organ function as demonstrated by any of the following
laboratory values: absolute neutrophil count<1,500/mcL, platelet<100,000/mcL,
hemoglobin<9.0 g/dL, total bilirubin >1.5 times the upper limit of normal (ULN) if no
demonstrable liver metastases or >3 times ULN in the presence of documented Gilbert's
Syndrome or liver metastases, AST(SGOT)/ALT(SGPT) >2.5 times ULN or >5 times ULN if
liver metastases are present, creatinine clearance <50 mL/min/1.73 m2 by
Cockcroft-Gault equation

13. Any of the following cardiac criteria: (a) Mean resting corrected QT interval (QTc
using Fridericia's formula) > 470 msec; (b) Any clinically important abnormalities in
rhythm, conduction or morphology of resting ECG e.g., complete left bundle branch
block, third degree heart block, second degree heart block, PR interval >250msec; (c)
Any factors that increase the risk of QTc prolongation or risk of arrhythmic events
such as heart failure, hypokalemia 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.

14. Patients will be excluded from randomization if they meet any of the following
criteria: (a) Any of the exclusion criteria; (b) Complete response to osimertinib or
prior treatment to all visible lesions, such that no lesion is amenable to LCT. Note
that patients can receive palliative radiation therapy prior to randomization to CNS
lesions or those requiring urgent treatment (e.g. for pain or bleeding), but are only
eligible for the study if they have one site amenable to further radiation therapy. In
addition, these lesions will be counted towards the total number of metastases, and
will also be counted as target lesions.
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