A Phase I Dose-Escalation, Pharmacokinetic and Pharmacodynamic Evaluation of Intravenous LY2275796 in Patients With Advanced Cancer
LY2275796 is designed to block the effect of a cancer-promoting gene called eIF-4E
(eukaryotic initiation factor 4E).
Before you can receive the drug on this study, you will have what are called "screening
tests." These tests will help the doctor decide if you are eligible to take part in the
study. Your complete medical history will be recorded and you will have a physical exam.
You will have an electrocardiogram (ECG -- a test that measures the electrical activity of
the heart). You may also have x-rays, computed tomography (CT) scans, or magnetic resonance
imaging, whichever imagining your doctor thinks is best to monitor the status of the
Blood (about 3 tablespoons) will be drawn for routine tests and to measure how the drug
moves around inside your body and effects your body. Your blood sample will also be tested
for human immunodeficiency virus (HIV, the virus that causes AIDS), Hepatitis B, and
Hepatitis C. If your test results show that you have HIV, Hepatitis B, or Hepatitis C, you
will be notified and given information about counseling services. The results of your HIV,
Hepatitis B, and Hepatitis C tests will be kept confidential and disclosed only as required
by law. If you do not take these tests for Hepatitis B, Hepatitis C, or HIV, or if you test
positive for any of these, you will not be eligible for this study. If there is more than a
2-week delay before beginning the study, these tests may need to be repeated. Within 3 days
of receiving the study drug, women who are able to have children must have a negative blood
If you are found eligible to take part in this study, LY2275796 will be given by an infusion
into your vein over 3 days. This is called a loading dose of the study drug and the purpose
is to make sure the tumor tissue gets enough of the study drug for it to target the disease.
This dose will be given either as 3 separate 3-hour infusions by vein for 3 days in a row
or as a nonstop infusion for 3 days (72 hours).
The way you receive the drug will be decided by your study doctor and the study sponsor.
This decision will be based upon the dose of the study drug that you are to receive and on
the information gathered from other participants who have already received the study drug.
Whichever way you are to receive the study drug, you may have to stay in the hospital for
the first 3 days. Days 1-7 will be considered Cycle 1 of this study.
After the first loading dose, you will continue to receive the study drug as a single,
3-hour infusion 1 time each week (this is called a maintenance dose). Maintenance doses will
be given on Days 8, 15, and 22 as a single, 3-hour infusion. Days 8-28 will be defined as
Cycle 2. All cycles beginning with Cycle 3 will be 28 days. In this study, different
participants will receive different dose levels.
During the first 29 days of the study, you will give 16 blood samples (about 1 teaspoon
each) for pharmacokinetic (PK) testing. PK testing measures the amount of study drug in the
blood at different times. On Cycle 1 Day 1, blood will be drawn 3 hours after the drug is
given. On Cycle 1 Day 3, blood will be drawn before the infusion, 1 hour after the drug is
given, at the end of the infusion, and again 20 minutes, 1 hour, 3 hours, and between 4-6
hours after the end of the infusion. On Cycle 1 Days 4-6, blood will be drawn on 1
occasion. On Cycle 2 Day 8, blood will be drawn before the infusion, and at the end of the
infusion. On Cycle 2 Day 15, blood will be drawn before the infusion, then again 3, 9, and
24 hours later. The last PK test will be drawn either at the time of your biopsy (Part B or
C only) or before the next dose of study drug is given on Day 29.
These blood samples will be used to measure the amount of whole molecules of LY2275796 in
your blood. However, smaller traces of LY2275796 may also be found. If there is a portion
of blood left over, it will be used to detect these broken down molecules of the study drug
in your blood, since testing for these traces may be an easier way to monitor the presence
of LY2275796 in the blood and may be better a predictor of how long the drug effects the
To test the effect of the drug in your body, a blood sample will be drawn (about 1
tablespoon) at the beginning of all cycles before you take LY2275796.
During Part A of the study, 1 participant will be enrolled at a time. In this part, doses
will be increased quickly, doubling the dose with each new participant enrolled.
Participants will continue to be enrolled until blood tests show a certain amount of study
drug or if a participant experiences an intolerable side effect. Part B will begin once
During Part B of the study, 3 participants will be given the same dose of the study drug.
If all 3 participants tolerate the dose of study drug well, another 3 participants will
enrolled at a higher dose. These dose increases will continue until tumor biopsies show
that the drug is having the required effect on the cancer in all 3 participants at 1 dose
(this is called the optimal biologic dose, or OBD). However, if 2 participants at 1 dose
experience the same intolerable side effect, additional participants will be enrolled at
slightly lower doses until the highest well tolerated dose is identified (this is called the
maximum tolerated dose, or MTD) this will be the maximum tolerated dose (MTD). Once the MTD
or OBD is found, Part C will begin.
Ten (10) participants will be enrolled in Part C. at the OBD or the MTD dose found in Part
If you are enrolled in Part B or Part C, you will have tumor biopsies. If you have tumors
that can be felt under the skin, the biopsy may will be done after a local anesthetic is
used to numb the skin. If the tumor is not detectable by touch, you would have the biopsy
performed with the help of a CT scan or ultrasound. The first biopsy will be within 4 weeks
before starting LY2275796. You will then have 1 more biopsy between 21-28 days after you
start taking LY2275796. The first biopsy taken before you receive the study drug is to get
a baseline evaluation of the tumor. The biopsy taken after you receive the study drug is to
check the level of the study drug in the tumor and also to see if the drug is working in the
cancer cells as it is expected to do.
On the days you receive the loading dose and weekly maintenance doses, your doctor will
perform a physical exam. Blood (about 2 tablespoons) will be drawn to measure the effects
of LY2275796 on your blood count, your blood chemistry, the ability of your blood to clot,
liver and kidney function, and possibly to check your tumor. If needed, extra samples may be
drawn to check blood levels of LY2275796.
You will be taken off study if you have intolerable side effects or the disease gets worse.
When you go off study, you will have a physical exam. Blood (about 2 tablespoons) will be
drawn to measure the effects of LY2275796 on your blood count, your blood chemistry, the
ability of your blood to clot, liver and kidney function, and possibly to check the tumor.
You will have the same imaging studies that have been performed during the study to monitor
the status of the disease.
You will also be required to visit your doctor about 30 days after your last dose of
LY2275796 for follow-up tests. You will have a physical exam. Blood (about 2 tablespoons)
will be drawn to measure the effects of LY2275796 on your blood count, your blood chemistry,
the ability of your blood to clot, liver and kidney function, and possibly to check the
tumor. You will have the same imaging studies that have been performed during the study to
monitor the status of the disease. You also will be asked about any side effects you have
experienced. If you have side effects, you will visit your doctor every 30 days until the
side effect stops or you begin a new cancer treatment. If you have no side effects from the
LY2275796, no further follow-up will be necessary for the study.
This is an investigational study. LY2275796 is not FDA approved or commercially available,
and it has been authorized for use in research only. About 40 patients may participate in
this multicenter study. About 20 patients will be enrolled at M. D. Anderson.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximum Tolerated Dose (MTD) of LY2275796
Maximum tolerated dose (MTD) defined as highest dose at which 0-1/6 patients experience Grade III toxicity with LY2275796 administered IV as a loading dose daily over 3 days, then as maintenance dose weekly.
Dose toxicity with each loading dose (daily for 3 days) then weekly
David Hong, MD
UT MD Anderson Cancer Center
United States: Food and Drug Administration
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